New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

Article abstract of DOI:10.1016/j.tetasy.2008.06.030

The development of efficient and stereoselective methods to produce 1,4-disubstituted-2-oxopiperazine in enantiomerically pure form, from a readily available starting material is crucial. Herein, we report a reduction modification to our previously descri

Full text of DOI:10.1016/j.tetasy.2008.06.030

Tetrahedron: Asymmetry 19 (2008) 1689–1697
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New efficient enantioselective synthesis of 2-oxopiperazines: a practical
access to chiral 3-substituted 2-oxopiperazines
*
Claiton Leoneti Lencina, Alexandra Dassonville-Klimpt, Pascal Sonnet
Laboratoire des Glucides, UMR-CNRS 6219, Faculté de Pharmacie, Université de Picardie Jules Verne, 1 Rue des Louvels, 80037 Amiens, Cedex 1, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of efficient and stereoselective methods to produce 1,4-disubstituted-2-oxopiperazine
in enantiomerically pure form, from a readily available starting material is crucial. Herein, we report a
reduction modification to our previously described synthesis of 1,4-disubstituted-2-oxopiperazine and
also two original shortly accessed pathways. These new pathways can be routinely performed on a mul-
tigram scale and should rapidly find a place in the preparation of the 3-substituted-2-oxopiperazine dia-
stereomers. Stereoselective alkylation of 1,4-disubstituted-2-oxopiperazine led to the corresponding
(3S)-diastereomer or (3R)-diastereomer from the corresponding 2-oxopiperazine enantiomer with the
chiral inductor substituted at the N1 (1*) position, respectively, in good yield.
Received 27 May 2008
Accepted 23 June 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselective alkylation of 2-oxopiperazine using a chiral auxil-
iary appended to the C-5 atom.14–16 Husson et al.17,18 have also
Substituted oxopiperazines are highly interesting scaffolds that
are found in a widespread variety of bioactive drugs used in central
nervous system therapies.1 Moreover, these azalactams have sig-
nificant potential as cancer chemotherapeutic agents,2,3 and are
promising candidates for the treatment and prevention of diverse
diseases such as rheumatoid arthritis,4 depression,5 sexual disfunc-
tions6 or venous and arterial thrombosis.7 In some cases, the oxo-
developed a regio- and stereoselective C3-alkylation of 1,4-disub-
stituted-2-oxopiperazines using various electrophiles. Very high
chiral induction (>95%) has been described using a chiral alcohol
as L D
-Leucinol17 or -phenylglycinol18b appended to N1. A rigid
intermediate that mandates the approach of the electrophile from
the face opposite to a lithium chelate involving N1 and an alcohol
appended to the 10-substituent was proposed to be at the origin
of the diastereoselectivity.17–19 Moreover, as the configuration of
the 2-oxopiperazine 3-position is totally governed by the configu-
ration of the chiral inductor, only one diastereomer is directly
accessible. Thereafter, we have reported an original, versatile and
diastereoselective method allowing, from a single precursor, the
synthesis of four diastereoisomers, in which the choice of the C3-
substituent is not limited by the availability of the corresponding
aminoacid.20 Indeed, the selected key intermediate 1 is substituted
at N1 with a chirality inductor, whose 10-configuration could be
unambiguously achieved as desired (Scheme 1). Indeed, these
two hydroxymethyl potentially chiral inductors are selectively
protected, at the 10-position, by two orthogonal protective groups
such as a benzyl group or tert-butyldimethylsilyl. A selective
deprotection, Bu4NF treatment or hydrogenolysis, of one of these
two alcohols at C01 followed by a diastereoselective alkylation leads
to the two desired enantiomers (3S) and (3R).
piperazine core is used as
a conformationally constrained
peptidomimetic in which the Ni and Ni+1 positions of the peptide
backbone fragments are linked by an ethylene bridge. These pepti-
domimetics have been found to stabilize inverse c-turn in small
peptides8 and allow biological property changes occasionally
enhancing affinity, specificity and enzymatic stability. Amongst
all of the useful azalactams, 1,3,4-trisubstituted-2-oxopiperazines,
which possess two stereogenic centres, one intracyclic (C3) and one
extracyclic ðC01Þ, are of particular interest as medicinal chemistry
tools. Many syntheses of diastereomerically pure 1,3,4-trisubsti-
tuted-2-oxopiperazine have been reported, such as the lactamiza-
tion of linear N,N0-bispeptides,9–11 N4–C5 bond formation12 or
N1–C6 bond formation.13 However, in these methods, the whole
synthesis has to be repeated if access to diastereomers is desired.
In the majority of these cases, in absence of an asymmetric synthe-
sis strategy, the final stereochemistry is dependant on the starting
material configuration. Recently, several asymmetric syntheses of
3,5-disubstituted 2-oxopiperazine have been reported from the
Herein, we report a reduction modification in our previously de-
scribed synthesis of 1,4-disubstituted-2-oxopiperazine 1 and also
two new original shortly accessed pathways to 1,4-disubstituted-
2-oxopiperazine 1. Indeed, it was necessary to find another way
due to low yields obtained in the reduction step of the key
intermediate desilylated (10R)-2. The development of efficient
* Corresponding author. Tel.: +33 322 82 74 94; fax: +33 322 82 74 69.
E-mail address: pascal.sonnet@u-picardie.fr (P. Sonnet).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.030

1690
C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
BnO
OH
O
BnO
OH
O
N
N
N
1'
N
N
Boc
(1'R)
R
BnO
Ot-BDMS
O
Boc
-2
-4
(1'R,3S)
3
N
Boc
1
HO
Ot-BDMS
O
HO
Ot-BDMS
O
N
N
N
N
R
Boc
Boc
(1'S)-3
(1'S,3R)-5
R = CH3, CH2Ph, CH2CH=CH2, C3H7
Scheme 1. Synthesis of two enantiomers (3S) and (3R) starting from the same key intermediate.
and stereoselective methods to produce such types of 1,4-disubsti-
tuted-2-oxopiperazine in enantiomerically pure form from readily
available starting material is crucial. Our two short and original
pathways can be performed on a multigram scale and should rap-
idly find a place in the preparation of the 3-substituted-2-oxopip-
erazine diastereomers (Scheme 1).
Similar to Smith et al., we have used other reducing reagents, such
as borane, DIBAL or silane catalyzed by ruthenium complex (Table
1, entries 7–10). Unfortunately, the best yield formation (42%) of
(R)-7 afforded other non-separable impurities, consequently not
identified (Table 1, entry 8).
To avoid this crucial amide reduction step, the synthesis of (R)-7
was performed in three steps via a thioamide reduction in 72%
overall yield (Scheme 3). This method involves the conversion of
amide (S)-6 to thioamide (S)-10 by using Lawesson’s reagent.22
Then, lithium aluminium reduction gives alcohol (R)-11 in 99%
yield. Finally, thioamide reduction using sodium borohydride in
the presence of nickel chloride affords the aminoalcohol (R)-7 in
93% yield.23
However, two additional steps are necessary to access to 2-oxo-
piperazine (10R)-2, this modification of our previously described
synthetic route is still so long. A shorter, more efficient route
should be feasible. Thus, we have investigated a direct cyclization
method, from dipeptide (S)-6, as previously mentioned by Pohl-
mann et al.17 This method requires the use of the ethylene glycol
bis-triflate as a dielectrophile (Scheme 4). Unfortunately, we were
unable to obtain the desired cyclized product, but recovered a sub-
stantial amount of starting material and also some unidentified
products. This is probably due to the fact that the hydrogen bound
to the carbamate nitrogen is not acidic enough.
Due to the multi-steps and/or low yield of amide reduction,
there remains a need for an easier and more practical method to
obtain 1,4-disubstituted-2-oxopiperazine. We disclose now two
new practical synthetic methods, which involves (i) the prepara-
tion of sulfonamide-2-oxopiperazine derivatives or; (ii) a regio-
selective ruthenium oxidation.
