Synthesis of (3S,5S)-3,5-diaminopiperidin-2-one as a conformationally restricted surrogate of Dab-Gly dipeptide

Article abstract of DOI:10.1016/j.tetasy.2004.12.018

An efficient and stereospecific synthesis of chiral 3,5-diaminopiperidin-2- one as a novel conformationally restricted surrogate of 2,4-diaminobutanoyl (Dab)-Gly dipeptide has been achieved. The key steps include (i) ruthenium tetroxide (RuO₄)

Full text of DOI:10.1016/j.tetasy.2004.12.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 809–815
Synthesis of (3S,5S)-3,5-diaminopiperidin-2-one as a
conformationally restricted surrogate of Dab-Gly dipeptide
Ken-ichi Tanaka,* Harumitsu Nemoto and Hiroyuki Sawanishi
Faculty of Pharmaceutical Science, Hokuriku University, Kanagawa-machi, Kanazawa 920-1181, Japan
Received 12 October 2004; accepted 3 December 2004
Available online 30 January 2005
Abstract—An efficient and stereospecific synthesis of chiral 3,5-diaminopiperidin-2-one as a novel conformationally restricted sur-
rogate of 2,4-diaminobutanoyl (Dab)-Gly dipeptide has been achieved. The key steps include (i) ruthenium tetroxide (RuO4) oxi-
dation of N-Boc-2-azidomethylpyrrolidines with a catalytic amount of RuO2ÆxH2O in a two-phase system of aq NaIO4/AcOEt
and (ii) intramolecular transamidation of the resulting 2-azidomethylpyrrolidin-2-ones with 10% Pd–C in MeOH/H2O (12/1, v/v)
under an H2 atmosphere (3 atm). This methodology represents a powerful tool for the synthesis of Dab-Gly dipeptide surrogate.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Our synthetic strategy for target compound 1 is outlined
retrosynthetically in Scheme 1. Key steps for the synthe-
sis of 1 are a ruthenium tetroxide (RuO4) oxidation of
N-protected 2-azidomethylpyrrolidines 4 and subse-
quent intramolecular transamidation of 5-aminomethyl-
Conformationally restricted peptidomimetics are valu-
able tools for the search for bioactive conformations,
biological potency, and also metabolic stability relative
to unmodified original peptides. One of the common ap-
proaches to such peptidomimetics is the incorporation
of 3-amino-lactams into peptide chains.1 This approach
was pioneered by Freidinger et al.1a,1b and the resulting
lactam-bridged dipeptides often referred to as ꢀFrei-
dinger lactamsꢁ. Consequently, the design and synthesis
of novel Freidinger lactams is currently an area of inten-
sive research in the field of peptide and medicinal chem-
istry.2,3 To the best of our knowledge, syntheses of
several types of Freidinger d-lactams have been re-
ported,2 however, the synthesis of compound 1 possess-
ing an amino function at the C3 and C5 positions on the
lactam ring is still not known.
pyrrolidin-2-one 6a produced by
a
catalytic
hydrogenation of the resulting 5-azidomethylpyrrol-
idin-2-one 3. More recently, ring expansion of azido c-
lactams to d-lactams by employing an intramolecular
transamidation with a catalytic hydrogenation was re-
ported by Langlois.5
2. Results and discussion
Our first synthetic targets were azido c-lactams 3a–c
having a variety of electron-withdrawing groups at the
pyrrolidine nitrogen to examine the effect of substituents
on the next intramolecular transamidation. Thus, N-
Boc-2-azidomethylpyrrolidine 4a was first prepared
from trans-4-hydroxy-L-proline according to Ref. 6.
The RuO4 oxidation of 4a using our previously reported
reaction conditions (RuO2ÆxH2O/aq NaIO4, AcOEt, rt)4
gave the requisite c-lactams 3a in 85% yield as a single
product, after column chromatography (Scheme 2). This
oxidation can be carried out on a 20 g scale of 4a with-
out loss of yield. Removal of the Boc group in 3a and
subsequent reprotection of the nitrogen atom with AcCl
and TsCl gave rise to 3b (78%, two steps) and 3c (72%,
two steps), respectively.
