Synthesis of enantiopure vicinal diaminoesters and ketopiperazines from N-sulfinylimidazolidines

Article abstract of DOI:10.1016/j.tet.2007.05.062

A short and efficient synthesis of mono- and bicyclic ketopiperazines bearing methoxycarbonyl substituents is described. The route entails selective protection and solvolysis of N-sulfinylimidazolidines to provide vicinal diaminoesters with the nitrogen a

Full text of DOI:10.1016/j.tet.2007.05.062

Tetrahedron 63 (2007) 8017–8026
Synthesis of enantiopure vicinal diaminoesters and
ketopiperazines from N-sulfinylimidazolidines
*
Alma Viso, Roberto Fernandez de la Pradilla, Aıda Flores and Ana Garcıa
*
ꢀ
ꢀ
ꢀ
Instituto de Quꢀımica Orgaꢀnica General, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
Received 13 April 2007; revised 11 May 2007; accepted 16 May 2007
Available online 21 May 2007
Abstract—A short and efficient synthesis of mono- and bicyclic ketopiperazines bearing methoxycarbonyl substituents is described. The
route entails selective protection and solvolysis of N-sulfinylimidazolidines to provide vicinal diaminoesters with the nitrogen atoms suitably
differentiated. Then, an N-acylation/cyclization protocol renders the ketopiperazines. In addition a diastereoselective route to an analog of the
natural diketopiperazine DKP 593A through a 2-piperidinylglycinate available by this method is described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
dihydropyrazine derivatives generated by elimination of
sulfinic acid on 3a.5c Moreover, piperazino-b-lactams (3b,
R3¼P¼–CH(R)–CO–) are easily obtained from these inter-
mediates.5d However, this method gave poor yields when
N-sulfinyldiaminoesters 2 (R2¼CO2Me), available through
selective imidazolidine hydrolysis,5b were used as starting
materials. Furthermore, more functionalized N-sulfinyl-
imidazolidines 1 [R1¼(CH2)4OTs] could not be submitted
to this protocol without losing the tosyloxy group during
the aminal reductive cleavage effected with lithium alumi-
num hydride.6
Piperazines are a class of structures truly ubiquitous in mol-
ecules involved in the regulation of a wide variety of biolog-
ical processes.1 The broad range of bioactivities found for
these molecules has led to their description as ‘privileged
structures’. In particular, ketopiperazines have gained im-
portance as conformationally restricted peptidomimetics,2
as fragments of natural products of diverse structural com-
plexity and biological activities,3 and also have been exam-
ined as ligands in enantioselective catalysis.4 The increasing
interest for these compounds entails the search of efficient
routes toward ketopiperazines. In spite of the existing routes
to prepare ketopiperazines, the synthesis of highly
substituted enantiopure piperazinones is still a challenge
especially for compounds that do not derive directly from
natural amino acids.
O
N
O
S
O
S
Ar
pTol
NH
pTolSON
Bn
pTol
NH
N
R2
R1
R1
OTBDMS
R1
CO2Me
NHBn
3a
1
2
In this context and within a program directed to the discovery
of new bioactive piperazine derivatives,1a a few years ago our
research group developed a process to obtain N-sulfinyl-2-pi-
perazinones 3a from enantiopure imidazolidines (Scheme 1).
N-Sulfinylimidazolidines 1, generated from enantiopure
p-tolylsulfinimines, were submitted to reductive cleavage
of the aminal moiety and protection producing N-sulfinyl-
diamines 25a (R2¼CH2OTBDMS) followed by N-acylation
with ClCH2COCl and cyclization by nucleophilic attack of
the sulfinamide onto the chloride. Subsequently, we found
that these N-sulfinyl-2-piperazinones 3a were practical
intermediates for the diastereoselective synthesis of enantio-
pure highly substituted piperazinones 3b [R3¼allyl, alkyl,
cyanide, P¼H] by nucleophilic addition onto 5,6-
O
R3
PN
R1
O
N
P2N
R1
NP1
NHP2
CO2Me
Bn
R1
CO2Me
NHP1
OP
5
P2HN
R1
O
3b
4
NH
R1
HN
NHP2
O
6
O
HN
NH
Cl
Cl
HN
NH
DKP 593A
Scheme 1. Routes to ketopiperazines from N-sulfinyl-1,3-imidazolidines.
O
* Corresponding authors. E-mail: iqov379@iqog.csic.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.062

8018
A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
To overcome the above limitations, we examined a new
route compatible with both ester and sulfonate functional-
ities providing ketopiperazines 5 from N-sulfinylimidazol-
idines 1 through vicinal diaminoesters 4 in which both
nitrogen atoms are suitably differentiated. Additionally, we
have explored the synthesis of an analog of the natural prod-
uct DKP 593A that contains a 2,5-diketopiperazine core
(6).7 Herein we disclose in full our efforts in pursuing these
goals.
ClCOCH2Cl under mild conditions to give chloroacetamides
4d–f and then cyclization of the carbamate onto the chloride
took place in the presence of Cs2CO3 giving 5-oxopipera-
zino-2-carboxylates 5a–c. The stereochemistry for 5a–c
was confirmed by the small coupling constants (J2,3¼1.7–
0 Hz) along with NOE experiments that indicate a trans
diaxial arrangement of the substituents thus ruling out any
epimerization a to the ester (C-2).
To broaden the scope of this procedure we explored the
N-acylation/cyclization protocol for 4g [R1¼–(CH2)4–] to
afford bicyclic ketopiperazines (Scheme 2). In previous re-
ports, we have demonstrated the efficient formation of meth-
yl 2-piperidinylglycinate 4g from 1d by selective aminal
solvolysis (H3PO4/THF), protection (CbzCl/NaOH), and
simultaneous desulfinylation/cyclization (H3PO4/MeOH)
procedures.5b Consequently, 2-piperidinylglycinate 4g was
treated with ClCH2COCl providing chloroacetamide 4h
(80%) followed by cyclization with Cs2CO3 affording 5d
in excellent yield (93%). Remarkably, piperidinylglycinate
4g is a cyclic a,b-diaminoester related to the antibacterial
and antitumor agent DKP 593A isolated from Streptomyces
griseoluteus.8 Efficient routes to prepare this natural product
and its analogs are scarce and they are often synthesized as
racemic and diastereomeric mixtures.9 Taking these facts
into consideration, we focused our attention on the
diastereoselective synthesis of 8b (Scheme 3), the simplest
tricyclic analog of DKP 593A from piperidinylglycinate 4g.
2. Results and discussion
2.1. Preparation of 2-oxopiperazines
The set of N-sulfinylimidazolidines 1a–d chosen for this
study was synthesized following the procedure previously
reported by us from p-tolylsulfinimines and glycine-derived
enolates.5 The synthetic approach to prepare ketopiperazines
5 begins with protection of 1 as benzyloxycarbamate and
then simultaneous hydrolysis and desulfinylation with
0.5 M aqueous H3PO4 in MeOH (Scheme 2). Initially, we
tested these protocols for 1a (R1¼CH2CH2Ph) to afford 1e
and 4a in good yields (75% and 65%). Under similar condi-
tions, N-benzyloxycarbonyl imidazolidine 1f (R1¼i-Pr) was
obtained as a single product in the crude mixture, however,
after column chromatography 1f partially decomposed pro-
viding finally only 35% yield of diaminoester 4b. Seeking an
improvement in yield of diaminoester 4b, we avoided puri-
fication of N-benzyloxycarbonyl imidazolidine 1f that was
directly treated under acidic conditions to afford 4b in
77% overall yield. Similarly, N-sulfinylimidazolidine 1c
(R1¼1-naphthyl) gave raise to 4c in good yields through
N-benzyloxycarbonyl imidazolidine 1g. Once we had pre-
pared diaminoesters 4a–c, with the nitrogen atoms differen-
tially protected, we carried out a selective N-acylation with
2.2. Synthesis of diketopiperazine 8b$2TFA
At the inception of this study, we considered a strategy con-
sisting of firstly creating the 2,5-diketopiperazine core from
N-sulfinyldiaminoester 2a5b and secondly effecting a double
cyclization of the side chains to form the piperidine rings.
Unfortunately, all attempts to carry out this challenging
O
S
O
S
Ph
NCbz
N
Ph
NH2
(b)
(a)
pTol
pTol
NH
N
CO2Me
R1
R1
NHCbz
R1
CO2Me
CO2Me
1a, R1 = CH2CH2Ph
4a, R1 = CH2CH2Ph (65%)
4b, R1 = iPr (77%)
1e, R1 = CH2CH2Ph (75%)
1b, R1 = iPr
1f, R1 = iPr
1c, R1 = 1-Naph
1d, R1 = (CH2)4OTs
4c, R1 = 1-Naph (76%)
1g, R1 = 1-Naph
ref 5b
(c)
O
NP
NHCbz
CO2Me
O
Cl
4g, P = H
4h, P = COCH2Cl
HN
(c)
(d)
N
Cbz
HN
R1
CO2Me
R1
NHCbz
CO2Me
(d)
O
5a, R1 = CH2CH2Ph (99%)
5b, R1 = iPr (73%)
4d, R1 = CH2CH2Ph (95%)
4e, R1 = iPr (85%)
5c, R1 = 1-Naph (67%)
4f, R1 = 1-Naph (83%)
Cbz
N
N
CO2Me
5d
Scheme 2. Synthesis of 5-oxopiperazino-2-carboxylates from N-sulfinyl-1,3-imidazolidines. Reagents and conditions: (a) CbzCl, NaOH 1 N, CH2Cl2, 0 ꢀC to
rt; (b) H3PO4, rt, MeOH/H2O; (c) ClCH2COCl, 0 ꢀC to rt, 50:50 EtOAc/NaHCO3 satd; (d) Cs2CO3, DMF, 62 ꢀC.

A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
8019
10
O
S
(b)
the benzyloxycarbamate group with Pd2dba3/HSiEt3 and
11
O
HSEt/BF3$OEt2 produced complete deprotection afford-
NH
pTol
ing the known methyl 2(S)-piperidin-(20R)-yl glycinate
thus ruling out any epimerization in our synthetic route.12
Nevertheless, we found that catalytic hydrogenation af-
forded amine 4m in almost quantitative yield. Subsequent
coupling of the acid 4l and the amine 4m using BOP and DI-
PEA provided 7a and further removal of Cbz group afforded
7b in 85% yield (two steps). At this stage we explored the
cyclization of aminoester 7b and found that refluxing 7b in
solvents such as MeOH, toluene, dioxane, and xylene led
to the recovery of starting material even in the presence of
Et3N. After other failed attempts,13 the diketopiperazine
ring was formed in refluxing DMF (22%) or with KCN in
DMF at 80 ꢀC (29%). In these two reaction conditions 8a
was obtained with modest yield but as a single isomer that
was deprotected with TFA/CH2Cl2 and then characterized
as 8b$2TFA. Seeking to improve the cyclization step, we
saponified 7b to afford aminoacid 7c that was treated under
coupling conditions (BOP/DIPEA, HATU/DIPEA) always
recovering starting material or complex reaction mixtures.