2. Results and discussion
In a previous work, we described the synthesis of 2-oxopipera-
zines (10R)-2 starting from O-benzyl-
L-serine in an eight-step se-
quence with 49% overall yield (Scheme 2).20 A peptide coupling
reaction with glycine was followed by a concomitant amide and
ester lithium aluminium hydride reduction to afford the amino-
alcohol (R)-7. After four steps, (i) protection by use of tert-butyl-
dimethylsilyl chloride; (ii) coupling with bromoacetic acid; (iii)
cyclization with NaH and (iv) deprotection of silyl group, the 2-
oxopiperazine (10R)-2 was obtained.
In a more recent work, many trials did not allow us to obtain
(R)-7 via the amide reduction with a satisfactory yield. To solve this
problem, we used various experimental conditions for lithium alu-
minium hydride reduction such as (i) concentration and equivalent
of aluminium powder; (ii) solvent and (iii) temperature (the most
significant results are shown in Table 1). Unfortunately, despite
extensive efforts, each experiment led to a mixture of three prod-
ucts (R)-7, (R)-8 partially reduced and (R)-9 Boc deprotected. The
nature of the solvent seems to play an important role. Indeed, in
THF, the amidoalcohol (R)-8 is afforded exclusively (Table 1, en-
tries 1 and 2). Whereas in Et2O the desired compound (R)-7 was
obtained in 50% yield at best but always in mixture with (R)-8
and/or (R)-9 (Table 1, entries 3–5). The formation of (R)-9 is ob-
served with an increasing hydride equivalents (Table 1, entry 6).
Smith and Williams have recently reported an identical reduction
problem when they attempted to repeat the total synthesis of qui-
nine previously originally published by Rabe and Kindler in 1918.21
Thus, similar to Smith et al., we can speculate that the old lithium
aluminium hydride powder that we had previously used could
contain significant AlIII impurities to give good conversion of the
amide substrate to the alcohol product without Boc deprotection.20
In this first synthesis strategy, to overcome the nitrogen acidity
issue as described above, we decided to use a sulfonamide group
instead of the carbamate group. The 2,4-dinitrosulfonamide group
is also an excellent protective group due to its good stability under
acidic, as well as basic conditions.13,24 The sulfonamide dipeptide
was prepared by the condensation of MeO-benzyl-L-serine 13
and N-nosyl-glycine 14 using 2-chloro-4,6-disubstituted-1,3,5-tri-
azine (DMTMM) as a condensing agent (Scheme 5). The cyclization
step was achieved under basic conditions in presence of an excess
COOMe
BnO
OH
O
BnO
OH
BnO
O
N
NH
ref 20
NH
COOH
NH2
BnO
N
Boc
(1'R)-2
NH
Boc
(R)-7
NH
Boc
(S)-6
Scheme 2. First synthesis of 2-oxopiperazine (10R)-2.

C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
1691
Table 1
Reduction of compound (S)-6
COOMe
BnO
OH
BnO
O
OH
BnO
OH
BnO
O
NH
NH
NH
NH
+
+
NH
Boc
(R)-7
NH
Boc
(R)-8
NH2
NH
Boc
(S)-6
(R)-9
Entry
Reduction reagent (equiv)
Solvent
Temp. (°C)
Time (h)
Concentrationa
Yield (%)
(R)-7
(R)-8
(R)-9
1
2
3
4
5
6
7
8
9
LiAlH4 (2.1)
LiAlH4 (4b)
THF
THF
Reflux
TA
TA
3
75
5
30
3
5
6
4
24
4
10
5
5
5
10
5
6
6
10
1
0
0
4
34
60
0
0
0
0
39
0
62
0
0
0
0
LiAlH4 (2.1)
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
Toluene
35
50
10
12
41
42d
16
10
LiAlH4 (4b)
TA
LiAlH4 (2.1)
LiAlH4 (4.1)
BH3ꢂDMSc (3)
BH3ꢂDMSc(4)
DIBALe (20)
Et3SiH, EtIf (4)
Reflux
Reflux
Reflux
Reflux
TA
60
18
36d
0
60d
80
10
110
a
mL (solvent)/mmol ((S)-6).
b
c
d
e
f
t = 0 h; addition of 1 equiv of reduction reagent, t = 1 h; three more equivalents are added.
2 M solution in THF.
With non separable impurities.
1.5 M solution in toluene.
Et3SiH (4 equiv), [RuCl2(CO)3]2 (1 mol %), EtI (5 mol %).
COOMe
NH
COOMe
NH
COOMe
NH
BnO
O
BnO
S
BnO
O
(a)
HO HN Nos
COOMe
(a)
BnO
+
NH2,HCl
O
NH
Boc
NH
Boc
10
(S)-
NH
Nos
13
14
(S)-15
6
(S)-
COOMe
BnO
BnO
OH
O
(b)
N
O
N
N
(c)
(b)
BnO
OH
N
BnO
OH
S
NH
Nos
(S)-16
NH
Nos
(R)-17
(c)
NH
Boc
11
(R)-
NH
Boc
Scheme 5. Synthesis of 2-oxo piperazine (10R)-2 via a sulfonamide. Reagents and
conditions: (a) DMTMM, NMM, THF, 77%; (b) dibromoethane, K2CO3, DMF, 88%; (c)
LiBH4, THF/MeOH, 78%.
7
(R)-
Scheme 3. Reduction of (S)-6 via thioamide. Reagents and conditions: (a) Lawes-
son’s reagent, THF, 78%; (b) LiAlH4, THF, 99%; (c) NiCl2 ꢂ 6H2O/NaBH4, MeOH–THF,
to afford (10R)-2. The Fukayama conditions were used initially for
the deprotection of the nosyl group (PhSH, K2CO3, DMF, 23 °C);
but only 40% of the desired product was isolated. The reaction
between 17 and PhSH resulting in competitive N-deprotection to
mainly give (60%) the 4-phenylthioether (R)-19 (Scheme 6). The
mechanism underlying the unsuccessful regioselectivity resulted
in nucleophilic attack of the thiophenolate. Indeed, two pathways
are possible: nucleophilic aromatic substitution via the Mei-
shenmeisher complex (path A) or nucleophilic attack on the carbon
93%.
COOMe
O
COOMe
NH
BnO
BnO
O
N
N
NaH, (TfOCH2)2
NH
Boc
12
Boc
6
(S)-
(S)-
Scheme 4. Assay of N,N-cyclization with ethylene glycol bis-triflate.
BnO
OH
O
BnO
OH
O
BnO
OH
O
N
N
N
(a)
(b)
amount of 1,2-dibromoethane. Then, the expected 2-oxopiperazine
N
Nos
17
(R)-
{½a 2D8
¼ ꢁ4 (c 0.4, EtOH)} was isolated with an excellent yield
ꢀ
N
H
N
Boc
(88%). Ester reduction of (S)-16 with lithium borohydride afforded
18
(R)-
the ketoalcohol (R)-17 {½a D28
ꢀ
¼ þ6 (c 0.1, EtOH)} in 78% yield.
-2
(1'R)
Two final steps are necessary to obtain the 2-oxopiperazine ring
Scheme 6. Synthesis of 2-oxopiperazine (10R)-2 via a sulfonamide. Reagents and
conditions: (a) method 1: PhSH, K2CO3, DMF, 23 °C, 40%; method 2: PhSH, K2CO3,
AcCN/DMSO, 96%; (b) Boc2O, MeOH, 100%.