Herein we report the preparation of enantiomerically
pure (3S,5S)-3,5-diaminopiperidin-2-one derivative 1
as a novel conformationally restricted surrogate of 2,4-
diaminobutanoyl (Dab)-Gly dipeptide, in which the
conformational restriction is caused by the introduction
of a methylene linker between the c-carbon of the 2,4-
diaminobutanoic acid and the nitrogen of the glycine.
*
Corresponding author. Tel.: +81 76 229 6186; fax: +81 76 229
2781; e-mail: k-tanaka@hokuriku-u.ac.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.12.018

810
K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
CbzHN
Dab
O
NHBoc
5S
3S
TBSO
TBSO
O
TBSO
NHR
N3
N3
N
N
N
O
N
H
H
H
Gly
R
4
R
3
CO2Et
1
2
Scheme 1.
TBSO
spectral features, the stereostructure of 2a could be rig-
orously assigned as shown. This reactionꢁs efficiency, by
employing additive H2O as more polar solvents can be
explained due to the increase in electrophilicity of lac-
tam carbonyl carbon by favorable hydrogen bonding
between the H2O and the oxygen atom of the carbonyl
group, consequently nucleophilic attack on the carbonyl
carbon of the amino group of the N-Boc aminomethyl
intermediate 6a may be enhanced (Fig. 1). Next, the
application of the optimum conditions for the ring
transformation of 3b and 3c afforded 2b and 2c with
good success (entries 4 and 5, respectively).
HO
TBSO
O
CO2H
H
ref. 6
i
N3
N3
N
H
N
R
N
R
H
H
4a R=Boc
3a R=Boc
3b R=Ac
3c R=Ts
ii
iii
Scheme 2. Reagents and conditions: (i) RuO2ÆxH2O, aq NaIO4,
AcOEt, rt, 85%; (ii) (a) CF3CO2H, CH2Cl2, rt; (b) AcCl, 4-DMAP,
CH2Cl2, 0 ꢁC to rt, 78% (two steps); (iii) (a) CF3CO2H, CH2Cl2, rt; (b)
TsCl, 4-DMAP, CH2Cl2, 0 ꢁC to rt, 72% (two steps).
With the azido c-lactams 3a–c in hand, we examined an
a catalytic
intramolecular transamidation5,7 using
NOE
hydrogenation as a next key step. These results are sum-
marized in Table 1. First, a catalytic hydrogenation of
the azido group in 3a with 10% Pd–C was carried out
at 3 atm hydrogen atmosphere under different condi-
tions of temperature and solvents to examine the opti-
mum conditions on the intramolecular transamidation
(entries 1–3). In the presence of H2O as a co-solvent
(MeOH/H2O = 12/1, v/v), the intramolecular transami-
dation of 3a could be effected to afford the expected
NH d-lactam 2a in 90% yield after column chromatogra-
phy on silica gel (entry 3). In order to confirm the stereo-
chemistries of the stereogenic centers at the C3 and C5
positions in 2a, it was converted to the 3-hydroxypiperi-
din-2-one derivative 5 by treatment with tetra-n-but-
ylammonium fluoride (TBAF) in THF at room
temperature as shown in Scheme 3. The stereochemical
H
Ha
H
H
TBSO
O
NHR
i
3 5
3
5
HO
NHBoc
O
N
N
H
5
H
2a
Scheme 3. Reagents and conditions: (i) TBAF, THF, rt, 92%.