NBoc
N
CO2Me
NH
NHP
(
)
4
(a)
+
NHP
TsO
CO2Me
CO2Me
4j
2a, P = H
4g, P = Cbz
4i, P = Boc
2b, P = Cbz
2c, P = Boc
2d, P = Fmoc
(c)
NHCbz
NBoc
CO2Me
(d)
4k
(e)
NBoc
NH
NBoc
2
NHCbz
CO2H
CO2Me
4m
4l
(f)
P1
N
P1
N
O
CO2R
NHP2
HN
(g)
N
NH
NH
O
N
Alternatively, we envisioned that dipeptide 7d lacking N-
piperidine protecting groups could be a suitable substrate
for preparing the diketopiperazine nucleus. Therefore, tert-
butoxycarbamates were uneventfully removed from 7b
with TFA to obtain 7d$3TFA in high conversion (75%).
After some failed experiments,14 7d$3TFA was treated
with 0.1 N NaOH monitoring the pH to 8,15 providing after
16 days diketopiperazine 8b in 99% yield, but as a mixture of
diastereomers, that was finally isolated and characterized as
8b$2TFA. Controlling the pH proved crucial since a higher
base concentration (10% NaOH) produced saponification of
the ester group (7e not shown) and latter efforts to cyclize the
aminoacid were fruitless.
P1
P1
O
8a, P1 = Boc
7a, P1 = Boc, P2 = Cbz, R = Me
7b, P1 = Boc, P2 = H, R = Me
7c, P1 = Boc, P2 = H, R = H
7d, P1 = P2 = H, R = Me
(h)
(d)
(e)
8b·2TFA, P1 = H
single diastereomer
(h)
(i, h)
8b·2TFA
mixture of diastereomers
Scheme 3. Synthesis of an analog of DKP 593A, 8b. Reagents and condi-
tions: (a) (i) H3PO4, MeOH/H2O; (ii) K2CO3, rt; (b) (Cl3CO)2CO,
CH2Cl2, ꢁ78 ꢀC; (c) (Boc)2O, NEt3, dioxane/H2O, 0 ꢀC to rt; (d) Pd(C),
H2 (45 psi), rt; (e) LiOH, THF/H2O, 0 ꢀC, rt; (f) BOP, DIPEA, CH2Cl2,
0 ꢀC to rt; (g) DMF, reflux, 40 h or KCN, DMF, 80 ꢀC, four days; (h)
TFA, CH2Cl2, 2 h; (i) NaOH, 0.1 N, rt, 16 days.
In summary, we have developed an efficient synthesis of
enantiopure mono- and bicyclic ketopiperazine-2-carboxyl-
ates from N-sulfinyl-1,3-imidazolidines. In addition, we
have addressed a diastereoselective synthesis of an analog
of DKP 593A containing the three main cycles of the struc-
ture from an enantiopure 2-piperidinylglycinate available
from N-sulfinylimidazolidines through the methodology
developed in our laboratory.
route were fruitless and therefore we planned a different
approach. Thus, several protecting groups were installed in
N-sulfinyldiaminoester 2a to evaluate their behavior in the
synthesis of 2-piperidinylglycinates 4 and eventually in the
synthesis of 8b (Scheme 3). Consequently, we prepared car-
bamate 2c (P¼Boc) from N-sulfinyldiaminoester 2a in 65%
yield and subsequent treatment with H3PO4 in MeOH fol-
lowed by addition of solid K2CO3 allowed for the isolation
of 4i (60%) and 4j (17%). Imidazolidinone 4j was probably
formed from 4i during treatment with K2CO3 since perform-
ing basic treatment with a solution of NaOH (1 N) prevented
formation of 4j although it provided a lower yield of 4i
(42%). The structural assignment of 4j was further con-
firmed by chemical means by submitting 4i to cyclization
with Cl3COC(O)OCl3 affording 4j (91%). Similarly, 2d
(P¼Fmoc) was obtained from 2a in moderate yield (41%),
however, this carbamate failed in giving the expected N-
Fmoc piperidinylglycinate. The above results made us
choose 4g as the starting point to address the synthesis of 8b.
3. Experimental section
3.1. General procedures
Reagents and solvents were handled by using standard
syringe techniques. CH2Cl2 was distilled from CaH2, and
THF from sodium. DMF was dried over CaH2 and filtered
before distillation under reduced pressure. Then, it was col-
˚
lected over 4 A molecular sieves and argon was bubbled
through for 10 min before storing it. Crude products were
purified by flash chromatography on Merck 230–400 mesh
silica gel with distilled solvents. Analytical TLC was carried
out on Merck (Kieselgel 60 F254) silica gel plates with detec-
tion by UV light, iodine, and 10% phosphomolybdic acid so-
lution in ethanol. Throughout this article, the volume of
solvents is reported in mL/mmol of starting material. Infra-
red spectra (IR) were obtained on a Perkin–Elmer 681 and
Accordingly, benzyloxycarbamate 4g was further protected
with a Boc group attached to the piperidine nitrogen afford-
ing 4k (82%) that was saponified with LiOH/H2O to render
acid 4l in excellent yield. At this point chemoselective de-
protection of 4k was also studied. Initial efforts to remove

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A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
on a Perkin–Elmer Spectrum one. 1H and 13C NMR spectra
were recorded on a Br€uker AM-200 (200 MHz), Varian
Gemini-200 (200 MHz), Varian INOVA-300 (300 MHz),
and Varian INOVA-400 (400 MHz) using CDCl3 as solvent
and with the residual solvent signal as internal reference
(CDCl3, 7.24 and 77.0 ppm) unless otherwise noted. NMR
signal assignments were based on selective decoupling,
HSQC, HMBC, COSY, and NOESY-1D experiments. Melt-
ing points were determined on a Reichert Kofler microscope
and are uncorrected. Optical rotations were measured on
a Perkin–Elmer 241 polarimeter at 20 ꢀC using a sodium
lamp and in CHCl3 solution. Low resolution mass spectra
in the positive mode were recorded by direct injection on
a Hewlett Packard 5973 MSD instrument using the elec-
tronic impact technique with an ionization energy of 70 eV
or on a Hewlett Packard 1100 MSD instrument using the
atmospheric pressure chemical ionization (APCI) or electro-
spray (ES) chemical ionization techniques in its positive or
negative mode. Elemental analyses were carried out on a
Perkin–Elmer 240 C and on a Heraus CHN-O-Rapid instru-
a purified sample (chromatography on silica gel 20–40%
Et2O/hexane). Data for (+)-methyl [(2S,4R,5S,SS)-1-benzyl-
oxycarbonyl-2-phenyl-4-(2-phenethyl)-3-(p-tolylsulfinyl)-
1,3-imidazolidin-5-yl] carboxylate, 1e: Rf ¼0.30 (80% Et2O/
1
hexane). [a]2D0 +18.1 (c 1.00). H NMR (200 MHz) (some
signals appear broadened and display fine splittings due to
the presence of rotamers) d 2.15–2.31 (m, 1H, H-10), 2.46–
2.71 (m, 2H, H-10, CH2Ph), 2.82–2.95 (m, 1H, CH2Ph),
2.41+2.44 (2s, 3H, Me-Tol), 3.56+3.79 (2s, 3H, CO2Me),
3.88 (m, 1H, H-5), 4.43 (ap t, 1H, J¼9.0 Hz, H-4), 4.98–
5.21 (m, 2H, OCH2Ph), 6.12+6.22 (2s, 1H, H-2), 7.04–
7.38 (m, 15H, Ar-H), 7.47 (d, 2H, J¼7.5 Hz, Ar-H), 7.61
(d, 2H, J¼8.2 Hz, Ar-H). 13C NMR (50 MHz) d 21.4,
32.0+30.7 (1C), 32.7, 52.6+53.4 (1C), 62.4+63.6 (1C),
65.4, 67.3+67.6 (1C), 73.6, 126.1–129.9 (19CH-Ar),
136.0–142.0 (5C-Ar), 154.0 (CO), 170.7 (CO). IR (KBr):
3030, 2951, 2855, 2246, 1755, 1713, 1603, 1496, 1454,
1403, 1349, 1208, 1095, 1016, 916, 813, 734, 698 cmꢁ1
.
MS (ES): 1187 [2M+Na]+, 583 [M+1]+ (100%), 445
[Mꢁ(TolSO)+1]+. Data for 4a: Rf ¼0.28 (0.4% EtOH/
Et2O). Mp: 62–63 ꢀC. [a]2D0 ꢁ1.3 (c 2.00). 1H NMR
(300 MHz) d 1.20 (br s, 2H, NH2), 1.59 (m, 1H, H-4), 1.75
(m, 1H, H-4), 2.70 (ap t, 2H, J¼7.9 Hz, H-5), 3.30 (m, 1H,
H-3), 3.73 (s, 3H, CO2Me), 4.40 (d, 1H, J¼7.7 Hz, H-2),
5.12 (s, 2H, OCH2Ph), 5.70 (d, 1H, J¼8.5 Hz, NH–CO),
7.14–7.20 (m, 4H, Ar-H), 7.25–7.33 (m, 6H, Ar-H). 13C
NMR (50 MHz) d 32.5, 36.2, 52.2, 52.4, 57.9, 67.1, 126.0
(2C), 128.1 (3C), 128.4, 128.5 (2C), 128.6 (2C), 136.3,
141.3, 156.6 (N–CO), 172.3 (CO2Me). IR (KBr): 3321,
3062, 3029, 2951, 2857, 1715, 1659, 1603, 1497, 1454,
1437, 1228, 1086, 1051, 1029, 774, 749, 699 cmꢁ1. MS
(ES): 357 [M+1]+ (100%). Anal. Calcd for C20H24N2O4:
C, 67.40; H, 6.79; N, 7.86. Found: C, 67.34; H, 6.63; N, 7.95.
ꢀ
ments at Instituto de Quımica Organica, CSIC (Madrid).
ꢀ
3.1.1. General procedure for the synthesis of N-benzyl-
oxycarbonyl-a,b-diaminoesters, 4a–c. The synthesis of
4a–c was performed in two steps avoiding purification of
the unstable intermediates 1e–g, therefore, just partial data
of 1e–g were obtained. Synthesis of N-benzyloxycarbonyli-
midazolidines: to a solution of 1 equiv of N-sulfinylimidazo-
lidine 1a–c in CH2Cl2 (10 mL/mmol) at 0 ꢀC was added
a solution of 1 N aqueous NaOH (4 mL/mmol) and then
0.9 equiv of CbzCl followed by three consecutive additions
of 0.2 equiv every 45 min. The mixture was allowed to warm
up to room temperature until disappearance of the starting
material (monitored by TLC) and then was diluted with
CH2Cl2 (10 mL/mmol) and water (10 mL/mmol). The layers
were separated and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with
a saturated solution of NaCl, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give crude
products 1e–g that were used without further purification.