(10R)-2 (Scheme 5): (i) deprotection of the nosyl group to give
(R)-18 {½a 2D0
¼ þ25 (c 0.05, EtOH)} and (ii) Boc protection of 18
ꢀ

1692
C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
COOH
OH
(R)-20
COOH
(b)
(a)
BnO
BnO
BnO
BnO
OH
O
BnO
OH
O
NH2
N
N
Ph
S
K
N
S
O
path A
PhS
COOMe
N
H
O
N
COOMe
(c)
(R)-18
(d)
BnO
BnO
O2N
OH
BnO
OH
O
N
Boc
N
(R)-21
(S)-22
N
S
COOMe
O
O
BnO
OH
O
(e)
N
N
O
N
N
O2N
(R)-17
BnO
OH
O
BnO
OH
O
N
Boc
(S)-12
Boc
(1'R)-2
N
N
Ph
S
K
N
S
Scheme 8. Synthesis of 2-oxopiperazine (10R)-2 via regioselective ruthenium
oxidation. Reagents and conditions: (a) NaNO2, H2SO4 2 N, 90%; (b) (MeO)3CH,
MeOH, HCl 1 M, 87% ; (c) (i) Tf2O, DIPEA, toluene; (ii) N-bocpiperazine, 98%; (d)
RuO2ꢂxH2O, NaIO4 10% (H2O), 58%; (e) LiBH4, THF/MeOH, 73%; global yield: 32%.
path B
O
O
S
O
PhS
O2N
O
S
19
(R)-
Ph
Scheme 7. Regioselectivity of the attack of the thiophenolate during the deprotec-
tion of the nosyl group.
O
O
H
OH
OH
NH2
NaNO2, H2SO4
BnO
BnO
H
N
N
bearing the nitro group (path B) to obtain the diphenylthioether
(Scheme 7). This ‘‘path B” reaction had already been evoked by
Wuts et al.25 This lack of regioselectivity was overcome by heating
at 50 °C a mixture of two solvents (AcCN/DMSO: 98:2) in which
acetonitrile promotes the complete deprotection, whereas addition
of DMSO shortens the reaction time. Under these conditions, the
exclusive formation of the desired product (R)-18 was observed
in 96% yield.26 The final step leads to the key 2-oxopiperazine
O
O
O
OH
H2O
OH
OBn
OH
OBn
BnO
H
H
OH
H
20
(R)-
(1’R)-2 {½a 2D4
¼ þ7 (c 0.1, EtOH)} by carbamate formation with
ꢀ
Figure 1. Synthesis of hydroxyacid (R)-20 with retention of configuration.
tert-butyldicarbonate.
This strategy of this synthesis gave 2-oxopiperazine in a seven-
step sequence with 49% overall yield, starting from O-benzyl-
L-ser-
et al.31 on a mechanistic study of the oxidation of 1,4-dibenzylpip-
erazine and 1-benzoyl-4-benzylpiperazine by ruthenium tetroxide.
They proposed RuO4 attack (generated in situ) at the endocyclic
ine, with excellent enantiomeric excesses (ees) of 95%. In this
pathway, two steps in the (10R,3S)-disubstituted-2-oxopiperazine
synthesis can be gained by using the nosyl piperazine (R)-17 in-
stead of the boc compound (R)-2 (not published).
In a continuation of our work regarding the structure–activity
relationships of the segetalins,27,28 there remains a need to reduce
the number of steps to obtain the N-boc piperazine (10R)-2. Thus,
by taking note of the work of Watson et al.29 and of Vetuschi
et al.30 we have developed a third strategy of synthesis starting
and exocyclic (benzylic) aminic N–a-C–H bonds resulting in endo-
cyclic or exocyclic iminium cations. These react with water while
further oxidation leads to various oxygenated derivatives. In our
case, the regioselectivity could be obtained by two factors: (i)
amides are less reactive than amines and (ii) there is no benzylic
amine. In our synthesis, oxidation was accomplished in the pres-
ence of catalytic amounts of ruthenium dioxide in a double layer
(ethyl acetate/water) with an additional oxidant, sodium perio-
date, to re-oxidize the transiently formed ruthenium dioxide and
thus completing the catalytic cycle. This reaction led to the 2-oxo-
from O-benzyl-D-serine (Scheme 8). The synthesis begins with a
diazotation reaction in presence of sodium nitrite to give hydroxy-
acid (R)-20 with retention of configuration {½a D22
¼ ꢁ2 (c 0.5,
ꢀ
EtOH)} which could be explained by the carbonyl assistance of
the carboxylic group as shown in Figure 1. Thus, the two equilib-
rium oxiran cations are attacked by H2O to afford the hydroxyacid
(R)-20. Subsequently, this compound was converted to methyl es-
ter (R)-21 using methyl orthoformiate in acid conditions. The treat-
ment of alcohol (R)-21 with triflic anhydride, in toluene, furnished
the corresponding triflate intermediate which immediately under-
went an N-Boc-piperazine SN2 substitution to afford piperazine
piperazine (S)-12 {½a D23
¼ ꢁ12 (c 0.3, EtOH)} with an excellent reg-
ꢀ
ioselectivity in 58% yield. The final ester reduction step of
compound 12 gave the desired 2-oxopiperazine (10R)-2 in 73%
yield. Thus, with only five steps, we are able to access to this first
enantiomer with ees (>95%) in 32% global yield.
The same strategy of synthesis was used to obtain the 2-oxopip-
erazine (10S)-2 in a 40% global yield (Scheme 9). Also in this case,
no epimerization has occurred, as observed by chiral HPLC analysis
and, by determination of the specific rotation of compound (10S)-2:
(S)-22 {½a 2D3
¼ ꢁ16 (c 0.5, EtOH)} with a good yield of 98% and an
ꢀ
ees superior to 95%. No epimerization at the stereogenic carbon
was observed, as determined by chiral HPLC analysis, using the
½
a 2D4
ꢀ
¼ ꢁ7 (c 0.1, EtOH).This observed value was identically op-
posed to its enantiomer (10R)-2.
opposite enantiomer as a standard {(piperazine (R)-22: ½a D23
ꢀ
¼
Being able to prepare (10R)-2 and (10S)-2 in satisfactory yields
and enantiomerically pure form, we then studied its C3-substitu-
tion. Stereoselective alkylation of 2 was achieved in THF in the
presence of HMPA as previously described,20 using LDA as a strong
þ16 (c 0.5, EtOH)}. The next key step in our strategy involved a reg-
ioselective oxidation at the
a-position to the nitrogen atom bearing
the function methylester. Previous work was carried out by Petride

C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
1693
BnO
OH
O
N
COOH
NH2
COOH
OH
BnO
BnO
N
Boc
2
20
(S)-
(1'S)-
Scheme 9. Synthesis of 2-oxopiperazine (10S)-2; global yield: 40%.
were recorded on a Micromass-Waters Q-TOF Ultima spectrome-
ter. HPLC analyses were performed on a Shimadzu instrument
using a Chirobiotic (18 mm) column.
BnO
OH
O
BnO
OH
O
N
N
1. LDA, HMPA, THF
2. PhCH2Br
80%
N
Boc
CH2Ph
N
Boc
4.2. Methyl (2S)-6-tert-butoxycarbonyl-2-benzyloxymethyl-3,6-
diaza-4-thioxohexanoate (S)-10
(1'R,3S)-23
(1'R)-2
To a solution of compound (S)-6 (12 g, 33.8 mmol) in THF
(180 mL), lawesson’s reagent (14.6 g, 36.1 mmol) was added. The
reaction mixture was stirred for 20 h at room temperature. The
crude mixture was filtered on CeliteÒ and the filtrate was evapo-
rated under reduced pressure. The desired compound (S)-10
(10.1 g, 78%), yellow oil, was achieved after silica gel column
BnO
OH
O
BnO
OH
O
N
N
1. LDA, HMPA, THF
2. PhCH2Br
N
Boc
(1'S)-2
N
Boc
CH2Ph
86%
chromatography (eluent: cyclohexane/ethyl acetate, 7:3). ½a D28
¼
ꢀ
(1'S,3R)-23
þ32 (c 0.3, EtOH). IR
m
max/cmꢁ1: 3342, 1742, 1718, 1520, 1162.