Next, alkylation of the d-lactam ring nitrogen of 2a with
ethyl bromoacetate using LiN(TMS)2 as a base afforded
8 in 80% yield without epimerization at the C3 center
(Scheme 3). Sequential deprotection of the silyl group
with TBAF and mesylation of the resulting alcohol pro-
vided mesylate 11 in 81% yield (two steps), after purifi-
cation by column chromatography. The stereochemical
integrity of the process was determined by the prepara-
tion of Moscherꢁs ester 10 with (S)-MTPA chloride in
the presence of 4-dimethylaminopyridine.8 Analysis of
the 1H NMR spectra of 10 showed the presence of a sin-
gle stereoisomer, indicating an enantiomeric purity
>95%. Thus, we were confident that no racemization
had occurred during the whole sequence. Displacement
of 11 with sodium azide gave d-lactam 12 in 95% yield.
Finally, catalytic hydrogenation of 12 using 10% Pd–C
followed by protection of the amine moiety with carbo-
benzyloxy chloride gave the target Dab-Gly dipeptide
surrogate (3S,5S)-1 in 82% yield (two steps), in which
1
assignment of 5 was determined by H NMR experi-
ments including difference NOE. Irradiation of the C3–
H (d 4.15) resulted in enhancements of both the signals
due to the C4–Ha (d 2.12) and C5–H (d 4.05). Accord-
ingly, the C3–H and C5–H in 5 was assigned to have a
cis-configuration. The absolute configuration of 5 was
unambiguously determined as (3R,5S)-5. Based on these
Table 1. Intramolecular transamidation of 3a–c
TBSO
10% Pd-C/H2,
MeOH, 3 atm, 48h
NHR
TBSO
O
3 5
N3
O
N
R
3a-c
H
N
H
2a-c
H
Entry Substrate
R
Conditions Product Yield (%)
N
TBSO
TBSO
H
1
2
3
4
5
3a
3a
3a
3b
3c
Boc rt
Boc 40–45 ꢁC
2a
2a
2a
2b
2c
65
80
90
75
80
δ
NH2
O
O
N
3a
2a
N
H
H
Boc rt, H2Oa
Boc
Boc
δ
H
H
rt, H2Oa
rt, H2Oa
O
Ac
Ts
6a
7a
a MeOH/H2O (12/1, v/v).
Figure 1.

K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
811
NHBoc
TBSO
O
N3
CbzHN
NHBoc
NHBoc
CO2Et
RO
O
NHBoc
vi
3 5
i
v
3 5
N
3 5
N
3 5
N
N
O
O
H
2a
CO2Et
CO2Et
8:R=TBS
1
12
ii
9:R=H
iv iii
10:R=(R)-MTPA
11:R=Ms
Scheme 4. Reagents and conditions: (i) BrCH2CO2Et, LiN(TMS)2, THF, 0 ꢁC to rt, 80%; (ii) TBAF, THF, 92%; (iii) (S)-MTPACl, 4-DMAP,
CH2Cl2, 95%; (iv) MsCl, Et3N, CH2Cl2, 0 ꢁC, 88%; (v) NaN3, DMF, 70 ꢁC, 95%; (vi) (a) 10% Pd–C/H2, MeOH; (b) CbzCl, Et3N, CH2Cl2, 82% (two
steps).
a-, c-diamino functions and terminus carboxyl function
were differentially protected (Scheme 4).
for 10 h at room temperature. The layer was separated
and the aqueous layer extracted with AcOEt (120 mL).
The extract was treated with 2-propanol (0.2 mL).
Black-colored RuO2, which precipitated from the solu-
tion, was filtered off and the filtrate washed with brine
and dried over Na2SO4. Concentration of the solvent
in vacuo gave a residue, which was purified by column
chromatography (hexane–AcOEt = 8:1) to give 3a
(17.6 g, 85%) as a colorless solid. Recrystallization from
3. Conclusion
In summary, we have developed an efficient and stereo-
specific synthesis of novel 3,5-diaminopiperidin-2-one
derivative 1 as a conformationally restricted surrogate
of Dab-Gly dipeptide by a sequence of RuO4 oxidation
and intramolecular transamidation starting from trans-
4-hydroxy-L-proline. In addition, compound 1 can be
incorporated into biologically important peptides.