Simultaneous solvolytic cleavage of the aminal moiety and
desulfinylation: 4 equiv of H3PO4 (from a 0.5 M aqueous so-
lution) was added to a solution of the above crude in MeOH
(18 mL/mmol of 1a–c). The mixture was stirred from 0 ꢀC to
room temperature until disappearance of the starting mate-
rial, monitored by TLC of aliquots basified with solid
NaHCO3. The reaction mixture was diluted with Et2O
(10 mL/mmol) and the layers were separated. The aqueous
layer was basified with solid K2CO3 to pH¼10–11 and
then extracted with CHCl3. Then the combined organic
extracts were dried over Na2SO4 and concentrated under
reduced pressure to give a crude product that was purified
by column chromatography on silica gel.
3.1.1.2. (L)-Methyl [(2S,3R)-3-amino-2-(benzyloxy-
carbonylamino)-4-methyl]pentanoate, 4b. From 1b
(183 mg, 0.474 mmol) and CbzCl (104 mL) according to
the general procedure (3 h), a crude product (1f) was ob-
tained that underwent reaction with H3PO4 (18 h) isolating
4b (107 mg, 0.364 mmol, 77%) after column chromato-
graphy (60–100% Et2O/hexane) as a colorless oil. Complete
characterization of 1f was carried out with a purified sample.
Data for (+)-methyl [(2S,4R,5S,SS)-1-benzyloxycarbonyl-2-
phenyl-4-(iso-propyl)-3-(p-tolylsulfinyl)-1,3-imidazolidin-
5-yl]carboxylate, 1f: Rf ¼0.26 (60% Et2O/hexane). [a]D20
1
+46.5 (c 0.40). H NMR (300 MHz) (some signals appear
broadened and display fine splittings due to the presence
of rotamers) d 0.85 (d, 3H, J¼6.6 Hz, Me i-Pr), 0.93 (d,
3H, J¼6.6 Hz, Me i-Pr), 1.24 (m, 1H, CH i-Pr), 2.39 (s,
3H, Me-Tol), 3.60+3.84 (2s, 3H, CO2Me), 3.64–3.80 (m,
1H, H-4), 4.48 (m, 1H, H-5), 4.97–5.13 (m, 2H, OCH2Ph),
6.03+6.12 (2s, 1H, H-2), 6.87 (m, 1H, Ar-H), 7.18–7.59
(m, 13H, Ar-H). 13C NMR (75 MHz) d 18.8, 20.4, 21.4,
29.4+29.7 (1C), 52.3+52.7 (1C), 63.3, 67.3+67.6 (1C),
68.9, 75.5+76.0 (1C), 126.0 (2C), 127.2 (2C), 127.4, 127.9
(2C), 128.2, 128.4 (2C), 129.6 (2C), 129.7 (2C), 135.9,
137.2, 140.5+140.3 (1C), 141.7+141.9 (1C), 153.7+153.9
(1C, N–CO), 171.4+171.7 (1C, CO2Me). IR (film): 3028,
2956, 2869, 1743, 1714, 1494, 1407, 1343, 1212, 1094,
753, 697 cmꢁ1. MS (ES): 521 [M+1]+ (100%), 383
[Mꢁ(pTolSO)+2]+. Data for 4b: Rf¼0.17 (Et2O). [a]2D0
ꢁ18.2 (c 0.55). 1H NMR (300 MHz) d 0.94 (d, 3H,
J¼6.6 Hz, Me i-Pr), 0.97 (d, 3H, J¼6.6 Hz, Me i-Pr), 1.14
3.1.1.1. (L)-Methyl [(2S,3R)-3-amino-2-(benzyl-
oxycarbonylamino)-5-phenyl]pentanoate, 4a. From 1a
(150 mg, 0.334 mmol) and CbzCl (57 mL) according to the
general procedure (25 h) was obtained a crude product (1e,
146 mg, 0.251 mmol, 75%). Then, 1e (40 mg, 0.069 mmol)
underwent reaction with H3PO4 (23 h) to produce 4a
(16 mg, 0.045 mmol, 65%) after column chromatography
(0–1% EtOH/Et2O) and crystallization as a white solid.
The complete characterization of 1e was carried out with

A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
8021
(br s, 2H, NH2), 1.52–1.61 (m, 1H, CH i-Pr), 2.90 (dd,
1H, J¼8.2, 2.3 Hz, H-3), 3.72 (s, 3H, CO2Me), 4.46 (d,
1H, J¼8.8 Hz, H-2), 5.10 (s, 2H, OCH2Ph), 5.75 (d, 1H,
J¼8.3 Hz, NH–CO), 7.33 (m, 5H, Ar-H). 13C NMR
(75 MHz) d 19.1, 19.8, 31.0, 52.4, 56.1, 58.5, 67.0, 128.0
(2C), 128.1, 128.5 (2C), 136.3, 156.5 (N–CO), 173.0
(CO2Me). IR (film): 3339, 3028, 2959, 2869, 1721, 1499,
1342, 1217, 1046, 697 cmꢁ1. MS (ES): 295 [M+1]+ (100%).
NMR (50 MHz) d 32.3, 33.5, 42.4, 51.9, 52.9, 56.7, 67.5,
126.2 (2C), 128.3 (3C), 128.4 (3C), 128.6 (2C), 135.9,
140.6, 156.3 (NH–CO2Bn), 166.0 (CO–NH), 170.7
(CO2Me). IR (KBr): 3435, 3341, 3314, 3027, 2953, 2851,
1731, 1697, 1644, 1539, 1518, 1453, 1436, 1406, 1353,
1266, 1222, 1160, 1042, 744, 706, 611, 475 cmꢁ1. MS
(ES): 455 [M+Na]+, 433 [M+1]+ (100%). Anal. Calcd for
C22H25ClN2O5: C, 61.04; H, 5.82; N, 6.47. Found: C,
60.78; H, 5.49; N, 6.46.
3.1.1.3. (L)-Methyl [(2S,3R)-3-amino-2-(benzyloxy-
carbonylamino)-3-(1-naphthyl)]propionate, 4c. From 1c
(90 mg, 0.191 mmol) and CbzCl (42 mL) according to the
general procedure (3 h), a crude product (1g) was obtained
that underwent reaction with H3PO4 (27 h) isolating 4c
(55 mg, 0.146 mmol, 77%) after column chromatography
(30–50% EtOAc/hexane) as a colorless oil. Partial data for
methyl [(2S,4R,5S,SS)-1-benzyloxycarbonyl-4-(1-naphthyl)-
2-phenyl-3-(p-tolylsulfinyl)-1,3-imidazolidin-5-yl]carboxyl-
3.1.2.2. (D)-Methyl [(2S,3R)-2-(benzyloxycarbonyl-
amino)-3-(chloroacetylamino)-4-methyl]pentanoate, 4e.
From 4b (75 mg, 0.255 mmol) and chloroacetylchloride
(41 mL) according to the general procedure (4 h) was ob-
tained chloroacetamide 4e (80 mg, 0.216 mmol, 85%) after
purification by crystallization (Et2O) as a white solid. Data
for 4e: Rf ¼0.27 (80% Et2O/hexane). Mp: 139–141 ꢀC.
[a]2D0 +81.3 (c 0.89). 1H NMR (300 MHz) (some signals ap-
pear broadened and display fine splittings due to the pres-
ence of rotamers) d 0.93 (d, 3H, J¼6.8 Hz, Me i-Pr), 1.07
(d, 3H, J¼6.3 Hz, Me i-Pr), 1.79–1.91 (m, 1H, CH i-Pr),
3.72 (s, 3H, CO2Me), 3.96+3.97 (2s, 2H, CH2Cl), 4.05
(ddd, 1H, J¼9.6, 8.3, 3.9 Hz, H-3), 4.60 (dd, 1H, J¼8.5,
3.9 Hz, H-2), 5.10 (s, 2H, OCH2Ph), 5.53 (d, 1H,
J¼9.0 Hz, NHCbz), 6.49 (d, 1H, J¼9.3 Hz, CONH), 7.30–
7.36 (m, 5H, Ar-H). 13C NMR (50 MHz) d 18.4, 19.9,
29.1, 42.5, 52.8, 55.0, 57.6, 67.4, 128.2 (2C), 128.4, 128.6
(2C), 135.9, 156.4 (NH–CO2Bn), 166.2 (N–CO), 171.4
(CO2Me). IR (KBr): 3427, 3309, 3057, 2956, 2876, 1727,
1648, 1537, 1434, 1285, 1247, 1160, 1051, 1008,
701 cmꢁ1. MS (ES): 763 [2M+Na]+, 393 [M+Na]+, 373
[M+3]+, 371 [M+1]+ (100%), 327 [Mꢁ(i-Pr)]+.
1
ate, 1g: Rf¼0.36 (80% Et2O/hexane). H NMR (300 MHz)
(some signals appear broadened and display fine splittings
due to the presence of rotamers) d 2.35+2.38 (s, 3H, Me-
Tol), 3.48+3.56 (2s, 3H, CO2Me), 5.05–5.17 (m, 2H,
OCH2Ph), 5.65+5.69 (2d, 1H, J¼3.1 Hz, H-4), 6.28+6.37
(2s, 1H, H-2). Data for 4c: Rf ¼0.26 (80% EtOAc/hexane).
1
[a]2D0 ꢁ50.0 (c 0.05). H NMR (300 MHz) d 1.58 (br s,
2H, NH2), 3.82 (s, 3H, CO2Me), 4.64 (d, 1H, J¼8.1 Hz,
H-2), 4.93 (s, 2H, OCH2Ph), 5.43 (ap s, 1H, H-3), 6.00 (d,
1H, J¼8.1 Hz, NH–CO), 7.29–7.59 (m, 8H, Ar-H), 7.64
(d, 1H, J¼7.3 Hz, Ar-H), 7.77 (d, 1H, J¼8.1 Hz, Ar-H),
7.87 (d, 1H, J¼8.5 Hz, Ar-H), 8.10 (d, 1H, J¼8.1 Hz, Ar-
H). 13C NMR (75 MHz) d 51.2, 52.7, 58.1, 66.8, 122.0,
123.2, 125.1, 125.7, 126.7 (2C), 127.4, 128.0, 128.4 (2C),
129.2 (2C), 130.4, 132.9, 133.8, 136.3, 156.3 (N–CO),
172.1 (CO2Me). IR (film): 3401, 2949, 2920, 2847, 1700,
1647, 1508, 1467, 1352, 1212, 1053, 775 cmꢁ1. MS (ES):
379 [M+1]+ (100%), 318 [MꢁCO2Me+1]+.