Scheme 10. Alkylation of 2-oxopiperazine (10R)-2 and (10S)-2.
1H NMR (500 MHz, CDCl3): d 1.50 (s, 9H), 3.82 (s, 3H), 3.94 (dd,
1H, 2J = 10, 3J = 2.7), 4.01 (dd, 1H, 2J = 10, 3J = 2.7), 4.26 (m, 2H),
4.51 (d, 1H, 2J = 12.2), 4.59 (d, 1H, 2J = 12.2), 5.37 (se, 1H), 6.9 (se,
1H), 7.30–7.40 (m, 5H), 8.9 (se, 1H). MS m/z 405 [MNa]+ (100),
305, 236. HRMS calcd for C18H26N2NaO5S: 405.4636. Found:
405.4633.
base and benzyl bromide as a model electrophile (Scheme 10). The
(3S)-diastereomer 23 could then be prepared from (10R)-2 and the
(3R)-diastereomer 23 from (10S)-2 respectively in 80% or 86% yield.
Only one diastereomer was observed on the 1H NMR spectrum
(500 MHz) of the alkylation products demonstrating their high dia-
stereomeric purity (above 96%).
4.3. (2R)-6-tert-Butoxycarbonyl-2-benzyloxymethyl-1-
hydroxy-3,6-diazahexane-4-thione (R)-11
3. Conclusion
To a solution of ester (S)-10 (11.0 g, 28.80 mmol) in THF
(140 mL), at 0 °C, lithium aluminium hydride (2.13 g, 57.6 mmol)
was added. The reaction mixture was stirred for 2 h at room tem-
perature. The reaction mixture was quenched by 1 M NaOH
(4.65 mL) and then stirred for 1 h. After this time, H2O (7 mL)
was added and the suspension was stirred for a further 12 h. The
precipitate was filtered and washed by Et2O. The filtrate was dried
over anhydrous sodium sulfate and the excess solvent removed
under reduced pressure to yield the desired compound (10.2 g,
In conclusion, we have proposed a new key-reduction amide
pathway and as an alternative; we have developed two short prac-
tical syntheses of 1*, 2-oxopiperazine that allow the preparation of
chiral 3-subsituted 2-oxopiperazine starting from inexpensive and
readily starting materials. The reported methodology appears very
suitable for the synthesis of a large number of piperazinone-based
peptidomimetic. Studies directed at the utilization of these 3-
substituted 2-oxopiperazines as chiral building blocks to obtain
segetalins analogues are currently under investigation in our
laboratory.
99%) as a yellow oil. ½a D28
ꢀ
¼ þ27 (c 0.4, EtOH). IR
m :
max/cmꢁ1
3338, 1697, 1526, 1249, 1161. 1H NMR (500 MHz, DMSO-d6): d
1.48 (s, 9H), 3.52 (se, 1H), 4.21 (m, 2H), 3.85 (m, 2H), 3.88 (m,
1H), 4.02 (dd, 1H, 2J = 11.4, 3J = 3.4), 4.60 (d, 1H, 2J = 11.9), 4.65
(d, 1H, 2J = 11.9), 4.80 (m, 1H), 5.30 (se, 1H), 7.40–7.50 (m, 5H),
8.70 (se, 1H). MS m/z 377 [MNa]+ (100), 343.
4. Experimental
4.1. General methods
4.4. (2R)-6-tert-Butoxycarbonyl-2-benzyloxymethyl-1-
hydroxy-3,6-diazahexane (R)-7
THF and acetonitrile were dried by distillation from sodium-
benzophenone. Diisopropylamine was dried by distillation from
calcium hydride. DMF and DMSO were distilled. MeOH was dried
by distillation using Magnesium–I2. Column chromatography was
To a solution of the thioamide (R)-11 (10 g, 28.24 mmol) in a
mixture of solvent THF/MeOH (136 mL, 1:3: v/v), hexahydrate
nickel chloride (20 g, 98.8 mmol) was added. The reaction mixture
was cooled to 0 °C and sodium borohydride (11.7 g, 310.6 mmol)
was added in small portions. The mixture was stirred for 18 h at
room temperature. Then, the solution was quenched with satu-
rated solution of sodium bicarbonate (250 mL). The aqueous layer
was extracted successively with Et2O (3 ꢃ 100 mL) and with ethyl
acetate (3 ꢃ 100 mL). The organic layers were combined and fil-
tered on CeliteÒ. The filtrate was concentrated under reduced pres-
sure to afford compound (R)-7 (8.5 g, 93%) as a yellow oil.
performed on Kielselgel 60 (40–63 lm) ASTM (Merck). Reactions
were analyzed on precoated Silica Gel 60 F254 plates (Merck) and
the compounds were visualized with a UV lamp (254 nm) and by
staining with phosphomolybdic acid (in EtOH). IR spectra were re-
corded on a Jasco FT/IR-4200 spectrometer. Optical rotations were
measured with a Jasco P1010 polarimeter. Melting point (mp) was
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
Avance 500 instrument. The residual signal of the solvent protons
with the chemical shifts d 7.27 (CDCl3) or d 2.54 (DMSO-d6) was
used as internal standards. J values are given in Hertz. Mass spectra
½
a 2D8
ꢀ
¼ þ5 (c 0.4, EtOH). IR
m
max/cmꢁ1: 3321, 1693, 1524, 1365,

1694
C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
1169. 1H NMR (500 MHz, CDCl3): d 1.60 (s, 9H), 2.76 (m, 1H), 2.82
(m, 1H), 2.90 (m, 1H), 3.23 (m, 2H), 3.53 (m, 1H), 3.55 (m, 1H), 3.59
(m, 1H), 3.69 (m, 1H), 4.54 (d, 1H, 2J = 12), 4.55 (d, 1H, 2J = 12), 5.20
(se, 1H), 7.4–7.5 (m, 5H). MS m/z 347 [MNa]+ (100), 325. HRMS
calcd for C17H28N2O4Na: 347.1947. Found: 347.1965.
168 mmol) was added to the above solution which was left to stir
at 60 °C for 24 h. The DMF was removed in vacuo and the residue
dissolved in ethyl acetate. This organic layer was then washed with
hydrochloric acid (10% v/v) and brine successively. The organic
layer was then dried over anhydrous sodium sulfate and the excess
solvent removed under reduced pressure to yield the desired com-
4.5. O-Benzyl-
L
-serine methyl ester hydrochloride 13
pound (7.1 g, 88%) as a yellow oil. ½a D28
ꢀ
¼ ꢁ4 (c 0.4, EtOH). IR mmax
/
cmꢁ1: 1743, 1656, 1530, 1350, 1169. 1H NMR (500 MHz, CDCl3): d
3.29 (m, 1H), 3.58 (m, 1H), 3.59 (m, 1H), 3.67 (m, 5H), 3.72 (m, 5H),
3.76 (m, 5H), 3.81 (dd, 1H, 2J = 10.5, 3J = 3.5), 3.96 (dd, 1H, 2J = 10.5,
3J = 3.5), 4.00 (m, 2H), 4.47 (d, 1H, 2J = 11.9), 4.50 (d, 1H, 2J = 11.9),
5.25 (se, 1H), 7.20–7.39 (m, 5H), 8.02 (d, 2H, 3J = 7.9), 8.41 (d, 2H,
3J = 7.9). MS m/z 500 [MNa]+ (100). HRMS calcd for C21H23N3O8NaS:
500.1104. Found: 500.1124.
To a solution of carboxylic acid (10 g, 51 mmol) in MeOH
(200 mL), under a nitrogen atmosphere, SOCl2 (7.3 mL, 100 mmol)
was carefully added. The reaction mixture was stirred for 18 h at
room temperature. The solution was evaporated and the excess
HCl eliminated by successive addition/evaporation of diethyl ether.
