Synthesis of enantiopure 1-benzyl-2,3-disubstituted piperazines from enantiopure p-toluenesulfinimines

Article abstract of DOI:10.1055/s-2002-25336

The treatment of enantiopure N-sulfinyl-N′-benzyldiaminoalcohols with diethyl oxalate and sodium methoxide followed by reduction with BH₃ affords enantiopure 1-benzyl-2,3-disubstituted piperazines. A related sequence produces substituted monoke

Full text of DOI:10.1055/s-2002-25336

LETTER
755
Synthesis of Enantiopure 1-Benzyl-2,3-disubstituted Piperazines from
Enantiopure p-Toluenesulfinimines
Synthesis of
E
nant
l
iopure
m
1-Benzyl-2,3-disubs
a
titute
d
Piperazin
V
e
s
iso,*a Roberto Fernández de la Pradilla,*a María L. López-Rodríguez,b Ana García,a Mariola Tortosaa
a
Instituto de Química Orgánica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
b
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)5644853; E-mail: iqov379@iqog.csic.es; E-mail: iqofp19@iqog.csic.es
Received 7 February 2002
with carbon and nitrogen atoms differently functional-
ized.
Abstract: The treatment of enantiopure N-sulfinyl-N -benzyl-
diaminoalcohols with diethyl oxalate and sodium methoxide fol-
lowed by reduction with BH3 affords enantiopure 1-benzyl-2,3-
disubstituted piperazines. A related sequence produces substituted
monoketopiperazines in good yields.
We have previously reported the asymmetric synthesis of
enantiopure 1,3-imidazolidines C through the diastereo-
selective stepwise condensation between readily available
p-tolylsulfinimines A,13 and glycine iminoester enolates B
in the presence of boron trifluoride.12b Under these condi-
tions, enantiopure p-tolylsulfinimines display a moderate
to high facial selectivity rendering the corresponding N-
sulfinylimidazolidines in good to excellent diastereomeric
excess. Ensuing reductive cleavage of the aminal moiety
expediently transforms our 1,3-imidazolidines C into dif-
ferentially protected vicinal diamines D in good yields.
(Scheme 1). The availability of these substrates, along
with the aforementioned relevance of piperazines prompt-
ed us to examine the transformation of a series of our vic-
inal diamines 1 into the corresponding ketopiperazines
and piperazines.
Key words: piperazines, amino alcohols, sulfinimines, chiral aux-
iliaries, asymmetric synthesis
The piperazine ring is truly ubiquitous in molecules in-
volved in the regulation of a wide variety of biological
processes. Indeed, the piperazine scaffold is found in
HIV-protease inhibitors such as indinavir,1 potent antipro-
liferative agents such as ectenaiscidin 743,2 compounds
acting at different membrane receptors such as arylpiper-
azines, powerful 5-HT1A ligands,3 as well as in some
members of the dragmacines,4 a family of marine natural
products with a broad spectrum of biological activities.
On the other hand, the structurally related mono- and
diketopiperazines are gaining importance as farnesyl
transferase inhibitors,5 and as conformationally restricted
peptidomimetics,6 among several biological activities.7 In
addition, recent findings have revealed piperazines and
diketopiperazines as efficient chiral ligands in asymmet-
ric catalysis.8
Ar
O
S
Ar
O
S
N
Li
p-Tol
N
NH
N
p-Tol
O
+
a
b
R1
R1
OCH3
CO2CH3
A
B
O
S
C
Despite the increasing interest on these compounds, the
existing routes to prepare chiral piperazines are scarce,9
and not fully applicable to the straightforward synthesis of
highly substituted derivatives. This is particularly true for
non-symmetrical 2,3-disubstituted piperazines for which
the simplest route entails reduction of 2,3-disubstituted
diketopiperazines in turn prepared from the correspond-
ing vicinal diamines. In fact, the synthesis of suitably sub-
stituted enantiopure vicinal diamines may be quite
challenging,10 and this severely limits the viability of this
approach.
p-Tol
NH
NHBn
R1
OH
D
Scheme 1 Synthesis of N-sulfinyldiaminoalcohols.a Conditions:
(a) BF3 Et2, –78 ºC, THF, (60–93%); (b) LiAlH4, Et2O, r.t.,
(68–85%).