3.1.2.3. (D)-Methyl [(2S,3R)-2-(benzyloxycarbonyl-
amino)-3-(chloroacetylamino)-4-(1-naphthyl)]propionate,
4f. From 4c (50 mg, 0.132 mmol) and chloroacetylchloride
(21 mL) according to the general procedure (3 h) was ob-
tained chloroacetamide 4f (50 mg, 0.110 mmol, 83%) after
purification by column chromatography (10–30% EtOAc/
hexane) as a white solid. Data for 4f: Rf ¼0.22 (40%
3.1.2. General procedure for the synthesis of chloroacet-
amides 4d–f,h. To a cold (0 ꢀC) suspension of 4a–c,g in
EtOAc (10 mL/mmol) and a saturated solution of NaHCO3
(10 mL/mmol) was added 2 equiv of freshly distilled chloro-
acetylchloride. The mixture was stirred and allowed to
warm up to room temperature until disappearance of the
starting material (TLC). The layers were separated and the
aqueous phase was extracted twice with CH2Cl2. The com-
bined organic extracts were washed with a saturated solution
of NaCl, dried over Na2SO4, and filtered to give, after evap-
oration of the solvents, a crude product that was purified by
chromatography on silica gel to afford the chloroacetamide.
1
EtOAc/hexane). Mp: 125–129 ꢀC. [a]D20 +11.4 (c 0.14). H
NMR (300 MHz) d 3.54 (s, 3H, CO2Me), 3.95 (s, 2H,
CH2Cl), 4.98–5.14 (m, 3H, OCH2Ph, H-2), 5.57 (d, 1H,
J¼8.7 Hz, NH–Cbz), 6.25 (ap t, 1H, J¼6.0 Hz, H-3),
7.32–7.60 (m, 10H, NH–CO, Ar-H), 7.80–7.87 (m, 2H,
Ar-H), 8.11 (d, 1H, J¼8.1 Hz, Ar-H). 13C NMR (75 MHz)
d 42.5, 51.2, 52.8, 57.9, 67.3, 122.4, 123.8, 125.1 (2C), 126.1
(2C), 127.0, 128.2, 128.3, 128.5, 129.1, 129.3, 130.8, 133.0,
133.9, 135.9, 156.4 (NH–CO2Bn), 165.9 (N–CO), 170.2
(CO2Me). IR (KBr): 3467, 2920, 2847, 1743, 1662, 1533,
1432, 1226, 1158, 1046, 775 cmꢁ1. MS (ES): 931
[2M+Na]+, 477 [M+Na]+, 457 [M+3]+, 455 [M+1]+ (100%).
3.1.2.1. (D)-Methyl [(2S,3R)-2-(benzyloxycarbonyl-
amino)-3-(chloroacetylamino)-5-phenyl]pentanoate, 4d.
From 4a (43 mg, 0.121 mmol) and chloroacetylchloride
(19 mL) according to the general procedure (3 h) was ob-
tained chloroacetamide 4d (50 mg, 0.115 mmol, 95%) after
purification by crystallization (Et2O) as a white solid. Data
for 4d: Rf ¼0.31 (80% Et2O/hexane). Mp: 114–116 ꢀC.
3.1.2.4. (D)-Methyl [(2S)-2-(benzyloxycarbonyl-
amino)-3-(N-chloroacetylamino)piperidin-(20R)-yl]acetate,
4h. From 4g (20 mg, 0.065 mmol) and chloroacetylchloride
(11 mL) according to the general procedure (21 h) was ob-
tained chloroacetamide 4h (20 mg, 0.052 mmol, 80%) after
purification by column chromatography (30–50% Et2O/hex-
ane) and crystallization (Et2O) as a white solid. Data for 4h:
Rf ¼0.22 (80% Et2O/hexane). Mp: 95–97 ꢀC. [a]D20 +22.8 (c
0.90). 1H NMR (300 MHz) (some signals appear broadened
and display fine splittings due to the presence of rotamers)
1
[a]2D0 +69.4 (c 1.00). H NMR (300 MHz) d 1.73–1.86 (m,
1H, H-4), 1.95–2.07 (m, 1H, H-4), 2.63–2.76 (m, 2H, H-
5), 3.75 (s, 3H, CO2Me), 3.95 (s, 2H, CH2Cl), 4.42 (ddd,
1H, J¼13.4, 9.4, 5.0 Hz, H-3), 4.53 (m, 1H, H-2), 5.13 (s,
2H, OCH2Ph), 5.58 (d, 1H, J¼7.6 Hz, NH–Cbz), 6.52 (d,
1H, J¼9.3 Hz, CO–NH), 7.15–7.36 (m, 10H, Ar-H). 13C

8022
A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
d 1.60 (m, 6H, piperidine-H), 3.25 (td, 1H, J¼13.9, 2.9 Hz,
pip-H-60ax), 3.58 (dd, 1H, J¼14.2, 3.7 Hz, pip-H-60eq),
3.74+3.77 (2s, 3H, CO2Me), 3.89 (s, 2H, CH2Cl), 4.76
(dd, 1H, J¼11.0, 9.0 Hz, H-2), 4.84 (dd, 1H, J¼11.0,
4.2 Hz, pip-H-20), 5.01 (d, 1H, J¼12.2 Hz, OCH2Ph), 5.08
(d, 1H, J¼12.2 Hz, OCH2Ph), 5.47 (d, 1H, J¼8.8 Hz, NH–
CO), 7.28–7.35 (m, 5H, Ar-H). 13C NMR (75 MHz)
d 18.9, 25.3, 25.6, 41.0, 42.7, 50.2, 52.5, 53.9, 67.0, 128.2
(2C), 128.2, 128.5 (2C), 136.2, 156.0 (NH–CO2Bn), 167.3
(N–CO), 171.0 (CO2Me). IR (KBr): 3467, 3231, 3057,
2949, 2862, 1741, 1716, 1639, 1556, 1433, 1311, 1252,
1198, 1022, 754, 699 cmꢁ1. MS (ES): 385 [M+3]+, 383
[M+1]+ (100%). Anal. Calcd for C18H23ClN2O5: C, 56.47;
H, 6.06; N, 7.32. Found: C, 56.71; H, 6.30; N, 7.46.
1H, J¼19.0, 18.6 Hz, H-6), 4.93+5.08 (2d, 1H, J¼1.7 Hz,
H-2), 5.15+5.18 (2s, 2H, OCH2Ph), 6.86 (br s, 1H, CO–
NH), 7.34 (m, 5H, Ar-H). H NMR (CD3OD, 300 MHz)
1
d 1.11+1.17 (2d, 3H, J¼6.8 Hz, Me i-Pr), 1.17+1.19 (2d,
3H, J¼6.8 Hz, Me i-Pr), 1.94 (ap hept, 1H, J¼6.8 Hz, CH
i-Pr), 3.62+3.67 (2dd, 1H, J¼8.5, 1.3 Hz, H-3), 3.91+3.95
(2s, 3H, CO2Me), 4.13+4.21 (2d, 1H, J¼18.5, 18.1 Hz, H-
6), 4.31+4.38 (2d, 1H, J¼18.5, 18.1 Hz, H-6), 5.19+5.24
(2d, 1H, J¼1.3 Hz, H-2), 5.33–5.44 (m, 2H, OCH2Ph),
7.51–7.57 (m, 5H, Ar-H). DNOE between H-2 and H-3:
6.0%, H-2 and H (i-Pr): 2.6%, H-3 and NH: 5.7%, H-3 and
H-2: 5.2%. 13C NMR (75 MHz) d 18.8, 19.2+19.3 (1C),
32.7+32.9 (1C), 45.7, 53.0, 53.5+54.1 (1C), 58.6+58.7
(1C), 67.9+68.0 (1C), 127.7+128.0 (2C), 128.3+128.4 (1C),
128.6 (2C), 135.7+135.8 (1C), 154.6+155.4 (1C, N–CO2Bn),
167.0+167.3 (NH–CO), 170.3 (CO2Me). IR (film): 3427,
2963, 1743, 1667, 1456, 1411, 1320, 1261, 1211, 1110,
1012, 778, 701 cmꢁ1. MS (ES): 691 [2M+Na]+, 669
[2M+1]+, 357 [M+Na]+, 335 [M+1]+ (100%).
3.1.3. General procedure for the synthesis of ketopipera-
zines, 5a–d. A solution of chloroacetamide 4d–f,h in DMF
(10 mL/mmol) and 1.8 equiv of solid Cs2CO3 was stirred at
65 ꢀC until disappearance of the starting material monitored
by TLC. The reaction mixture was cooled down to room tem-
perature and diluted with CH2Cl2 and H2O. The layers were
separated and the organic phase was washed with cold water
and a saturated solution of NaHCO3, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure to give
a crude product that was purified by column chromatography.
3.1.3.3. (L)-Methyl [(2S,3R)-1-benzyloxycarbonyl-3-
(1-naphthyl)-5-oxopiperazin-2-yl]carboxylate, 5c. From
4f (15 mg, 0.033 mmol) and Cs2CO3 (19 mg) according to
the general procedure (4 h 30 min) was obtained after puri-
fication by chromatography (30–50% EtOAc/hexane) 5c
(8 mg, 0.019 mmol, 57%) as a colorless oil. Data for
5c: Rf¼0.18 (50% EtOAc/hexane). [a]2D0 ꢁ67.7 (c 0.26).
1H NMR (300 MHz) (some signals appear broadened and
display fine splittings due to the presence of rotamers)
d 3.88+3.91 (2s, 3H, CO2Me), 4.14+4.23 (2d, 1H,
J¼18.7 Hz, H-6ax), 4.53+4.69 (2d, 1H, J¼18.7 Hz, H-6eq),
4.60 (m, 1H, OCH2Ph), 4.97 (m, 1H, OCH2Ph), 5.27+5.29
(2s, 1H, H-2), 6.01+6.02 (2d, 1H, J¼6.0 Hz, H-3), 6.33 (d,
1H, J¼7.1 Hz, Ar-H), 6.47 (m, 1H, CO–NH), 6.98 (t, 1H,
J¼7.7 Hz, Ar-H), 7.09–7.21 (m, 1H, Ar-H), 7.28–7.64 (m,
7H, Ar-H), 7.83 (t, 1H, J¼7.9 Hz, Ar-H), 7.90+7.96 (2d,
1H, J¼7.6 Hz, Ar-H), 8.03+8.07 (2d, 1H, J¼8.6 Hz, Ar-
H). DNOE between H-3 and H-2: 6.5%, H-3 and NH:
8.5%, H-3 and ArH-8: 17%, H-2 and H-3: 3.4%, H-2
and ArH-8: 5.1%. 13C NMR (75 MHz) d 45.4+45.8
(1C), 53.4, 53.6+54.0 (1C), 56.9+57.3 (1C), 67.5+67.9 (1C),
121.3+121.5 (1C), 123.4+123.9 (1C), 125.0+125.3 (1C),
126.2, 126.9, 127.4, 127.7+128.0 (2C), 128.0+128.5
(1C), 129.3+129.4 (2C), 129.5+129.6 (1C), 133.7, 134.0,
135.2, 135.6, 154.2+155.2 (1C, N–CO2Bn), 167.4+167.6
(1C, NH–CO), 169.2+169.9 (1C, CO2Me). IR (film): 3459,
2949, 1747, 1707, 1679, 1418, 1411, 1317, 1268, 1212,
1010, 779, 699 cmꢁ1. MS (ES): 859 [2M+Na]+, 837
[2M+1]+, 441 [M+Na]+, 419 [M+1]+ (100%).