The ester 13 (12.7 g, quantitative yield) is obtained as a white solid.
Mp = 143 °C. ½a 2D6
ꢀ
¼ þ9 (c 0.3, EtOH). IR
m
max/cmꢁ1: 2847, 1742,
1500, 1251, 1105. 1H NMR (500 MHz, DMSO-d6): d 3.78 (s, 3H),
3.92 (m, 2H), 4.51 (m, 1H), 4.60 (d, 1H, 2J = 12.6), 4.63 (d, 1H,
2J = 12.6), 7.3–7.4 (m, 5H), 8.67 (se, 3H).
4.9. (10R)-4-(4-Nitrobenzenesulfonyl)-1-[10-benzyloxymethyl-
20-hydroxyethyl]-2-oxopiperazine (R)-17
A solution of ester (5 g, 10.48 mmol) in anhydrous THF (70 mL)
was cooled to 0 °C. Then, LiBH4 (0.5 g, 21 mmol) was carefully
added in absolute MeOH (280 mL) and the reaction mixture was
adjusted to pH 4 by the addition of a 10% (w/v) aqueous solution
of citric acid. This solution was extracted with ethyl acetate
(3 ꢃ 40 mL). The organic phases were combined, dried over anhy-
drous sodium sulfate and concentrated to obtain the desired alco-
4.6. N-4-Nitrobenzylsulfonyl-glycine 14
To a cold solution (0 °C) of the amino acid (3 g, 40.2 mmol) in
1 M NaOH (42 mL) was added 4-nitrobenzylsulfonyl chloride
(8.9 g, 40.2 mmol). The reaction mixture was stirred for 2 h at room
temperature. The pH was kept at 9. The crude mixture was then
washed with ethyl acetate (3 ꢃ 100 mL). The pH of the aqueous
phase was adjusted to 2 by the addition of 1 N hydrochloric acid.
This solution was extracted with ethyl acetate (3 ꢃ 100 mL). The
combined organic phases were washed with H2O and saturated
aqueous solution of sodium chloride. The organic layer was then
dried over anhydrous sodium sulfate and the excess solvent re-
moved under reduced pressure. The peptide (8.2 g, 79%) was affor-
hol (3.8 g, 78%) as a transparent oil. ½a D28
¼ þ6 (c 0.1, EtOH). IR
ꢀ
m
max/cmꢁ1: 3460, 1633, 1524, 1348, 1172. 1H NMR (500 MHz,
CDCl3): d 3.37 (m, 1H), 3.38 (m, 1H), 3.60 (m, 1H), 3.65 (m, 1H),
3.67 (m, 1H), 3.73 (m, 1H), 3.80 (m, 2H), 3.82 (m, 2H), 4.46 (se,
1H), 4.49 (d, 1H, 2J = 12), 4.51 (d, 1H, 2J = 12), 7.28–7.39 (m, 5H),
8.03 (d, 2H, 3J = 8.6), 8.45 (d, 2H, 3J = 8.6). MS m/z 472 [MNa]+
(100). HRMS calcd for C20H23N3O7NaS
472.1177.
: 472.1154. Found:
ded as a yellow solid. Mp: 154–155 °C. IR m
max/cmꢁ1: 3412, 3285,
1728, 1524, 1350, 1160, 1084. 1 H NMR (500 MHz, CDCl3): d 3.73
(s, 2H), 8.08 (d, 2H, 3J = 8.3), 8.43 (d, 2H, 3J = 8.3), 8.52 (se, 1H),
12.61 (se, 1H). MS m/z 283 [MNa]+ (100), 271.
4.10. (10R)-1-[10-Benzyloxymethyl-20-hydroxyethyl]-2-
oxopiperazine (R)-18
4.10.1. Path A
4.7. Methyl (2S)-6-(4-nitrobenzenesulfonyl)-2-
(benzyloxymethyl)-3,6-diaza-4-oxohexanoate (S)-15
To a mixture of potassium carbonate (0.46 g, 3.3 mmol) in dry
DMF (5.6 mL) was added thiophenol (0.14 mL, 1.33 mmol). This
mixture was left to stir under nitrogen for 30 min. The sulfonamide
compound (0.5 g, 1.1 mmol) in dry DMF (5.6 mL) was slowly
injected into the above reaction mixture which was left to stir
for an additional six hours. The DMF was removed in vacuo and
the residue dissolved in ethyl acetate (50 mL). This organic layer
was washed with sodium bicarbonate (10% w/v). The organic
layer was dried over anhydrous sodium sulfate and the excess
solvent removed under reduced pressure. The desired compound
(R)-18 (0.13 g, 40%) was obtained after silica gel column chroma-
tography (eluent: cyclohexane/ethyl acetate, 1:1, then ethyl
acetate 100%).
To a solution of sulfonamide 14 (8 g, 30.8 mmol) in dry tetrahy-
drofuran was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-meth-
ylmorpholinium chloride, DMTMM (12.6 g, 46.2 mmol). The
reaction mixture was stirred for 1.5 h, after which amino acid
methyl ester hydrochloride (8.3 g, 33.8 mmol) and N-methyl mor-
pholine, NMM (5.4 mL, 50.7 mmol), were added. The reaction mix-
ture was stirred for 18 h at room temperature. The crude mixture
was filtered and washed with citric acid solution (5% w/v), water
and sodium bicarbonate (5% w/v) successively. The organic layer
was further concentrated to give compound (S)-15 (10.4 g, 77%)
as a yellow solid. Mp: 110–111 °C. ½a D24
¼ þ7 (c 0.1, EtOH). IR
ꢀ
m
max/cmꢁ1: 3321, 3279, 1741, 1656, 1522, 1347, 1147. 1H NMR
4.10.2. Path B
(500 MHz, CDCl3): d 3.64 (dd, 2H, 2J = 10, 3J = 3), 3.72 (s, 3H), 3.81
(dd, 2H, 2J = 10, 3J = 6), 3.82 (dd, 2H, 2J = 10, 3J = 6), 3.87 (dd, 2H,
2J = 10, 3J = 3), 4.45 (d, 2J = 12.1), 4.54 (d, 2J = 12.1), 4.70 (se, 1H),
6.60 (m, 1H), 7.35 (se, 1H), 8.04 (d, 2H, 3J = 8.7), 8.3 (d, 2H,
3J = 8.7). MS m/z 474 [MNa]+ (100). HRMS calcd for C19H21N3O8NaS:
474.0947. Found: 474.0950.
To a mixture of potassium carbonate (0.06 g, 0.4 mmol) in dry
acetonitrile/dimethyl sulfoxide (49:1 v/v, 0.8 mL) at 50 °C was
added thiophenol (0.035 mL, 0.3 mmol). The reaction mixture
was stirred for 30 min. The sulfonamide compound (R)-17
(0.05 g, 0.11 mmol) in dry acetonitrile/dimethyl sulfoxide (49:1
v/v, 0.1 mL) was slowly injected into the above reaction mixture
which was left to stir for an additional 1.5 h. The solvent was re-
moved in vacuo and the residue dissolved in ethyl acetate
(5 mL). This organic layer was washed with sodium bicarbonate
(10% w/v). The organic phase was dried over anhydrous sodium
sulfate and concentrated. Purification was achieved by column
chromatography (eluent: cyclohexane/ethyl acetate, 1:1, then
ethyl acetate 100%) to result compound (R)-18 (0.027 g, 95%) as a
4.8. Methyl (2S)-3-benzyloxy-2-[40-(4-nitrobenzenesulfonyl)-20-
oxopiperazin-10-yl]propanoate (S)-16
To
a solution of 4-nitrobenzenesulfonyl dipeptide (8 g,
16.8 mmol) in dry dimethylformamide (DMF) was added potas-
sium carbonate (23.2 g, 168 mmol). The reaction mixture was al-
lowed to stir at 60 °C for 30 min; 1,2-dibromoethane (14.4 mL,
yellow oil. ½a 2D0
ꢀ
¼ þ25 (c 0.05, EtOH). IR
m
max/cmꢁ1: 2925, 1725,

C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
1695
1269. 1 H NMR (500 MHz, CDCl3): d 3.27 (m, 1H), 3.29 (m, 1H), 3.51
(m, 1H), 3.60 (m, 1H), 3.68 (m, 1H), 3.71 (m, 2H), 3.79 (m, 2H), 3.80
(m, 1H), 3.83 (m, 2H), 4.30 (se, 1H), 4.53 (d, 2H, 2J = 12), 4.57 (d, 2H,
2J = 12), 7.28–7.39 (m, 5H). MS m/z: 287 [MNa]+ (100). HRMS calcd
for C14H20N2O3Na : 287.3094. Found: 287.3089.