AcOEt–isopropyl ether gave an analytical sample of
24
D
1
3a as colorless needles, mp 59–60 ꢁC. ½aꢀ ¼ þ17:8 (c
1.34, MeOH). IR (KBr): 2094, 1756, 1718. H NMR
(CDCl3): d 0.14, 0.18 (each s, 6H, Si(CH3)2), 0.91 (s,
9H, SiC(CH3)3), 1.55 (s, 9H, OC(CH3)3), 2.08 (ddd,
1H, J = 2.93, 9.89, 12.8 Hz, C4–H), 2.26 (ddd, 1H,
J = 1.10, 8.42, 12.8 Hz, C4–H), 3.56 (dd, 1H, J = 2.93,
12.5 Hz, CH2N3), 3.71 (dd, 1H, J = 4.76, 12.5 Hz,
CH2N3), 4.18–4.28 (m, 1H, C5–H), 4.57 (dd, 1H,
J = 8.42, 9.89 Hz, C3–H). 13C NMR (CDCl3): d ꢁ5.25,
ꢁ4.48 (q, Si(CH3)2), 18.29 (s, SiC(CH3)3), 25.76 (q,
SiC(CH3)3), 28.04 (q, OC(CH3)3), 32.66 (t, C4), 52.95
(d, C5), 53.64 (t, CH2N3), 70.01 (d, C3), 83.82 (s,
OC(CH3)3), 150.01 (s, urethane C@O), 172.65 (s, lactam
C@O). EIMS m/z: 371 (M+1+). Anal. Calcd for
C16H30N4O4Si: C, 51.86; H, 8.16, N, 15.12. Found: C,
51.78, H, 8.08, N, 15.22.
4. Experimental
4.1. General
Melting points were measured on a Yanako MP-S3
micro melting point apparatus and are uncorrected.
Optical rotations were measured with a JASCO DIP-
370 automatic digital polarimeter. Infrared (IR) spectra
were recorded with a HORIBA FT-720 spectrometer.
1H and 13C NMR spectra were measured with a JNM-
ECP-500 spectrometer. The chemical shifts were ex-
pressed in ppm (d) downfield from tetramethylsilane as
internal standard in CDCl3 solutions. Coupling con-
stants were expressed in Hz. Electron impact mass spec-
tra (EIMS), fast atom bombardment mass spectra
(FABMS), and high resolution fast atom bombardment
mass spectra (HRFABMS) were obtained with JMS-
SX-102A spectrometer. Routine monitoring of reaction
was carried out using Merck TLC aluminum sheet silica
gel 60 F254. All solvents were dried and purified before
use. The trans-4-hydroxy-L-proline used as homochiral
starting material was purchased from Sigma Chemical
Co.
4.3. (3R,5S)-1-Acetyl-5-azidomethyl-3-[(tert-butyldi-
methylsilyl)oxy]pyrrolidin-2-one 3b
To a solution of 3a (2.00 g, 5.4 mmol) in CH2Cl2
(20 mL) at 0 ꢁC was added dropwise TFA (5.0 mL).