3.1.3.1. (D)-Methyl [(2S,3R)-1-benzyloxycarbonyl-5-
oxo-3-(2-phenylethyl)piperazin-2-yl]carboxylate,
5a.
From 4d (40 mg, 0.092 mmol) and Cs2CO3 (55 mg) accord-
ing to the general procedure (3 h) was obtained 5a (36 mg,
0.091 mmol, 99%) after purification by chromatography
(20–50% EtOAc/hexane) as a colorless oil. Data for 5a:
Rf¼0.24 (60% EtOAc/hexane). [a]2D0 +14.3 (c 0.50). 1H
NMR (400 MHz) (some signals appear broadened and dis-
play fine splittings due to the presence of rotamers) d 1.87–
1.96 (m, 2H, H-10), 2.70 (t, 2H, J¼7.8 Hz, H-20), 3.70+3.74
(2s, 3H, CO2Me), 3.84+3.89 (m, 1H, H-3), 4.05+4.11 (2d,
1H, J¼18.6, 19.3 Hz, H-6), 4.30+4.32 (2d, 1H, J¼18.6,
19.3 Hz, H-6), 4.83+5.00 (2d, 1H, J¼1.4 Hz, H-2),
5.17+5.20 (2s, 2H, OCH2Ph), 6.23 (br s, 1H, CO–NH),
7.07 (d, 1H, J¼6.8 Hz, Ar-H), 7.14 (d, 1H, J¼6.8 Hz, Ar-
H), 7.20–7.36 (m, 8H, Ar-H). 13C NMR (75 MHz) d 32.7,
37.7+37.8 (1C), 46.6, 52.9+53.0 (1C), 53.7, 56.1+56.9
(1C), 68.7+68.9 (1C), 127.1 (2C), 128.6 (2C), 129.0, 129.1,
129.3 (2C), 129.4 (2C), 136.4, 140.7, 155.5+156.3 (1C,
CO-Cbz), 167.1+167.4 (1C, N–CO), 170.4 (CO2Me). IR
(film): 3423, 2956, 2920, 2847, 1743, 1677, 1436, 1326,
1265, 1021, 799 cmꢁ1. MS (ES): 793 [2M+1]+, 419
[M+Na]+, 397 [M+1]+ (100%).
3.1.3.2. (L)-Methyl [(2S,3R)-1-benzyloxycarbonyl-3-
(iso-propyl)-5-oxopiperazin-2-yl]carboxylate, 5b. From
4e (42 mg, 0.113 mmol) and Cs2CO3 (66 mg) according to
the general procedure (4 h) was obtained after purification
by chromatography (20–40% EtOAc/hexane) 5b (20 mg,
0.060 mmol, 53%) as a white foam. Data for 5b: Rf¼0.22
(70% EtOAc/hexane). [a]2D0 ꢁ5.2 (c 0.82). 1H NMR
(300 MHz) (some signals appear broadened and display
fine splittings due to the presence of rotamers) d 0.90+0.97
(2d, 3H, J¼6.6 Hz, Me i-Pr), 0.99 (d, 3H, J¼6.6 Hz, Me i-
Pr), 1.69–1.80 (m, 1H, CH i-Pr), 3.43+3.50 (2ddd, 1H,
J¼8.7, 4.9, 1.7 Hz, H-3), 3.70+3.74 (2s, 3H, CO2Me),
4.02+4.09 (2d, 1H, J¼19.0, 18.6 Hz, H-6), 4.24+4.25 (2d,
3.1.3.4. (L)-Methyl [(1S,8aR)-2-(benzyloxycarbonyl)-
4-oxoperhydropyrido[1,2-a]piperazin-1-yl]carboxylate,
5d. From 4h (30 mg, 0.078 mmol) and Cs2CO3 (46 mg) ac-
cording to the general procedure (4 h 30 min) was obtained
5d (25 mg, 0.072 mmol, 93%) as a colorless oil after purifi-
cation by chromatography (20–50% Et2O/hexane). Data for
5d: Rf¼0.13 (80% Et2O/hexane). [a]2D0 ꢁ6.3 (c 0.91). H
1
NMR (300 MHz) (some signals appear broadened and dis-
play fine splittings due to the presence of rotamers)
d 1.41–1.97 (m, 6H, pip-H), 2.53 (ap t, 1H, J¼12.7 Hz, H-
5ax), 3.71+3.75 (2s, 3H, CO2Me), 3.88+3.93 (2d, 1H,
J¼15.0 Hz, H-8a), 3.93+3.98 (2d, 1H, J¼16.5 Hz, H-3ax),
4.39+4.44 (2d, 1H, J¼16.5 Hz, H-3eq), 4.64 (br d, 1H,

A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
8023
J¼12.7 Hz, H-5eq), 4.69+4.82 (2 br s, 1H, H-1), 5.18 (s, 2H,
OCH2Ph), 7.35 (m, 5H, Ar-H). 13C NMR (75 MHz) d 24.6,
24.9, 31.7, 44.8, 45.5+45.6 (1C), 53.0, 56.4+57.2 (1C), 57.7,
68.1, 127.9 (2C), 128.3, 128.6 (2C), 135.7, 155.8 (NH–
CO2Bn), 163.2+163.5 (1C, N–CO), 169.6 (CO2Me). IR
(film): 2925, 2854, 1744, 1711, 1651, 1432, 1325, 1261,
2H, J¼7.3, 3.7 Hz, Ar-H), 7.53 (d, 2H, J¼7.9 Hz, Ar-H),
7.61 (t, 2H, J¼8.4 Hz, Ar-H), 7.73 (dd, 2H, J¼7.5, 4.4 Hz,
Ar-H), 7.76 (d, 2H, J¼8.4 Hz, Ar-H).
3.1.6. Synthesis of methyl (2S)-[2-(tert-butoxycarbonyl-
amino)-2-piperidin-(20R)-yl]acetate, 4i. Compound 2c
(46 mg, 0.079 mmol) in MeOH (1.5 mL) was treated with
a 0.5 M solution of aqueous H3PO4 (0.63 mL, 0.316 mmol)
according to the procedure for the simultaneous solvolytic
cleavage of the aminal moiety and desulfinylation (21 h).
Then, the mixture was basified with solid K2CO3 (45 min
at 0 ꢀC) isolating after chromatography (5–20% EtOH/
Et2O) 4i (13 mg, 0.048 mmol, 60%) as a white foam and 4j
(4 mg, 0.013 mmol, 17%) as a white solid. Alternatively
when 1 N NaOH was used (0 ꢀC, 1 h 30 min), 4i (10 mg,
0.037 mmol, 42%) was produced as a single product after pu-
rification. Data for 4i: Rf¼0.22 (20% EtOH/Et2O). 1H NMR
(300 MHz) (some signals appear broadened and display fine
splittings due to the presence of rotamers) d 1.30–1.45 (m,
12H, 3H, pip-H, 9H, t-Bu Boc), 1.60 (m, 2H, pip-H), 1.78
(m, 1H, pip-H), 2.62 (ap t, 1H, J¼11.6 Hz, pip-H-60ax),
3.12 (m, 2H, pip-H-20, pip-H-60eq), 3.76 (s, 3H, CO2Me),
4.24 (ap d, 1H, J¼5.5 Hz, H-2), 5.82 (d, 1H, J¼6.8 Hz,
NH–CO). 13C NMR (50 MHz) d 23.8, 24.9, 28.3 (3C), 28.7,
46.4, 52.6, 57.4 (2C), 79.9, 156.1 (N–CO2t-Bu), 172.2
(CO2Me). MS (ES): 295 [M+Na]+, 273 [M+1]+ (100%).
1230, 1126, 1074, 1003, 955, 915, 752, 698, 504 cmꢁ1
MS (ES): 369 [M+Na]+, 347 [M+1]+ (100%).
.
3.1.4. Synthesis of (D)-methyl [(2S,3R,SS)-2-(tert-butoxy-
carbonylamino)-3-(p-tolylsulfinylamino)-7-(p-tolylsulfo-
nyloxy)]heptanoate, 2c. To a solution of 2a (46 mg,
0.095 mmol) in CH2Cl2 (2 mL) at 0 ꢀC, was added 1 N
NaOH (2 mL/mmol) and 1.1 equiv of Boc2O (23 mg,
0.105 mmol) in CH2Cl2 (0.2 mL). The mixture was allowed
to warm up to room temperature until total disappearance of
the starting material (4 h) monitored by TLC. The mixture
was partitioned with H2O (5 mL) and CH2Cl2 (5 mL). The
layers were separated and the aqueous phase was extracted
with CHCl3. The combined organic extracts were washed
with a saturated solution of NaCl, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude
product that was purified by column chromatography (30–
40% EtOAc/hexane). Compound 2c (36 mg, 0.062 mmol,
65%) was obtained as a colorless oil. Data for 2c: Rf ¼0.32
(60% EtOAc/hexane). [a]2D0 +70.5 (c 1.02). 1H NMR
(400 MHz) d 1.42 (s, 9H, t-Bu Boc), 1.44–1.62 (m, 6H, H-
6, H-5, H-4), 2.39 (s, 3H, Me-Tol), 2.42 (s, 3H, Me-Ts),
3.77 (s, 3H, CO2Me), 3.77 (m, 1H, H-3), 3.92 (d, 1H,
J¼7.5 Hz, S–NH), 3.97 (m, 2H, H-7), 4.39 (br d, 1H,
J¼7.0 Hz, H-2), 5.46 (d, 1H, J¼8.6 Hz, NH–CO), 7.28 (d,
2H, J¼8.1 Hz, Ar-H), 7.32 (d, 2H, J¼8.1 Hz, Ar-H), 7.50
(d, 2H, J¼8.2 Hz, Ar-H), 7.76 (d, 2H, J¼8.2 Hz, Ar-H).
13C NMR (75 MHz) d 21.3, 21.6, 26.9, 28.2 (3C, Me t-Bu
Boc), 28.4, 32.5, 52.7, 57.0 (2C), 70.1, 80.3, 125.5 (2C),
127.9 (2C), 129.6 (2C), 129.9 (2C), 133.1, 141.5, 141.7,
144.7, 155.9 (N–CO2t-Bu), 171.5 (CO). IR (film): 3289,
2927, 2855, 1743, 1710, 1523, 1450, 1364, 1208, 1175,
1049, 1010, 811 cmꢁ1. MS (ES): 1187 [2M+Na]+, 605
[M+Na]+, 583 [M+1]+, 445 [Mꢁ(pTolSO)+2]+ (100%),
273 [Mꢁ(pTolSO)ꢁOTs+1]+.