Our initial efforts to obtain homochiral diketopiperazines
were focussed on substrates 1a–e,14 originally obtained
from glycine-derived enolates (Scheme 2, R2 = H). After
testing different experimental conditions we found that
the treatment of 1a (R1 = Et) with diethyl oxalate in
CH2Cl2 afforded 2,3-diketopiperazine 2a in moderate
yields (60%), along with a small amount of morpholinedi-
one 3a derived from N,O ring closure. After chromato-
graphic separation we observed that 3a slowly converted
into 2a upon standing in a solution of MeOH, (5 days) and
that a catalytic amount of NaOMe accelerated (1 h) this
conversion. Substrates 1b and 1c paralleled this behavior,
after removal of the diketopiperazine by filtration. Seek-
Within a program directed to the discovery of new thera-
peutically valuable piperazine derivatives,11 and taking
advantage of our previous experience in the asymmetric
synthesis of non-symmetrical vicinal diamine deriva-
tives,12 we now disclose a straightforward entry to a new
family of homochiral piperazines and ketopiperazines,
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0755,0758,ftx,en;D02602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

756
A. Viso et al.
LETTER
ing to increase the efficiency of the process, we added a To address the preparation of monoketopiperazines from
solution of NaOMe in MeOH to the reaction mixture, and our substrates,18 the primary alcohol of 1a and 1f was pro-
this promoted in situ nucleophilic displacement at sulfur, tected uneventfully as a silyl ether in excellent yields, af-
rendering methyl p-toluenesulfinate along with the de- fording 9a and 9b, respectively (Scheme 3). Not
sired diketopiperazine in excellent yields. This procedure unexpectedly, 9b did not undergo N-acylation with
was also satisfactorily extended to aromatic substrates (1d ClCH2COCl under mild conditions, presumably due to the
and 1e) to produce diketopiperazines 2d and 2e.15
quaternary carbon hindering the amino moiety and, at this
stage, no further efforts were conducted on this substrate.
In contrast, 9a underwent smooth acylation to give chlo-
roacetamide 10 that cyclized to N-sulfinyl-N -benzyl
monoketopiperazine 11 in excellent yield, often accompa-
nied by small amounts of a desulfinylated product, tenta-
tively assigned as imine 12, presumably derived from 11
by enolate formation and elimination of the sulfur moiety.
Treatment of 11 with NaH in refluxing THF afforded an
excellent yield of imine 12 that was fully characterized.19
We believe that 11 and 12 hold considerable potential for
further selective manipulations at ‘C-5’ and ‘C-6’.
After considerable experimentation,16 diketopiperazines
2a–e were efficiently transformed into the corresponding
enantiopure 2,3-disubstituted piperazines 4a–e in good
yields (60–84%), upon treatment with borane dimethyl
sulfide complex.17 These hydroxymethylpiperazines are
amenable to selective protection at the secondary nitrogen
as benzyloxycarbonyl derivatives as illustrated by the
preparation of hydroxymethylpiperazine 5.
c
O
O
S
O
O
N
S
p-Tol
Bn
Cl
NH Bn
N
O
S
O
S
O
p-Tol
O
O
HN
NH NHBn
R2
R1
a or b
+
p-Tol
p-Tol
NH
N
Bn
NH NHBn
R2
b
a
1a
1f
77-90%
R1
OH
R1
OH
O
82%
75-88%
R1
1a R1 = Et, R2 = H
OTBDMS
3a-c (15%)
Et
2a-e
OTBDMS
1b R1 = (CH2)2Ph, R2 = H
1c R1 = i-Pr, R2 = H
9a, R1 = Et, R2 = H
10
d
9b, R1 = i-Pr, R2 = CH3
1d R1 = Ph, R2 = H
60-84%
O
O
1e R1 = p-FC6H4, R2 = H
1f R1 = i-Pr, R2 = CH3
CbzN
Et
O
HN
R1
e
d
c
NBn
OH
NBn
OH
N
NBn
OTBDMS
S
N
NBn
71%
92%
83%
p-Tol
4a-e
5
f
Et
Et
OTBDMS
80%
12
11
Scheme 3 Synthesis of monoketopiperazines.a Conditions:
(a) TBDMSCl, imidazole, cat. DMAP, CH2Cl2, r.t., 90 min;
(b) ClCH2COCl, EtOAc, sat. NaHCO3, (1:1), 0 ºC to r.t., 2 h;
(c) Cs2CO3, DMF, 65 ºC, 2 h; (d) NaH, THF, 0 ºC to reflux, 1 h.