The solution was stirred for 3 h and then the solvent
evaporated in vacuo. The residue was dissolved in
AcOEt (30 mL) and washed with saturated aqueous
NaHCO3, brine, and dried with Na2SO4. Concentration
of the solvent in vacuo gave a crude NH lactam (1.4 g),
which was directly used for the next acetylation without
purification. 4-Dimethylaminopyridine (1.9 g, 1.5 mmol)
and acetyl chloride (0.8 g, 7.7 mmol) was added to a
solution of crude NH lactam (1.4 g) in CH2Cl2
(20 mL) and the mixture stirred at 0 ꢁC for 3 h. The mix-
ture was washed successively with 10% aqueous citric
acid, saturated aqueous NaHCO3, and brine. The
organic layer was dried over Na2SO4. Concentration
of the solvent in vacuo gave a residue, which was puri-
(2S,4R)-2-Azidomethyl-1-tert-butoxycarbonyl-4-[(tert-but-
yldimethylsilyl)oxy]pyrrolidine 4a was prepared accord-
ing to a literature procedure.6
4.2. (3R,5S)-5-Azidomethyl-1-(tert-butoxycarbonyl)-3-[(tert-
butyldimethylsilyl)oxy]pyrrolidin-2-one 3a
A solution of 4a (20.0 g, 56.0 mmol) in AcOEt (250 mL)
was added to a mixture of RuO2ÆxH2O (0.3 g) and 10%
aq NaIO4 (250 mL). The solution was stirred vigorously
fied by column chromatography (hexane–AcOEt = 5:1)
25
to give 3b (1.3 g, 78%) as a colorless oil. ½aꢀ ¼ þ22:7
D
1
(c 1.1, MeOH). IR (neat): 2111, 1756, 1702. H NMR

812
K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
(CDCl3): d 0.16, 0.19 (s, 6H, Si(CH3)2), 0.93 (s, 9H,
SiC(CH3)3), 2.10 (ddd, 1H, J = 8.80, 9.89, 12.82 Hz,
C4–H), 2.30 (ddd, 1H, J = 0.73, 8.80, 12.82 Hz, C4–H),
2.54 (s, 3H, COCH3), 3.48 (dd, 1H, J = 2.56, 12.45 Hz,
CH2N3), 3.82 (dd, 1H, J = 4.03, 12.45 Hz, CH2N3),
4.38–4.44 (m, 1H, C5–H), 4.71 (dd, 1H, J = 8.80,
9.89 Hz, C3–H). 13C NMR (CDCl3): d ꢁ5.15, ꢁ4.55
(q, Si(CH3)2), 18.30 (s, SiC), 25.22 (q, COCH3), 25.72
(q, C(CH3)3), 32.81 (t, C4), 51.88 (d, C5), 53.05 (t,
CH2N3), 70.46 (d, C3), 171.32 (s, COCH3), 174.76 (s,
lactam C@O). FABMS m/z: 313 (M+1+). HRFABMS:
calcd for C13H25N4O3Si (M+1+): 313.1696. Found:
313.1690.
2.02–2.08 (m, 2H, C4–H2), 3.37–3.45 (m, 2H, C6–H2),
4.02–4.01 (m, 1H, C5–H), 4.16–4.21 (m, 1H, C3–H),
6.02–6.25 (m, 2H, NH · 2). 13C NMR (CDCl3): d
ꢁ5.60, ꢁ4.57 (q, Si(CH3)2), 18.07 (s, SiC(CH3)3), 25.72
(q, SiC(CH3)3), 28.37 (q, OC(CH3)3), 34.39 (t, C4),
42.59 (d, C5), 47.67 (t, C6), 68.03 (d, C3), 79.33 (s,
OC(CH3)3), 155.28 (s, urethane C@O), 170.33 (s, lactam
C@O). FABMS m/z: 345 (M+1+). Anal. Calcd for
C16H32N2O4: C, 55.78; H, 9.36; N, 8.13. Found: C,
55.80; H, 9.05; N, 8.12.