3.1.7. Synthesis of (L)-2-(tert-butyl)-1-methyl (1S,8aR)-
3-oxohexahydroimidazo[1,5-a]pyridin-1,2-(3H)dicar-
boxylate, 4j. To a solution of 0.3 equiv of Cl3COC(O)OCCl3
(1 mg, 0.004 mmol) in CH2Cl2 (0.5 mL) at ꢁ78 ꢀC was
added a solution of 1.0 equiv of 4i (4 mg, 0.015 mmol) and
3.0 equiv of NEt3 (6 mL, 0.044 mmol) in CH2Cl2 (2 mL).
The mixture was allowed to warm up to room temperature
(2 h, monitored by TLC) and then was washed with saturated
solution of NaCl (2 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure to give a crude that
was purified by column chromatography (40–50% EtOAc/
hexane) to isolate 4j (4 mg, 0.013 mmol, 91%) as a white
solid. Data for 4j: Rf¼0.24 (60% EtOAc/hexane). [a]D20
ꢁ28.6 (c 0.36). 1H NMR (300 MHz) d 1.41 (m, 3H, pip-H),
1.48 (s, 9H, t-Bu Boc), 1.61 (m, 1H, pip-H), 1.90 (m, 2H,
pip-H), 2.71 (td, 1H, J¼12.5, 3.7 Hz, H-5ax), 3.38 (dt, 2H,
J¼10.8, 3.7 Hz, H-5eq), 3.76 (s, 3H, CO2Me), 3.98 (ap dd,
1H, J¼13.5, 4.2 Hz, H-8a), 4.18 (d, 1H, J¼4.1 Hz, H-1).
13C NMR (75 MHz) d 23.2, 24.3, 28.0 (3C, Me t-Bu Boc),
31.6, 41.0, 52.7, 55.1, 60.0, 82.9, 150.2 (N–CO–N), 151.8
(N–CO2t-Bu), 170.3 (CO2Me). IR (KBr): 2920, 2847,
2572, 2000, 1747, 1707, 1447, 1367, 1150, 858 cmꢁ1. MS
(ES): 619 [2M+Na]+, 321 [M+Na]+ (100%).
3.1.5. Synthesis of methyl [(2S,3R,SS)-2-(9H-fluoren-9-yl-
methoxycarbonylamino)-3-(p-tolylsulfinylamino)-7-(p-
tolylsulfonyloxy)]heptanoate, 2d. To a solution of 2a
(74 mg, 0.153 mmol) in dioxane was added a solution of
10% aqueous Na2CO3 (0.46 mL) and 1.0 equiv of FmocCl
(40 mg, 0.153 mmol) at 0 ꢀC. The mixture was stirred at
room temperature until disappearance of the starting material
monitored by TLC (4 h). Then it was diluted with H2O
(5 mL) and the aqueous layer was extracted with Et2O
(5 mL), brought to pH¼2with 0.5 M aqueous H3PO4, and ex-
tracted with EtOAc (2ꢂ5 mL). The organic extracts were
washed with H2O, dried over Na2SO4, filtered, and concen-
trated under reduced pressure to yield after purification by
chromatography (20–40% EtOAc/hexane) 2d (44 mg,
0.063 mmol, 41%) as a colorless oil. Partial data for 2d:
Rf¼0.24 (50% EtOAc/hexane). 1H NMR (300 MHz)
d 1.41–1.59 (m, 6H, H-6, H-5, H-4), 2.40 (s, 6H, Me-Tol,
Me-Ts), 3.78 (s, 3H, CO2Me), 3.78 (m, 1H, H-3), 3.97 (m,
2H, H-7), 4.04 (m, 1H, S–NH), 4.22 (t, 1H, J¼7.2 Hz, NH–
Fmoc), 4.41 (m, 3H, H-2, CH2-Fmoc), 6.04 (d, 1H,
J¼8.4 Hz, NH–CO), 7.28–7.32 (m, 6H, Ar-H), 7.37 (td,
3.1.8. Synthesis of (D)-methyl (2S)-[2-(benzyloxycarbo-
nylamino)-2-(N-tert-butoxycarbonyl)piperidin-(20R)-
yl]acetate, 4k. To a solution of 4g (480 mg, 1.569 mmol) in
dioxane/H2O 1:1 (10 mL/mmol) at 0 ꢀC were added
1.2 equiv of NEt3 (0.26 mL, 1.882 mmol) and 1.1 equiv of
a solution of Boc2O 1 M (376 mg, 1.73 mL, 1.725 mmol)
in THF. The mixture was allowed to warm up to room tem-
perature until disappearance of the starting material (15 h)
monitored by TLC and then the organic layer was concen-
trated under reduced pressure. The aqueous phase was ex-
tracted with CHCl3 and the combined organic extracts
were washed with a saturated solution of NaCl, dried over

8024
A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
Na2SO4, filtered, and concentrated under reduced pressure to
give a crude product that was purified by column chromato-
graphy (10–20% Et2O/hexane) to obtain 4k (522 mg,
1.286 mmol, 82%) as a colorless oil. Data for 4k: Rf ¼0.14
(40% Et2O/hexane). [a]2D0 +9.9 (c 0.89). 1H NMR
(300 MHz) (some signals appear broadened and display
fine splittings due to the presence of rotamers) d 1.41 (m,
9H, t-Bu Boc), 1.45–1.65 (m, 6H, pip-H), 2.80 (t, 1H,
J¼12.5 Hz, pip-H-60ax), 3.73 (s, 3H, CO2Me), 3.95 (m,
1H, pip-H-60eq), 4.45 (m, 1H, pip-H-20), 4.68+4.72 (2d,
1H, J¼9.0 Hz, H-2), 5.06 (s, 2H, OCH2Ph), 5.73 (m, 1H,
NH–CO), 7.25–7.34 (m, 5H, Ar-H). 13C NMR (50 MHz)
d 18.9, 24.8, 25.7, 28.2 (3C), 40.0, 50.9, 52.3, 54.1, 66.8,
80.2, 127.8 (2C), 127.9, 128.3 (2C), 136.2, 155.9 (N–
CO2t-Bu), 155.9 (NH–CO2Bn), 171.7 (CO2Me). IR (film):
3362, 2934, 2862, 1726, 1682, 1515, 1493, 1457, 1413,
1366, 1309, 1272, 1172, 1042, 873, 699 cmꢁ1. MS (ES):
832 [2M+Na]+, 429 [M+Na]+ (100%), 307 [MꢁBoc+2]+.
(CD3OD, 75 MHz) d 20.4, 26.3, 27.3, 28.8 (3C),
40.1+41.2 (1C), 52.7, 54.9 (2C), 81.6, 157.7 (N–CO2t-Bu),
176.2 (CO2Me). IR (film): 3400, 2935, 2862, 1739, 1714,
1692, 1414, 1368, 1270, 1162, 1060 cmꢁ1. MS (ES): 295
[M+Na]+, 273 [M+1]+ (100%), 217 [Mꢁt-Bu+2]+.
3.1.11. Peptide coupling. (D)-tert-Butyl (2R)-2-[(1S)-1-
({(2S)-2-(benzyloxycarbonyl)amino-2-[1-(tert-butoxy-
carbonyl)piperidin-(2R)-yl]acetyl}amino)-2-methoxy-2-
oxoethyl]piperidin-1-yl carboxylate, 7a. To a solution of
1 equiv of acid 4l (216 mg, 0.550 mmol) and 1 equiv of
amine 4m (150 mg, 0.550 mmol) in CH2Cl2 (8 mL/mmol)
at 0 ꢀC, was added 1.2 equiv of a solution of BOP (292 mg,
0.660 mmol) in CH2Cl2 (1.2 mL/mmol) and 2.5 equiv of DI-
PEA (0.24 mL, 1.376 mmol). The reaction mixture was al-
lowed to warm up to room temperature (monitored by
TLC) and then it was diluted with EtOAc (10 mL). The or-
ganic phase was washed with a 0.5 M solution of H3PO4,
with saturated solution of NaHCO3 and with brine, dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography (20–30% EtOAc/hexane) to give 7a (347 mg,
0.537 mmol, 98%) as a white foam. Data for 7a: Rf¼0.24
(40% EtOAc/hexane). [a]2D0 +10.0 (c 0.30). 1H NMR
(300 MHz) (some signals appear broadened and display
fine splittings due to the presence of rotamers) d 1.38 (s,
9H, t-Bu Boc), 1.45 (s, 9H, t-Bu Boc), 1.45–1.65 (m, 11H,
pip-H), 1.79 (m, 1H, pip-H), 2.79 (m, 2H, pip-H-6ax, pip-
H-600ax), 3.69+3.70 (2s, 3H, OMe), 3.93 (m, 2H, pip-H-6eq,
pip-H-600eq), 4.42 (m, 3H, pip-H-200, pip-H-2, CHNHCbz),
4.76 (m, 1H, H-10), 5.03 (m, 2H, OCH2Ph), 5.37+5.61 (2 br
s, 1H, NH–CO2Bn), 7.28 (m, 5H, Ar-H). 1H NMR
(CD3OD, 300 MHz) d 1.44 (s, 9H, t-Bu Boc), 1.46 (s, 9H,
t-Bu Boc), 1.56–1.83 (m, 12H, pip-H), 2.97 (m, 2H, pip-H-
6ax, pip-H-600ax), 3.78 (s, 3H, OMe), 3.98 (m, 2H, pip-H-
6eq, pip-H-600eq), 4.40 (m, 1H, pip-H-200), 4.51 (m, 1H,
pip-H-2), 4.67+4.71 (2d, 1H, J¼10.0 Hz, CHNHCbz), 5.07
(m, 3H, H-10, OCH2Ph), 6.54 (br s, 1H, NH–CO2Bn), 7.36
(m, 5H, Ar-H), 8.55 (s, 1H, NH–CO). 13C NMR (50 MHz)
d 19.1, 19.3, 24.8, 25.0, 25.5, 26.0, 28.3 (6C), 39.8, 40.2, 51.0,
51.7, 52.3, 53.5, 54.4, 66.7+66.9 (1C), 80.1, 80.7, 127.8 (2C),
127.9, 128.3 (2C), 136.2+136.3 (1C), 155.7 (2C, N–CO2t-
Bu), 156.2 (NH–CO2Bn), 170.7 (CO–NH), 171.1 (CO2Me).
IR (KBr): 3333, 2936, 2862, 1740, 1690, 1515, 1416, 1366,
1311, 1273, 1039, 890, 755 cmꢁ1. MS (ES): 1316
[2M+Na]+, 669 [M+Na]+, 217 [MꢁCO2t-Bu+2]+ (100%).