H2N
i-Pr
NHBn
CH3
OH
N
NBn
CH3NH
NHBn
a
d
CH3
OH
CH3
OH
68%
55%
i-Pr
i-Pr
6
7
8
Scheme 2 Synthesis of enantiopure hydroxymethylpiperazines and
ketopiperazines.a Conditions: (a) (CO2Et)2, NaOMe, CH2Cl2, MeOH,
r.t.; (b) i) (CO2Et)2, CH2Cl2, r.t.; ii) NaOMe, MeOH, r.t.; (c) NaOMe,
MeOH, r.t.; (d) BH3 SMe2, THF, reflux; (e) CbzCl, NaOH, CH2Cl2,
r.t.; (f) TFA, MeOH, r.t.
In summary, readily available enantiopure N-sulfinyl-N -
benzyl diaminoalcohols have been expediently trans-
formed into a variety of homochiral 2,3-disubstituted pip-
erazines with adequate functionalization for subsequent
transformations. In addition, a simple entry to more func-
tionalized monoketopiperazines from the same precur-
sors has been outlined. We are currently exploring the
scope, limitations and further developments of the meth-
odology.
To broaden the scope of these procedures we considered
vicinal diamine 1f, originally obtained from alanine
(Scheme 2).14 Unfortunately, the presence of a quaternary
carbon in its skeleton (R2 = CH3) prevented any cycliza-
tion from taking place. Thus, when compound 1f was
treated with diethyl oxalate, cyclic derivatives 2 or 3 were
not observed, even in the presence of NaOMe, instead la-
bile open-chain acylated intermediates were detected. To
enhance the nucleophilicity of the substrate we prepared
desulfinylated diamine 6, and the treatment of 6 with di-
ethyloxalate (Scheme 2), surprisingly, afforded hy-
droxymethylimidazoline 7 (68%). Subsequent reductive
cleavage of the imidazoline ring produced exclusively N-
benzyl-N -methyldiaminoalcohol 8 in fair yield (55%).
The generality of these serendipitous findings remains to
be tested.
Acknowledgement
This research was supported by CAM (Grant 08.5/0079/2000) and
DGI MCYT (Grants PPQ2000-1330 and BQV2001-0582). We
thank MEC for a doctoral fellowship to M.T.
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Synlett 2002, No. 5, 755–758 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiopure 1-Benzyl-2,3-disubstituted Piperazines
757
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M. Eur. J. Org. Chem. 2001, 1449.
(14) The preparation of 1a–c and 1f was carried out following the
procedures described in ref.12b; details will be published
soon in a full account on this chemistry.
(15) (a) The treatment of enantiopure N-sulfinyloxazolidinones
with lithium alkoxides results in clean inversion at sulfur to
produce enantiopure sulfinate esters. See: Evans, D. A.;
Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry,
D. J. Am. Chem. Soc. 1992, 114, 5977. (b) Synthesis of (+)-
(5R,6S)-1-benzyl-5-ethyl-6-hydroxymethylpiperazin-2,3-
dione, 2a. From 1a (416 mg, 1.20 mmol) in anhyd CH2Cl2 (6
mL/mmol) at r.t., with diethyl oxalate (0.98 mL, 7.20 mmol,
6 equiv) and 0.5 equiv of a solution of NaOMe in MeOH (0.3
M, 2 mL, 0.60 mmol) a crude product was obtained after
standard extractive isolation. Purification by washing
thoroughly the crude product with 90% Et2O–hexane and
chromatography (5% MeOH–CH2Cl2) of the mother liquor
afforded 250 mg (0.95 mmol, 79%) of 2a as a white solid.
Data of 2a: mp: 90–92 °C. Rf = 0.25 (12:1 CH2Cl2–MeOH).