0.5, EtOH). Spectroscopic data of (S)-21 were identical with those
of (R)-21.
4.16. Methyl (2S)-3-benzyloxy-2-[40-(tert-butoxycarbonyl)-10-
piperazinyl]propanoate (S)-22
4.11. (10R)-4-(4-Thiophenylbenzenesulfonyl)-1-[10-
To a solution of alcohol (R)-21 (1.5 g, 7.14 mmol) in dry toluene
at 0 °C was added N,N-diisopropylethylamine (DIPEA) (1.18 mL,
7.14 mmol). The solution was stirred while triflic anhydride
(1.20 mL, 7.14 mmol) was added slowly and the temperature was
maintained at <5 °C. The reaction mixture was warmed to 20 °C.
After 1 h, the mixture was cooled to ꢁ78 °C and a solution of N-
Boc piperazine (1.33 g, 7.14 mmol) and DIPEA (1.18 mL,
7.14 mmol) in dry toluene (19 mL) was added. The mixture was
stirred for 18 h after which the insoluble material was removed
by filtration and washed with toluene. The filtrate was concen-
trated in vacuo and the crude product was purified by chromatog-
raphy using cyclohexane/ethyl acetate (6:4: v/v). The product
benzyloxymethyl-20-hydroxyethyl]-2-oxopiperazine (R)-19
Following the same procedure (path A) of (R)-18, the compound
(R)-19 was prepared (0.68 g, 60%) as a yellow oil. ½a D23
¼ ꢁ26 (c
ꢀ
0.01, EtOH). IR
m
max/cmꢁ1: 3398, 1644, 1349, 1167. 1H NMR
(500 MHz, CDCl3): d 3.23 (m, 1H), 3.28 (m, 1H), 3.45 (m, 1H),
3.52 (m, 1H), 3.60 (m, 1H), 3.73 (m, 1H), 3.75 (m, 1H), 3.77 (m,
1H), 3.85 (m, 2H), 4.32 (se, 1H), 4.49 (d, 1H, 2J = 12), 4.51 (d, 1H,
2J = 12), 7.27–7.63 (m, 14H).
4.12. (2R)-3-Benzyloxy-2-hydroxypropanoic acid (R)-20
(2.65 g, 98%) was afforded as orange oil. ½a D23
¼ ꢁ16 (c 0.5, EtOH).
ꢀ
IR m
max/cmꢁ1: 1733, 1689, 1164, 1116. 1H NMR (500 MHz, CDCl3):
A mixture of O-benzyl-
(24 mL) was cooled to 0 °C.
D
-serine (4 g, 20.5 mmol) in 2 N H2SO4
solution of NaNO2 (2.56 g,
d 1.46 (s, 9H), 2.58 (se, 2H), 2.59 (se, 2H), 3.42 (m, 1H), 3.43 (m,
1H), 3.53 (t, 1H, 3J = 6.5), 3.71 (s, 3H), 3.77 (m, 1H), 3.79 (m, 1H),
4.53 (d, 1H, 2J = 12), 4.55 (d, 1H, 2J = 12), 7.3–7.4 (m, 5H). MS m/z
401 [MNa]+ (100). HRMS calcd for C20H30N2O5Na: 401.2052.
Found: 401.2072.
A
36.96 mmol) in H2O was added over 2 h while the temperature
was maintained between 0 °C and 5 °C. After complete addition,
the reaction mixture was stirred at this temperature for 10 h fol-
lowed by stirring at ambient temperature for 2 h. The reaction
mixture was adjusted to pH 4 with 50% NaOH. EtOAc (3 ꢃ 20 mL)
was added, and the layers were vigorously stirred while the aque-
ous layer was adjusted to a pH of 2 with 2 N H2SO4. The aqueous
layer was extracted further with EtOAc (3 ꢃ 20 mL) and the com-
bined extracts were dried over Na2SO4. The drying agent was fil-
tered off and washed with EtOAc, and the filtrate was
concentrated. The compound (3.62 g, 90%) was obtained as a yel-
4.17. Methyl (2R)-3-benzyloxy-2-[40-(tert-butoxycarbonyl)-10-
piperazinyl]propanoate (R)-22
Following the same procedure for (S)-22, the compound (R)-22
was prepared (2.65 g, 98% of yield) as orange oil. ½a D23
¼ þ16 (c 0.5,
ꢀ
EtOH). Spectroscopic data of (R)-16 were identical with those of
(S)-16.
low oil. ½a 2D2
ꢀ
¼ ꢁ2 (c 0.5, EtOH). IR
m
max/cmꢁ1: 3439, 1725, 1096,
696. 1H NMR (500 MHz, DMSO-d6): d 3.65 (m, 1H), 3.66 (m, 1H),
4.20 (se, 1H), 4.51 (d, 1H, 2J = 11.6), 4.57 (d, 1H, 2J = 11.6), 7.31–
7.35 (m, 5H). MS m/z 677 [M3Na4]+, 241 [MNa2]+ (100). HRMS calcd
for C10H11O4Na2 : 241.0453. Found: 241.0426.
4.18. Methyl (2S)-3-benzyloxy-2-[40-(tert-butoxycarbonyl)-20-
oxopiperazin-10-yl]propanoate (S)-12
A solution of (S)-22 (1.53 g, 4.04 mmol) in ethyl acetate (12 mL)
was added to a mixture of RuO2ꢂxH2O (0.053 g, 0.40 mmol) and
10% aqueous NaIO4 (18.7 mL). The solution was stirred vigorously
for 16 h at room temperature. The layer was separated and the
aqueous layer was extracted with ethyl acetate (3 ꢃ 25 mL). The
4.13. (2S)-3-Benzyloxy-2-hydroxypropanoic acid (S)-20
Following the same procedure for (R)-20 starting from O-benz-
yl-L-serine (4 g, 20.5 mmol), the compound (S)-20 was prepared
(3.62 g, 90%) as yellow oil. ½a D22
ꢀ
¼ þ2 (c 0.5, EtOH). Spectroscopic
extract was treated with 2-propanol (30 lL). Black-coloured
data of (S)-20 were identical with those of (R)-20.