3.1.9. Synthesis of (D)-(2S)-[2-(benzyloxycarbonyl-
amino)-2-(N-tert-butoxycarbonyl)piperidin-(20R)-yl]ace-
tic acid, 4l. To a solution of 4k (224 mg, 0.552 mmol) in
THF/H2O 1:1 (10 mL/mmol) at 0 ꢀC was added 1.2 equiv
of LiOH/H2O (46 mg, 1.103 mmol). The reaction mixture
was stirred from 0 ꢀC to room temperature (15 h) and disap-
pearance of the starting material was monitored by TLC. The
organic layer was evaporated under reduced pressure and the
aqueous phase was washed with CH2Cl2, brought to pH¼2–
3 with 0.5 M H3PO4 solution, and extracted with EtOAc.
The combined organic extracts were dried over Na2SO4, fil-
tered, and evaporated under reduced pressure to produce 4l
(216 mg, 0.550 mmol, 100%) as white foam that was used
without further purification. Data for 4l: [a]2D0 +14.3 (c
0.44). 1H NMR (500 MHz) (some signals appear broadened
and display fine splittings due to the presence of rotamers)
d 1.39 (s, 9H, t-Bu Boc), 1.62 (m, 5H, pip-H), 1.80 (m,
1H, pip-H), 2.80 (t, 1H, J¼12.7 Hz, pip-H-60ax), 3.94 (br
d, 1H, J¼12.2 Hz, pip-H-60eq), 4.42 (br d, 1H, J¼7.8 Hz,
pip-H-20), 4.68+4.70 (2d, 1H, J¼9.8 Hz, H-2), 5.07 (m,
2H, OCH2Ph), 5.60+5.75 (2 br s, 1H, NH–CO), 6.94 (br s,
CO2H), 7.29 (m, 5H, Ar-H). 13C NMR (125 MHz) d 19.0,
24.8, 25.8, 28.3 (3C), 39.9, 51.3, 54.0, 67.0, 80.6, 127.9
(2C), 128.0, 128.4 (2C), 136.1, 156.2 (N–CO2t-Bu), 156.2
(NH–CO2Bn), 175.2 (CO2H). IR (film): 3304, 2929, 2855,
1724, 1687, 1515, 1415, 1270, 1161, 1042 cmꢁ1. MS
(ES): 807 [2M+Na]+, 415 [M+Na]+ (100%).
3.1.10. Synthesis of (D)-methyl (2S)-[2-amino-2-(N-tert-
butoxycarbonyl)piperidin-(20R)-yl]acetate, 4m. To a solu-
tion of 4k (283 mg, 0.697 mmol) in MeOH/H2O 5:1 (35 mL)
was added Pd–C 10% (52 mg) and was hydrogenated at
45 psi monitoring the reaction by TLC (4 h 30 min). The
mixture was filtered through Celite and the solvents were
evaporated under reduced pressure to give a crude product
that was purified by column chromatography (0–4%
EtOH/Et2O) to afford 4m (189 mg, 0.693 mmol, 100%) as
a colorless oil. Data for 4m: Rf¼0.22 (4% EtOH/Et2O).
[a]2D0 +2.2 (c 0.36). 1H NMR (CD3OD, 400 MHz) (some sig-
nals appear broadened and display fine splittings due to the
presence of rotamers) d 1.47 (m, 1H, pip-H), 1.51 (s, 9H,
t-Bu Boc), 1.65 (m, 5H, pip-H), 2.86 (m, 1H, H-60ax), 3.79
(s, 3H, CO2Me), 3.86 (d, 1H, J¼10.6 Hz, H-2), 4.05 (br d,
1H, J¼13.2 Hz, H-60eq), 4.32 (m, 1H, H-20). 13C NMR
3.1.12. Synthesis of (D)-tert-butyl (2R)-2-[(1S)-1-({(2S)-
2-amino-2-[1-(tert-butoxycarbonyl)piperidin-(2R)-yl]-
acetyl}amino)-2-methoxy-2-oxoethyl]piperidin-1-yl car-
boxylate, 7b. From 7a (83 mg, 0.128 mmol) in MeOH/
H2O 5:1 (5 mL) and Pd–C 10% (10 mg) according to the pro-
cedure described for 4l (4 h) was isolated 7b (57 mg,
0.111 mmol, 87%) as a white solid after purification by col-
umn chromatography (70% EtOAc/CH2Cl2). Data for 7b:
Rf¼0.24 (EtOAc). Mp: 134–137 ꢀC. [a]D20 +60.2 (c 0.13).
1H NMR (300 MHz) (some signals appear broadened and
display fine splittings due to the presence of rotamers)
d 1.46 (s, 9H, t-Bu Boc), 1.48 (s, 9H, t-Bu Boc), 1.57–1.64
(m, 11H, pip-H), 1.88 (m, 1H, pip-H), 2.70 (m, 2H, pip-
H-6ax, H-600ax), 3.63 (m, 1H, CHNH2), 3.73+3.74 (2s, 3H,
OMe), 4.02 (m, 2H, pip-H-6eq, pip-H-600eq), 4.14 (m, 1H,
pip-H-200), 4.52 (m, 1H, pip-H-2), 4.80+4.82 (2d, 1H,

A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
8025
J¼7.7 Hz, H-10), 7.74 (br s, 1H, NH–CO). 1H NMR (CD3OD,
400 MHz) d 1.51 (s, 9H, Me t-Bu Boc), 1.53 (s, 9H, Me t-Bu
Boc), 1.63–1.73 (m, 12H, pip-H), 2.88 (m, 2H, pip-H-6ax,
pip-H-600ax), 3.72 (d, 1H, J¼10.3 Hz, CHNH2), 3.79 (s, 3H,
OMe), 4.02 (ap t, 2H, J¼15.1 Hz, pip-H-6eq, pip-H-600eq),
4.24 (m, 1H, pip-H-200), 4.52 (m, 1H, pip-H-2), 4.98 (d, 1H,
J¼10.6 Hz, H-10). 13C NMR (75 MHz) d 19.1, 19.5, 24.8,
25.0, 25.5, 26.0, 28.4 (6C), 39.7, 40.2, 50.9 (2C),
52.3+52.4 (1C), 53.3, 54.0, 80.1+80.3 (1C), 80.5+80.6
(1C), 156.0 (N–CO2t-Bu), 156.7 (N–CO2t-Bu), 171.1 (CO–
NH), 171.3 (CO2Me). IR (KBr): 3340, 2935, 2862, 1745,
mixture that was purified by column chromatography (0–
2% MeOH/CH2Cl2) and crystallization (CH2Cl2/hexane) to
afford 8a (6 mg, 0.012 mmol, 22%) as a white solid. (b) To
a solution of 7b (52 mg, 0.102 mmol) in DMF (2 mL) was
added 1.8 equiv of KCN (12 mg, 0.182 mmol). The mixture
was stirred at 80 ꢀC for 60 h and then was added 2.0 equiv
more of KCN (14 mg, 0.204 mmol). After 72 h (monitored
by TLC) the reaction was diluted with Et2O (4 mL) and
washed with a saturated solution of NaCl, 0.5 M aqueous
solution of H3PO4, and a saturated solution of NaHCO3.
Finally, the combined aqueous layers were extracted with
CHCl3 and the organic phases were dried over Na2SO4,
filtered, and concentrated under reduced pressure to give
a crude product that was purified by column chromatography
(0–2% MeOH/CH2Cl2) to yield 8a (14 mg, 0.030 mmol,
29%) as a white solid. Subsequently, from a solution of 8a
(20 mg, 0.042 mmol) in CH2Cl2/TFA (0.4 mL) according
to the procedure for 7d, was isolated 8b$2TFA (15 mg,
0.031 mmol, 75%) after crystallization (Et2O/CH2Cl2) as a
white solid. Data for di(tert-butyl) (2R,20R)-2,20-[3,6-dioxo-
piperazino-(2S,5S)-diyl] dipiperidine-1-carboxylate, 8a:
Rf ¼0.14 (5% MeOH/CH2Cl2). MS (ES): 503 [M+Na]+
1689, 1416, 1366, 1310, 1274, 1163, 1038, 869, 755 cmꢁ1
.
MS (ES): 1025 [2M+1]+, 535 [M+Na]+, 513 [M+1]+
(100%). Anal. Calcd for C25H44N4O7: C, 58.57; H, 8.65;
N, 10.93. Found: C, 58.69; H, 8.79; N, 10.64.
3.1.13. Synthesis of (D)-(2R)-2-{(1S)-1-ammonium-2-
[{(1S)-2-methoxy-2-oxo-1-[piperidinium-(2R)-yl]ethyl}-
amino]-2-oxoethyl}piperidinium tris(trifluoroacetate),
7d$3TFA. N-Boc 7b (52 mg, 0.102 mmol) was dissolved
in a mixture of CH2Cl2/TFA 1:1 (10 mL/mmol) and was
stirred at 0 ꢀC (2 h). The solvent was evaporated under re-
duced pressure and the residue was redissolved in toluene
and concentrated (three times) to remove the excess of
TFA. Crystallization (Et2O) of this crude afforded 7d$3TFA
(50 mg, 0.076 mmol, 75%) as white solid. Data for 7d: [a]D20
1
(100%). Data for 8b$2TFA: H NMR (CD3OD, 500 MHz)
d 1.57–1.64 (m, 4H, pip-H), 1.72–1.75 (m, 2H, pip-H),
1.93–1.95 (m, 2H, pip-H), 2.02–2.06 (m, 4H, pip-H), 3.02
(ap t, 2H, J¼12.2 Hz, pip-H-60ax, pip-H-600ax), 3.42 (ap d,
2H, J¼9.8 Hz, pip-H-20, pip-H-200), 3.49 (ap d, 2H,
J¼12.7 Hz, pip-H-60eq, pip-H-600eq), 4.50 (ap s, 2H, H-2, H-
5). 13C NMR (CD3OD, 100 MHz) d 23.1 (2C), 23.4 (2C),
24.1 (2C), 47.1 (2C), 55.5 (2C), 58.6 (2C), 168.0 (2C, CO).
IR (KBr): 3436, 2946, 2851, 1674, 1631, 1449, 1205, 1051,
773 cmꢁ1. MS (ES): 281 [Mꢁ2TFA+1]+ (100%).
1
+4.5 (c 0.22, MeOH). Mp: 90–92 ꢀC. H NMR (CD3OD,
300 MHz) d 1.60–1.82 (m, 6H, pip-H), 1.85–2.02 (m, 6H,
pip-H), 3.09 (m, 2H, pip-H-6ax, pip-H-600ax), 3.49 (m, 3H,
pip-H-6eq, pip-H-600eq, pip-H-200), 3.64 (m, 1H, pip-H-2),
3.87 (s, 3H, OMe), 4.00 (d, 1H, J¼6.8 Hz, CHNH3), 4.94
(m, 1H, H-10). 13C NMR (CD3OD, 75 MHz) d 21.1 (2C),
21.2, 21.4, 24.7, 24.9, 45.0, 45.3, 52.0, 53.6, 54.9, 57.0, 57.2,
116.1 (q, J¼292.6 Hz, CF3), 161.4 (q, J¼36.3 Hz, COCF3),
165.2 (NHCO), 168.0 (CO2Me). IR (KBr): 3436, 2958,
1679, 1448, 1208, 1140, 842, 800, 724, 517 cmꢁ1. MS
(ES): 313 [M+1]+ (100%). Anal. Calcd for C21H31F9N4O9:
C, 38.54; H, 4.77; N, 8.56. Found: C, 38.75; H, 5.03; N, 8.91.