[ ]20D +166.5 (c 1.19, MeOH). 1H NMR (CD3OD, 400
MHz): = 0.75 (t, 3 H, J = 7.5 H), 1.33 (m, 1 H), 1.55 (m, 1
H), 3.52 (m, 1 H), 3.61 (ddd, 1 H, J = 7.6, 5.0, 1.1 Hz), 3.87
(dd, 1 H, J = 11.2, 7.6 Hz), 3.96 (dd, 1 H, J = 11.2, 5.0 Hz),
4.25 (d, 1 H, J = 14.2 Hz), 5.53 (d, 1 H, J = 14.2 Hz), 7.57
(m, 5 H). 13C NMR (DMSO-d6, 50 MHz): = 10.4, 28.2,
49.2, 50.6, 58.0, 61.0, 128.5, 129.3 (2 C), 129.6 (2 C), 137.5,
157.4, 157.8. IR(film): 3413, 2928, 1665, 1454, 1117, 1052,
757, 705 cm–1. MS (ES): 297 [M + Cl]+ (100%). Anal. Calcd
for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
63.85; H, 7.04; N, 10.49.
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Chem. 1995, 60, 4177.
(16) Initial attempts performed with LiAlH4 as reducing agent
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M.; Lardicci, L.; Giacomelli, G.; Marchetti, M. Tetrahedron
Lett. 1989, 30, 3551.
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(11) (a) López-Rodríguez, M. L.; Viso, A.; Benhamú, B.;
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Ayala, D.; Rominguera, J. L.; Murcia, M.; Ramos, J. A.;
(17) Synthesis of (–)-(2S,3R)-1-benzyl-3-ethyl-2-hydroxy-
methylpiperazine, 4a. From 2a (188 mg, 0.713 mmol) in
anhyd THF (10 mL/mmol) with 9 equiv of BH3 SMe2 in
THF (2 M, 3.21 mL, 6.417 mmol), after refluxing for 7 h,
removal of the solvent and sequential treatment with 4 equiv
of a 0.4 M HCl (30 min at 100 °C) and 6 equiv of a 0.4 M
solution of NaOH (90 min at 0 ºC) a crude product was
obtained after standard extractive isolation. Purification by
chromatography (0–20% MeOH–Et2O) afforded 123 mg
(0.525 mmol, 75%) of 4a as a colorless oil. Data of 4a:
Synlett 2002, No. 5, 755–758 ISSN 0936-5214 © Thieme Stuttgart · New York

758
A. Viso et al.
LETTER
Rf = 0.10 (40% MeOH–Et2O). [ ]20D –14.1 (c 0.91, CHCl3).
1H NMR (CDCl3, 300 MHz): = 0.92 (t, 3 H, J = 7.3 Hz),
1.48 (sept, 1 H, J = 7.6 Hz), 1.72 (m, 1 H), 2.19 (m, 1 H),
2.29 (dt, 1 H, J = 9.9, 3.0 Hz), 2.70 (m, 1 H), 2.78-2.96 (m,
3 H), 3.29 (d, 1 H, J = 13.3 Hz), 3.65 (dd, 1 H, J = 11.7, 1.6
Hz), 4.02 (d, 1 H, J = 13.3 Hz), 4.05 (dd, 1 H, J = 11.8, 3.2
Hz), 7.26 (m, 5 H). 13C NMR (CDCl3, 50 MHz): = 10.3,
25.1, 43.1, 50.5, 58.3, 59.1, 63.3, 127.0, 128.3 (2 C), 128.7
(2 C), 138.4. IR(film): 3306, 3057, 3021, 2958, 1490, 1452,
1027, 739, 699 cm–1. MS (ES): 235 [M + 1]+ (100%).
2 H, J = 8.1 Hz). 13C NMR (CDCl3, 50 MHz): = –5.3, –5.2,
10.3, 18.1, 21.3, 22.5, 25.8 (3 C), 39.7, 48.6, 57.8, 59.1, 62.4,
125.6 (2 C), 128.0, 128.8 (2 C), 128.9 (2 C), 129.8 (2 C),
136.6, 139.3, 141.8, 165.5. IR(film): 2963, 2855, 1732,
1646, 1435, 1260, 1090, 1018, 799 cm–1. MS (ES): 501 [M
+ 1]+ (100%), 502 [M + 2]+, 503 [M + 3]+, 523 [M + Na]+.