4.5.2. (3R,5S)-5-Acetylamino-3-[(tert-butyldimethylsil-
yl)oxy]piperidin-2-one 2b. Following the general pro-
cedure, transamidation of 3b, after column
chromatography (CHCl3–MeOH = 10:1), gave 2b
(1.03 g, 75%) as a colorless solid. Recrystallization from
4.4. (3R,5S)-5-Azidomethyl-3-(tert-butyldimethylsilyl-
oxy)-1-(p-toluenesulfonyl)pyrrolidin-2-one 3c
isopropyl ether gave an analytical sample of 2b as color-
24
D
The same treatment of 3a (3.5 g, 9.4 mmol) as described
for the preparation of 3b from 3a, except for the use of
p-toluenesulfonyl chloride (2.2 g, 11.3 mmol) instead of
acetyl chloride, gave, after column chromatography
less needles, mp 197–198 ꢁC. ½aꢀ ¼ ꢁ12:2 (c 1.0,
1
MeOH). IR (KBr): 3288, 3092, 1675, 1648. H NMR
(CDCl3): d 0.19, 0.21 (s, 6H, Si(CH3)2), 0.93 (s, 9H,
SiC(CH3)3), 1.95 (s, 3H, COCH3), 2.05–2.14 (m, 2H,
C4–H2), 3.39–3.52 (m, 2H, C6–H), 4.18–4.24 (m, 1H,
C5–H), 4.30–4.38 (m, 1H, C3–H), 6.14 (br s, 1H, lactam
NH), 7.28 (br d, J = 5.45 Hz, NHCOCH3). 13C NMR
(CDCl3): d ꢁ5.53, ꢁ4.57 (q, Si(CH3)2), 18.11 (s,
SiC(CH3)3), 23.37 (q, COCH3), 25.75 (q, SiC(CH3)3),
33.75 (t, C4), 41.60 (d, C5), 47.19 (t, C6), 68.03 (d, C3),
169.71, 169.90 (s, C@O). FABMS m/z: 287 (M+1+).
Anal. Calcd for C13H26N2O3Si: C, 54.51; H, 9.15; N,
9.78. Found: C, 54.48; H, 9.08, N, 9.80.
(benzene–AcOEt = 30:1), 3c (2.9 g, 72%, two steps)
26
as a colorless oil. ½aꢀ ¼ þ18:8 (c 0.98, MeOH). IR
D
(neat): 2111, 1751, 1596. 1H NMR (CDCl3): d 0.09,
0.11 (s, 6H, Si(CH3)2, 0.86 (s, 9H, SiC(CH3)3, 2.12
(ddd, 1H, J = 8.06, 9.90, 12.82 Hz, C4–H), 2.27 (ddd,
1H, J = 1.10, 8.06, 12.82 Hz, C4–H), 2.44 (s, 3H, Ph–
CH3), 3.64 (dd, 1H, J = 2.56, 12.82 Hz, CH2N3), 3.94
(dd, 1H, J = 4.40, 12.82 Hz, CH2N3), 4.36–4.42 (m,
1H, C5–H), 4.57 (dd, J = 8.06, 9.90 Hz, C3–H), 7.35,
7.94 (d, 4H, J = 8.43 Hz, Ph–H). 13C NMR (CDCl3): d
ꢁ5.24, ꢁ4.60 (q, Si(CH3)2), 18.23 (s, SiC), 21.70 (q,
Ph–CH3), 25.67 (q, SiC(CH3)3), 34.08 (t, C4), 54.67 (d,
C3), 128.34, 129.77, 135.22, 145.51 (Ph), 172.31 (lactam
C@O). FABMS m/z: 425 (M+1+). HRFABMS: calcd
for C18H29N4O4SSi (M+1+): 425.1679. Found:
425.1680.
4.5.3. (3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-(p-tolu-
enesulfonylamino)-piperidin-2-one 2c. Following the
general procedure, transamidation of 3c, after column
chromatography (CHCl3–MeOH = 10:1), gave 2c
(1.12 g, 80%) as a colorless solid. Recrystallization from
isopropyl ether gave an analytical sample of 2c as color-
24
less prisms, mp 155–156 ꢁC. ½aꢀ ¼ þ22:0 (c 0.93,
D
4.5. General procedure for the intramolecular transami-
dation of 3a–c
MeOH). IR (KBr): 3348, 1666, 1598. 1H NMR (CDCl3):
d 0.13, 0.15 (s, 6H, Si(CH3)2), 0.90 (s, 9H, SiC(CH3)3),
1.83–2.03 (m, 2H, C4–H2), 2.43 (s, 3H, Ph–CH3), 3.28–
3.38 (m, 2H, C6–H2), 3.67–3.76 (m, 1H, C5–H), 4.07–
4.12 (m, 1H, C3–H), 6.13–6.22 (m, 1H, lactam NH),
6.53–6.58 (m, 1H, NHTs), 7.30, 7.74 (d, 2H, J = 8.06,
Ph–H). 13C NMR (CDCl3): d ꢁ5.50, ꢁ4.57 (q,
Si(CH3)2), 18.13 (s, SiC(CH3)3), 21.53 (q, Ph–CH3),
25.73 (q, SiC(CH3)3), 35.20 (t, C4), 45.80 (d, C5), 47.95
(t, C6), 67.93 (d, C3), 126.83, 129.84, 138.08, 143.56
(Ph), 170.33 (s, lactam C@O). FABMS m/z: 399
(M+1+). Anal. Calcd for C18H30N2O4SSi: C, 54.24; H,
7.59; N, 7.03. Found: C, 54.20; H, 7.38; N, 7.12.