3.1.16. (2S)-2-({[(2S)-2-Amino-2-piperidin-(2R)-yl]-
acetyl}amino)-2-[piperidin-(2R)-yl]acetic acid, 7e. To a
solution of 7d (24 mg, 0.037 mmol) in Et2O (40 mL/
mmol) was added a solution of 10% aqueous NaOH
(40 mL/mmol). The mixture was stirred at room temperature
for 26 h and the layers were separated. The aqueous phase
was lyophilized and the solid residue was triturated with a
10% solution of MeOH/CH2Cl2 (5ꢂ2 mL). Finally, the
organic extracts were concentrated under reduced pressure
to afford 7e (11 mg, 0.037 mmol) as a white solid without
further purification. Data for 7e: 1H NMR (CD3OD,
300 MHz) d 1.28–1.60 (m, 6H, pip-H), 1.60–1.86 (m, 6H,
pip-H), 2.67 (ap t, 2H, J¼10.5 Hz, pip-H-60ax, pip-H-600ax),
2.77 (m, 1H, pip-H-200), 3.01 (m, 1H, pip-H-20), 3.12 (ap d,
2H, J¼11.5 Hz, pip-H-60eq, pip-H-600eq), 3.27 (d, 1H, J¼
5.9 Hz, CHNH2), 4.29 (d, 1H, J¼4.9 Hz, H-2), 8.59 (br s,
1H, OH). 13C NMR (CD3OD, 75 MHz) d 23.3, 23.4 (2C),
24.6, 27.4, 27.8, 45.5 (2C), 57.6, 58.2, 58.6, 58.9, 168.4
(CO–NH), 174.9 (CO2H). IR (KBr): 3397, 2925, 2860,
1729, 1652, 1437, 1024 cmꢁ1. MS (ES): 619 [2M+Na]+,
597 [2M+1]+, 321 [M+Na]+, 299 [M+1]+ (100%).
3.1.14. Synthesis of (2S)-2-{(2S)-2-amino[1-(tert-butoxy-
carbonyl)piperidin-(2R)-yl]acetyl}amino-2-[1-(tert-bu-
toxycarbonyl)piperidin-(2R)-yl]acetic acid, 7c. From
a solution of 7b (63 mg, 0.123 mmol) in THF/H2O and
LiOH/H2O (10 mg, 0.246 mmol) according to the procedure
described for 4m (16 h) was obtained a crude product of 7c
(56 mg, 0.112 mmol, 91%) as a white solid that did not re-
quire further purification. Data for 7c: 1H NMR (300 MHz)
(some signals appear broadened and display fine splittings
due to the presence of rotamers) d 1.41–1.56 (m, 30H, 18H
t-Bu Boc, 12H pip-H), 2.71 (m, 2H, pip-H-60ax, pip-H-
600ax), 3.89 (m, 3H, CHNH2, pip-H-60eq, pip-H-600eq), 4.24
(m, 1H, pip-H-200), 4.52 (m, 1H, pip-H-20), 4.77 (m, 1H, H-
2), 8.97+9.14 (2 br s, 1H, CO2H). IR (KBr): 3350, 2920,
2848, 1689, 1450, 1414, 1364, 1273, 1162, 1046 cmꢁ1. MS
(ES): 1019 [2M+Na]+, 521 [M+Na]+, 499 [M+1]+ (100%).
3.1.17. Synthesis of 2,20-[3,6-dioxopiperazine-(2S,5S)-
diyl]dipiperidinium bis(trifluoroacetate), 8b$2TFA. To
a solution of 7d$3TFA (24 mg, 0.036 mmol) in MeOH/
H2O 1:1 (7.2 mL) was added a solution of 0.1 M aqueous
NaOH (0.56 mL) until pH¼8.0. The reaction mixture was
stirred at room temperature for 16 days and then the organic
solvent was evaporated under reduced pressure and the aque-
ous residue was lyophilized to obtain a solid that was purified
3.1.15. Synthesis of (2R,20R)-2,20-[3,6-dioxopiperazino-
(2S,5S)-diyl]dipiperidinium bis(trifluoroacetate),
8b$2TFA. Diketopiperazine 8a was prepared by two differ-
ent pathways. (a) A solution of 7b (30 mg, 0.058 mmol) in
DMF (2 mL) was stirred under reflux until disappearance
of the starting material monitored by TLC (40 h). The solvent
was evaporated under reduced pressure to obtain a crude

8026
A. Viso et al. / Tetrahedron 63 (2007) 8017–8026
Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000, 65,
5879–5881; (d) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun,
J. Org. Lett. 2006, 8, 3045–3048.
by SCX resin to give 8b as a mixture of diastereoisomers
(10 mg, 0.018 mmol, 99%). Subsequently, from a solution
of 8b (10 mg, 0.036 mmol) in CH2Cl2/TFA (0.3 mL) accord-
ing to the procedure described for 7d was isolated 8b$2TFA
after crystallization (Et2O/CH2Cl2) as an equimolecular mix-
ture of three diastereoisomers (16 mg, 0.034 mmol, 93%).
ꢀ
5. (a) Viso, A.; Fernandez de la Pradilla, R.; Garcıa, A.; Guerrero-
Strachan, C.; Alonso, M.; Flores, A.; Martınez-Ripoll, M.;
ꢀ
ꢀ
ꢀ
Fonseca, I.; Andre, I.; Rodrıguez, A. Chem.—Eur. J. 2003, 9,
2867–2876; (b) Viso, A.; Fernandez de la Pradilla, R.;
ꢀ
1
Data for the mixture of 8b: [a]2D0 +3.9 (c 0.69, MeOH). H
ꢀ
ꢀ
Lopez-Rodrıguez, M. L.; Garcıa, A.; Flores, A.; Alonso, M.
J. Org. Chem. 2004, 69, 1542–1547; (c) Viso, A.; Fernandez
ꢀ
ꢀ
NMR (CD3OD, 400 MHz) d 1.33–1.57 (m, 5H, pip-H),
1.59–1.79 (m, 40H, pip-H), 1.85–1.97 (m, 3H, pip-H), 2.66
(m, 2H, pip-H-6 ax, pip-H-600ax), 2.99 (m, 2H, pip-H-20, pip-
H-200), 3.13 (ap d, 2H, J¼10.8 Hz, pip-H-60eq, pip-H-600eq),
3.99 (m, 2H, H-3, H-6). 13C NMR (CD3OD, 100 MHz)
d 25.2, 25.4, 26.7, 27.2, 28.2, 29.0, 47.7 (2C), 59.4, 59.6, 60.4,
60.7, 168.7 (NH–CO), 169.4 (NH–CO). IR (KBr): 3361,
2925, 2859, 1667, 1441, 1066, 1048 cmꢁ1. MS (ES): 583
[2M+Na]+, 303 [M+Na]+, 299 [M+H2O+1]+, 281 [M+1]+
(100%), 198 [Mꢁpip]+. Partial data for the mixture of
ꢀ
ꢀ
de la Pradilla, R.; Flores, A.; Garcıa, A.; Tortosa, M.; Lopez-
Rodrıguez, M. L. J. Org. Chem. 2006, 71, 1442–1448; (d)
ꢀ
ꢀ
ꢀ
Viso, A.; Fernandez de la Pradilla, R.; Flores, A. Tetrahedron
Lett. 2006, 47, 8911–8915.
6. Under conditions reported in Ref. 5a this imidazolidine led to
(2S,3R,SS)-N-[2-(benzylamino)-1-hydroxyheptan-3-yl] p-tol-
ylsulfinamide, 2 (R1¼Bu, R2¼CH2OH): 1H NMR (CDCl3,
300 MHz) d 0.58 (t, 3H, J¼6.8 Hz), 0.66–1.10 (m, 4H),
1.19–1.37 (m, 2H), 2.34 (s, 3H), 2.60 (ddd, 1H, J¼7.1, 4.7,
2.7 Hz), 3.18 (m, 1H), 3.49 (dd, 1H, J¼11.7, 7.1 Hz), 3.58
(dd, 1H, J¼11.7, 4.6 Hz), 3.64 (d, 1H, J¼13.0 Hz), 3.79 (d,
1H, J¼13.0 Hz), 4.89 (d, 1H, J¼8.4 Hz), 7.09–7.37 (m, 7H),
7.50 (d, 2H, J¼8.2 Hz). 13C NMR (CDCl3, 75 MHz) d 14.1,
21.7, 22.4, 28.1, 34.2, 51.9, 53.3, 59.3, 62.0, 126.4 (2C),
127.6, 128.6 (2C), 128.9 (2C), 129.8 (2C), 140.6, 140.7,
141.9. IR (film): 3434, 2924, 2854, 1631, 1455, 1261, 1034,
906, 700 cmꢁ1. EM (ES): 375 [M+1]+ (100%).
1
8b$2TFA: H NMR (CD3OD, 300 MHz) d 1.61–1.68 (m,
4H, pip-H), 1.73–1.76 (m, 2H, pip-H), 1.93–1.96 (m, 2H,
pip-H), 2.02 (m, 4H, pip-H), 3.06 (m, 2H, J¼12.2 Hz, pip-
H-60ax, pip-H-600ax), 3.49+3.63 (2m, 4H, J¼9.8 Hz, pip-H-
20, pip-H-200, pip-H-60eq, pip-H-600eq), 4.28+4.35+4.56+4.50
(4m, 2H, H-2, H-5).
Acknowledgements
7. (a) Gitterman, C. O.; Rickes, E. L.; Wolf, D. E.; Madas, J.;
Zimmerman, S. B.; Stoudt, T. H.; Demmy, T. C. J. Antibiot.
1970, 23, 305–310; (b) Arison, B. H.; Beck, J. L.
Tetrahedron 1973, 29, 2743–2746; (c) Pettit, G. R.; Von
Dreele, R. B.; Herald, D. L.; Edgar, M. T.; Wood, H. B., Jr.
J. Am. Chem. Soc. 1976, 98, 6742–6743; (d) Von Dreele,
R. B. Acta Crystallogr. 1981, B37, 93–98.
This research was supported by DGICYT (CTQ2005-04632/
BQU, CTQ2006-04522/BQU) and CAM (S-SAL-0249-
2006). We thank JANSSEN-CILAG for generous additional
support and CAM for a doctoral fellowship to A.F.
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