RuO2, which precipitated from the solution, was filtered off and
the filtrate was washed with brine. The organic layer was dried
over Na2SO4. The drying agent was filtered off and washed with
EtOAc, and the filtrate was concentrated. The crude product was
purified by column chromatography using as eluent cyclohexane/
ethyl acetate (6:4: v/v). The product (0.93 g, 58%) was afforded as
4.14. Methyl (3R)-3-benzyloxy-2-hydroxypropanoate (R)-21
A mixture of acid (R)-20 (3 g, 13.7 mmol), MeOH and freshly
prepared methanolic HCl 1 M (5.4 mL) was stirred at ambient tem-
perature for 1.5 h. Trimethyl orthoformate (2.98 mL, 27.4 mmol)
was added, and the mixture was stirred at ambient temperature
for 18 h. The solution was concentrated with vacuo and the crude
product was purified by column chromatography using cyclohex-
ane/ethyl acetate (1:1: v/v). The compound (2.8 g, 87%) was affor-
a yellow oil. ½a 2D3
ꢀ
¼ ꢁ12 (c 0.3, EtOH). IR
m
max/cmꢁ1: 1744, 1694,
1657, 1166. 1H NMR (500 MHz, CDCl3): d 1.51 (s, 9H), 3.53
(m, 1H), 3.55 (m, 2H), 3.80 (m, 1H), 3.76 (s, 3H), 3.89 (dd, 1H,
2J = 10.5, 3J = 3.6), 4.00 (dd, 1H, 2J = 10.5, 3J = 3.6), 4.12 (d,
1H, 2J = 18.3), 4.21 (d, 1H, 2J = 18.3), 4.51 (d, 1H, 2J = 12), 4.53 (d,
1H, 2J = 12), 5.36 (se, 1H), 7.3–7.4 (m, 5H). MS m/z 807 [M2Na]+,
415 [MNa]+ (100). HRMS calcd for C20H28N2O6Na: 415.1845.
Found: 415.1849.
ded as a transparent liquid. ½a D23
ꢀ
¼ ꢁ6 (c 0.5, EtOH). IR
m :
max/cmꢁ1
3480, 1738, 1208, 1104. 1H NMR (500 MHz, CDCl3): d 3.74 (se, 3H),
3.75 (m, 1H), 3.76 (m, 1H), 4.40 (se, 1H), 4.55 (m, 1H), 4.62 (d, 1H,
2J = 12), 4.62 (d, 1H, 2J = 12), 7.32–7.36 (m, 5H). MS m/z 233
[MNa]+ (100). HRMS calcd for C11H14O4Na : 233.0790. Found:
233.0789.
4.19. Methyl (2R)-3-benzyloxy-2-[40-(tert-butoxycarbonyl)-20-
oxopiperazin-10-yl]propanoate (R)-12
4.15. Methyl (3S)-3-benzyloxy-2-hydroxypropanoate (S)-21
Following the same procedure for (S)-12, the compound (R)-12
was prepared (0.93 g, 58%) and was afforded as a yellow oil.
Following the same procedure for (R)-21, = compound (S)-21
½
a 2D3
ꢀ
¼ þ12 (c 0.3, EtOH). Spectroscopic data of (R)-12 were identi-
was prepared (2.8 g, 87%) as a transparent liquid. ½a D23
¼ þ6 (c
ꢀ
cal with those of (S)-12.

1696
C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
4.20. (10R)-4-(tert-Butoxycarbonyl)-1-[10-benzyloxymethyl-20-
hydroxyethyl]-2-oxopiperazine (10R)-2
4.24. (1S,3R)-4-(tert-Butoxycarbonyl)-1-[10-hydroxymethyl-20-
hydroxyethyl]-3-benzyl-2-oxopiperazine (1S,3R)-23
From (R)-18: To a solution of amine (R)-18 (0.287 g, 1 mmol)
in dry MeOH (3.4 mL) at 0 °C was slowly dropped a solution of
di-tert-butyldicarbonate (0.13 g, 0.6 mmol) in dry MeOH
(1.7 mL). The reaction mixture was stirred for 36 h at room tem-
perature. The solvent was eliminated under reduced pressure
and the residue dissolved in diethyl ether (1.7 mL). This solution
was filtered and then washed with citric acid solution (5% w/v).
The aqueous phases were combined and pH adjusted to 9 by
addition of NaOH (50% w/v) and extracted with ethyl acetate.
The organic layers were combined, dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give com-
Following the same procedure for (1R,3S)-23, the compound
(1S,3R)-23 was prepared (0.4 g, 86%) as
a transparent oil.
½
a 1D8
ꢀ
¼ ꢁ16 (c 0.1, EtOH). IR
m
max/cmꢁ1: 3364, 2974, 1687, 1641,
1172. 1H NMR (500 MHz, CDCl3): d 7.0–7.3 (10H, m), 4.62 (1H,
m), 4.45 (1H, d, J = 11.6), 4.41 (1H, d, J = 11.6), 4.36 (1H, t, J = 8.3),
3.90 (1H, br m), 3.70 (2H, d, J = 8.3), 3.62 (2H, m), 3.50 (2H, m),
3.31 (2H, m), 3.16 (1H, m), 3.09 (1H, m), 3.02 (1H, m), 1.20 (9H,
s). 13C NMR (125 MHz, CDCl3) d 169.1, 153.6, 137.7, 129.9, 128.5,
128.4, 127.9, 126.8, 80.6, 73.3, 68.2, 61.7, 61.6, 58.7, 58.1, 44.9,
38.7, 28.2. MS m/z 477 (M+Na)+, 421, 377. HRMS calc. for
(M+Na)+ 477.2349, found 477.2367.
pound (10R)-2 (0.387 g, 100%). ½a 2D4
ꢀ
¼ þ7 (c 0.1, EtOH). IR mmax
/
cmꢁ1: 3348, 1696, 1644, 1168. 1H NMR (500 MHz, CDCl3): d
1.47 (s, 9H); 3.00 (se, 1H); 3.50 (m, 1H); 3.56 (m, 1H); 3.64
(m, 2H); 3.74 (m, 1H); 3.84 (m, 1H); 3.90 (m, 2H); 4.13 (d,
1H, 2J = 17.8); 4.22 (d, 1H, 2J = 17.8); 4.42 (m, 1H); 4.55 (d, 1H,
2J = 12.0); 4.59 (d, 1H, 2J = 12.0); 7.31–7.42 (m, 5H). MS m/z:
387 [MNa]+ (100), 331. HRMS calcd for C19H28N2O5Na:
387.1896. Found: 387.1897.
Acknowledgments
The authors are grateful to AlBan Office for the fellowship to C.L.
Lencina (scholarship E04D041890BR). We thank Sophie Da Nasci-
mento for obtaining the mass spectra, Filippo De Simone and Sab-
rina Cutri for their help and participation in the thioamide
reduction modification of our previously described synthesis of
1,4-disubstituted-2-oxopiperazine.
4.21. Starting from (R)-12
Following the same procedure for (R)-17, compound (10R)-
2 was prepared (0.282 g, 73%) starting from (R)-12 (0.392 g,
1 mmol).
References
1. For example see: Prisinzano, T.; Rice, K. C.; Baumann, M. H.; Rothman, R. B.
Curr. Med. Chem.: Central Nervous System Agents 2004, 4, 47–59.
2. 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, J. B.; Koblan, K. S.; Kohl, N. E.; Lobell,
R. B.; Chen, I.-W.; McLoughlin, D. A.; Olah, T. V.; Graham, S. L.; Hartman, G. D.;
Williams, T. M. Bioorg. Med. Chem. Lett. 2001, 11, 537.
4.22. (10S)-4-(tert-Butoxycarbonyl)-1-[10-benzyloxymethyl-20-
hydroxyethyl]-2-oxopiperazine (10S)-2
3. 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. Bioorg. Med. Chem. Lett. 2001,
11, 1411.
4. Seibel, J.; Brown, D.; Amour, A.; Macdonald, S. J.; Oldham, N. J.; Schofield, C. J.
Bioorg. Med. Chem. Lett. 2003, 13, 387.
Following the same procedure for (R)-17, the compound (10S)-2
was prepared (0.42 g, 75%) as a transparent oil. ½a D24
¼ ꢁ7 (c 0.1,
ꢀ
EtOH). Spectroscopic data of (10S)-2 were identical with those of
(10R)-2.
5. Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65,
2484.
6. 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. Bioorg.
Med. Chem. Lett. 2006, 16, 4668.
4.23. (1R,3S)-4-(tert-Butoxycarbonyl)-1-[10-hydroxymethyl-20-
hydroxyethyl]-3-benzyl-2-oxopiperazine (1R,3S)-23
7. Su, T.; Yang, H.; Volkots, D.; Woolfrey, J.; Dam, S.; Wong, P.; Sinha, U.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13, 729–732.