A
mixture of 5-azidomethyl derivative 3 (1.5 g,
4.0 mmol) and 10% Pd–C in MeOH/H2O (65 mL, 12:1
v/v) was stirred for 48 h at room temperature under an
H2 atmosphere (3 atm). The catalyst was filtered off
and the filtrate concentrated in vacuo to give a residue,
which was partitioned between CHCl3 and H2O. The
aqueous layer was backwashed with CHCl3. The com-
bined organic layer was dried over Na2SO4. Concentra-
tion of the solvent in vacuo gave a residue, which was
purified by column chromatography. The results are
summarized in Table 1.
4.6. (3R,5S)-5-(tert-Butoxycarbonylamino)-3-hydroxy-
piperidin-2-one 5
4.5.1. (3R,5S)-5-[(tert-Butoxycarbonyl)amino]-3-[(tert-
butyldimethylsilyl)oxy]piperidin-2-one
2a. Following
the general procedure, transamidation of 3a, after col-
umn chromatography (CHCl3–MeOH = 30:1), gave 2a
(1.25 g, 90%) as a colorless solid. Recrystallization from
Tetra-n-butylammonium fluoride (TBAF) in THF
(1.0 M solution, 4.8 mL) was added dropwise to a stir-
red solution of 2a (0.84 g, 2.4 mmol) in THF (20 mL)
at room temperature for 3 h. The reaction mixture was
concentrated, and the residue purified by column chro-
matography (AcOEt–MeOH = 10:1) to give 5 (0.52 g,
92%) as a colorless solid. Recrystallization from
AcOEt–isopropyl ether gave an analytical sample of 5
isopropyl ether gave an analytical sample of 2a as color-
26
D
less needles, mp 125–126 ꢁC. ½aꢀ ¼ ꢁ13:5 (c 1.11,
1
MeOH). IR (KBr): 3436, 3230, 1724, 1682. H NMR
(CDCl3): d 0.16, 0.17, 0.18, 0.19 (s, 6H, Si(CH3)2),
0.91, 0.92 (s, 9H, SiC(CH3)3), 1.42, 1.43 (s, OC(CH3)3),

K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
813
1
25
as colorless needles, mp 199–200 ꢁC. ½aꢀ ¼ ꢁ14:9 (c
(c 1.12, MeOH). IR (KBr): 3355, 1733, 1683, 1664. H
NMR (CDCl3): d 1.28, 1.29 (t, 3H, J = 6.96 Hz,
OCH2CH3), 1.45 (s, 9H, OC(CH3)3), 1.80–1.91 (m,
1H, C4–H), 3.30 (dd, 1H, J = 6.23, 12.09 Hz, C6–H),
3.62 (dd, 1H, J = 4.40, 12.09 Hz, C6–H), 3.94 (d, 1H,
J = 17.22 Hz, NCH2CO2Et), 4.05–4.18 (m, 3H, C3–H,
C5–H, OH), 4.20, 4.21 (q, 2H, J = 6.96 Hz, OCH2CH3),
4.25 (d, 1H, J = 17.22 Hz, NCH2CO2Et), 5.40 (br d, 1H,
J = 8.06 Hz, NH). 13C NMR (CDCl3): d 14.14 (q,
CO2CH2CH3), 28.37 (q, OC(CH3)3), 34.81 (t, C4),
43.25 (d, C5), 48.72 (t, C6), 53.62 (t, NCH2CO2Et),
61.61 (t, OCH2CH3), 66.17 (d, C3), 79.94 (s, OC(CH3)3),
155.22 (s, urethane C@O), 168.59, 172.55 (s, ester and
lactam C@O). FABMS m/z: 317 (M+1+). Anal. Calcd
for C14H24N2O6: C, 53.15; H, 7.65; N, 8.86. Found: C,
53.08; H, 7.48; N, 8.72.