Synthesis of (+)-(5R,6S)-1-benzyl-6-(t-butyldimethylsilyl-
oxymethyl)-5-ethyl-5,6-dihydro-1H-pyrazin-2-one, 12.
From a cold (0 °C) suspension of 4 equiv of NaH in anhyd
THF (5 mL/mmol of NaH), with a solution of 11 (72 mg,
0.144 mmol) in THF (5 mL/mmol) after stirring at r.t. (1 h)
and at reflux (1 h), a crude product was obtained after
standard extractive isolation. Purification by chromato-
graphy on silica gel (30–80% Et2O–hexane) afforded 43 mg
(0.119 mmol, 83%) of 12 as a colorless oil. Data of 12:
Rf = 0.38 (80% Et2O–hexane). [ ]20D +188.3 (c 1.23,
CHCl3). 1H NMR (CDCl3, 500 MHz): = 0.05 (s, 6 H), 0.54
(t, 3 H, J = 7.4 Hz), 0.86 (s, 9 H), 0.86–0.98 (m, 1 H), 1.40–
1.49 (m, 1 H), 3.27 (ap t, 1 H, J = 6.5 Hz), 3.55 (dd, 1 H,
J = 10.2, 6.9 Hz), 3.63 (dd, 1 H, J = 10.2, 5.8 Hz), 3.78 (dd,
1 H, J = 7.7, 5.5 Hz), 3.92 (d, 1 H, J = 14.3 Hz), 5.34 (d, 1
H, J = 14.3 Hz), 7.26–7.34 (m, 5 H), 7.70 (d, 1 H, J = 1.5
Hz). 13C NMR (CDCl3, 50 MHz): = –5.6, –5.5, 10.2, 18.1,
25.8 (4 C), 48.4, 55.2, 59.4, 63.0, 128.1, 128.8 (2 C), 129.1
(2 C), 136.1, 155.1 (2 C). IR(film): 3400, 3030, 2929, 2857,
1674, 1632, 1454, 1361, 1258, 1101, 908, 838, 804, 779, 704
cm–1. MS (ES): 361 [M + 1]+ (100%), 743 [2 M + Na]+.
(18) Dinsmore, C. J.; Bergman, J. M.; Bogusky, M. J.; Culberson,
J. C.; Hamilton, K. A.; Graham, S. L. Org. Lett. 2001, 3, 865.
(19) Synthesis of (+)-(5R,6S,SS)-1-benzyl-6-[(t-butyldimethyl-
silyloxy)methyl]-5-ethyl-4-(p-tolylsulfinyl)piperazin-2-one,
11. From 10 (315 mg, 0.59 mmol) in DMF (6 mL, 10 mL/
mmol) at r.t., with 1.8 equiv of Cs2CO3 (340 mg, 1.04 mmol)
at 65 °C (2 h) a crude product was obtained after standard
extractive isolation. Purification by chromatography on
silica gel (0–30% Et2O–CH2Cl2) afforded 269 mg (0.54
mmol, 92%) of 11 as a white foam. Data of 11: Rf = 0.27
(10% Et2O–CH2Cl2). [ ]20D +61.1 (c 1.10, CHCl3). 1H NMR
(CDCl3, 500 MHz): = 0.07 (s, 3 H), 0.10 (s, 3 H), 0.54 (t,
3 H, J = 7.5 Hz), 0.90 (s, 9 H), 1.33–1.42 (m, 1 H), 1.75–1.83
(m, 1 H), 2.39 (s, 3 H), 3.08 (d, 1 H, J = 17.7 Hz), 3.26 (ddd,
1 H, J = 8.3, 5.3, 1.5 Hz), 3.66 (dd, 1 H, J = 9.8, 8.5 Hz),
3.71 (dd, 1 H, J = 9.7, 5.3 Hz), 3.75 (ddd, 1 H, J = 10.2, 4.7,
1.5 Hz), 3.80 (d, 1 H, J = 17.7 Hz), 3.84 (d, 1 H, J = 14.3
Hz), 5.33 (d, 1 H, J = 14.3 Hz), 7.24-7.33 (m, 7 H), 7.47 (d,
Synlett 2002, No. 5, 755–758 ISSN 0936-5214 © Thieme Stuttgart · New York