8. Pohlmann, A. R.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P. J. Pept. Res. 1997,
51, 116.
9. Schoenberg, L. N.; Cooke, D. W.; Liu, C. F. Inorg. Chem. 1968, 7, 2386–
2393.
10. (a) Yamashita, T.; Kojima, Y.; Hirotsu, K.; Ohsuka, A. Int. J. Pept. Protein Res.
1989, 33, 110–114; (b) Lammek, B.; Czaja, M.; Derdowska, I.; Lempicka, E.;
Sikora, P.; Szkrobka, W.; Trzeciak, H. I. J. Pept. Res. 1998, 51, 149–154; (c)
Lempicka, E.; Derdowska, I.; Jastrzebska, B.; Kuncarova, P.; Slaninova, J.;
Lammek, B. J. Pept. Res. 2001, 57, 162–167; (d) Yamashita, T.; Hatamoto, E.;
Takenada, H.; Kojima, Y.; Inoue, Y.; Gemba, M.; Yasuda, M. Chem. Pharm. Bull.
1996, 44, 856–859.
A solution of diisopropylamine (1 mL, 7.35 mmol) in THF
(20 mL) was cooled to ꢁ78 °C and kept under a nitrogen atmo-
sphere. A 1.6 M solution of n-BuLi in hexane (4 mL, 6.3 mmol)
was slowly added to the cold solution and the mixture was stir-
red for 15 min. A solution of (10R)-2 (813 mg, 2.1 mmol) and
HMPA (6.3 mmol) in THF (5 mL) was slowly poured into the cold
solution and stirred for 15 min. A solution of benzyl bromide
(1.07 g, 6.3 mmol) in THF (5 mL) was added and the mixture
was stirred for 5 h at ꢁ50 °C, then for 30 min at ꢁ15 °C. The reac-
tion mixture was quenched by the addition of an aqueous satu-
rated solution of NH4Cl (80 mL) then extracted three times with
CH2Cl2. The combined organic phases were washed with H2O,
dried over Na2SO4, filtered and concentrated in vacuo. The crude
product was finally purified by column chromatography using
cyclohexane/EtOAc (1:20) as an eluent to give diastereoisomer
11. Yamashita, T.; Tsuru, E.; Banjyo, D.; Shibata, K.; Yasuda, M.; Gemba, M. Chem.
Pharm. Bull. 1997, 45, 1940–1944.
12. (a) Bhatt, U.; Mohamed, N.; Just, G. Tetrahedron Lett. 1997, 38, 3679–3682; (b)
Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. Bioorg. Med. Chem.
Lett. 1998, 8, 1679–1682; (c) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.;
Moeller, K. D. J. Org. Chem. 2000, 65, 2484–2493; (d) DiMaio, J.; Belleau, B. J.
Chem. Soc., Perkin Trans. 1 1989, 1687–1689; (e) Sugihara, H.; Fukushi, H.;
Miyawaki, T.; Imai, Y.; Terashita, Z. I.; Kawamura, M.; Fujisawa, Y.; Kita, S. J.
Med. Chem. 1998, 41, 489–502; (f) Kitamura, S.; Fukushi, H.; Miyawaki, T.;
Kawamura, M.; Konishi, N.; Terashita, Z. I.; Naka, T. J. Med. Chem. 2001, 44,
2438–2450; (g) Su, T.; Yang, H.; Volkots, D.; Woolfrey, J.; Dam, S.; Wong, P.;
Sinha, U.; Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13, 729–
732.
13. Mohamed, N.; Bhatt, U.; Just, G. Tetrahedron Lett. 1998, 39, 8213–8216.
14. Chen, Z.; Kende, A. S. Synth. Commun. 2006, 36, 473–479.
15. Viso, A.; Pradilla, R. F.; Flores, A.; Garcia, A.; Tortosa, M.; Lopez-Rodrigues, M. L.
J. Org. Chem. 2006, 71, 1442–1448.
16. Reginato, G.; Di Credico, B.; Andreotti, D.; Mingardi, A.; Paio, A.; Donati, D.
Tetrahedron: Asymmetry 2007, 18, 2680–2688.
(1R,3S) (761 mg, 76%). ½a D18
ꢀ
¼ þ16 (c 0.1, EtOH). IR
m :
max/cmꢁ1
3364, 2974, 1687, 1641, 1172. 1H NMR (500 MHz, CDCl3): d
7.0–7.3 (10H, m), 4.60 (1H, m), 4.44 (1H, d, J = 11.6), 4.40 (1H,
d, J = 11.6), 4.37 (1H, t, J = 8.3), 3.89 (1H, br m), 3.71 (2H, d,
J = 8.3), 3.62 (2H, m), 3.51 (2H, m), 3.32 (2H, m), 3.16 (1H, m),
3.10 (1H, m), 3.00 (1H, m), 1.20 (9H, s). 13C NMR (125 MHz,
CDCl3) d 169.5, 154.0, 138.2, 130.3, 129.4, 128.8, 128.2, 128.0,
127.1, 80.9, 73.6, 68.6, 61.6, 61.5, 59.3, 58.1, 45.1, 38.3, 28.5.
MS m/z 477 (M+Na)+, 421, 377, 345. HRMS calcd for (M+Na)+
477.2349, found 477.2343.
17. Pohlmann, A.; Schanen, V.; Guillaume, D.; Quirion, J. C.; Husson, H. P. J. Org.
Chem. 1997, 62, 1016–1022.

C. L. Lencina et al. / Tetrahedron: Asymmetry 19 (2008) 1689–1697
1697
18. (a) Schanen, V.; Riche, C.; Chiaroni, A.; Quirion, J. C.; Husson, H. P. Tetrahedron
Lett. 1994, 35, 2533–2536; (b) Schanen, V.; Cherrier, M. P.; Melo, S. J.; Quirion, J.
C.; Husson, H. P. Synthesis 1996, 7, 833–869.
19. (a) Micouin, L.; Jullian, V.; Quirion, J. C.; Husson, H. P. Tetrahedron: Asymmetry
1996, 7, 2839–2846; (b) Micouin, L.; Varea, T.; Riche, C.; Chiaroni, A.; Quirion, J.
C.; Husson, H. P. Tetrahedron Lett. 1994, 35, 2529–2532.
20. Franceschini, N.; Sonnet, P.; Guillaume, D. Org. Biomol. Chem. 2005, 3, 787–793.
21. Smith, A. C.; Williams, R. M. Angew. Chem., Int. Ed. 2008, 47, 1736–1740.
22. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087.
23. Guziec, F. S.; Wasmund, L. M. Tetrahedron Lett. 1990, 31, 23–26.
24. Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–6374.
25. Wuts, P. G. M.; Northuis, J. M. Tetrahedron Lett. 1998, 39, 3889–3890.
26. Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett. 1997, 38,
5253–5256.
27. Sonnet, P.; Petit, L.; Marty, D.; Guillon, J.; Rochette, J.; Brion, J. D. Tetrahedron
Lett. 2001, 42, 1681–1683.
28. Sonnet, P.; Da Nascimento, S.; Marty, D.; Franceschini, N.; Guillon, J.; Brion, J.
D.; Rochette, J. Tetrahedron Lett. 2003, 44, 3293–3296.
29. Watson, T. J.; Ayers, T. A.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.;
Horgan, S.; Carey, J. P. Org. Process Res. Dev. 2003, 7, 521–532.
30. Vetuschi, C.; Tangari, N.; Giovine, M.; Franchini, C.; Tortorella, V. Il Farm 1992,
47, 599–605.
31. Petride, H.; Drãghici, C.; Florea, C.; Petride, A. Cent. Eur. J. Chem. 2006, 4, 674–
694.