D
0.85, MeOH). IR (KBr): 3400, 3370, 1693, 1638. 1H
NMR (CDCl3): d 1.45 (s, 9H, OC(CH3)3), 1.76–1.86
(m, 1H, C4–H), 2.40–2.50 (m, 1H, C4–H), 3.18–3.28
(m, 1H, C6–H), 3.48–3.56 (m, 1H, C6–H), 3.80 (br s,
1H, OH), 4.02–4.14 (m, 1H, C5–H), 4.10–4.18 (m, 1H,
C3–H), 5.05, 6.17 (br s, 2H, NH · 2). 13C NMR
(CDCl3): d 28.36 (q, OC(CH3)3), 34.46 (t, C4), 43.54
(d, C5), 47.13 (t, C6), 65.67 (d, C3), 79.52 (s, OC(CH3)3),
155.07 (s, urethane C@O), 173.28 (s, lactam C@O).
FABMS m/z: 231 (M+1+). Anal. Calcd for
C10H18N2O4: C, 52.16; H, 7.88; N, 12.17. Found: C,
52.07; H, 7.68; N, 12.04.
4.7. (3R,5S)-5-(tert-Butoxycarbonylamino)-3-(tert-butyl-
dimethylsilyloxy)-1-(ethoxycarbonylmethyl)piperidin-2-
one 8
4.9. (3R,5S)-5-(tert-Butoxycarbonylamino)-1-(ethoxycar-
bonylmethyl)-3[(S)-2-methoxy-2-(trifluoromethyl)phenyl-
acetyloxy]piperidin-2-one 10
Lithium bis(trimethylsilyl)amide (LiN(TMS)2) in THF
(1.0 M solution, 3.6 mL) was added to a solution of 2a
(1.00 g, 2.90 mmol) in THF (30 mL) under nitrogen at
ꢁ15 ꢁC, and the reaction mixture stirred for 30 min.
Then ethyl bromoacetate (0.97 g, 5.81 mmol) was added
to the reaction mixture. After stirring for 1 h at ꢁ15 ꢁC,
the reaction mixture was allowed to warm up to room
temperature. The reaction was quenched with saturated
NH4Cl solution (10 mL) and the mixture extracted with
AcOEt (40 mL). The extract was washed with brine and
dried over Na2SO4. Concentration of the solvent in
vacuo gave a residue, which was purified by column
(S)-2-Methoxy-2-(trifluoromethyl)phenylacetyl chloride
[(S)-MTPACl] (0.17 g, 0.52 mmol) was added to a stir-
red solution of 9 (0.15 g, 0.47 mmol) and 4-DMAP
(0.29 g, 2.35 mmol) in CH2Cl2 (15 mL) at 0 ꢁC and the
mixture stirred at 0 ꢁC for 1 h. The reaction mixture
was concentrated in vacuo and the residue purified by
short column chromatography (hexane–AcOEt = 2:1)
to give 10 (0.24 g, 95%) of MTPA ester as a single com-
pound. The enantiomeric excess of 10 was more than
1
chromatography (hexane–AcOEt = 1:1) to give
8
95% based on H NMR analysis of this MTPA ester.
23
D
22
D
(1.15 g, 80%) as a colorless oil. ½aꢀ ¼ ꢁ14:0 (c 1.30,
½aꢀ ¼ ꢁ31:0 (c 0.98, MeOH). 1H NMR (CDCl3): d
1
MeOH). IR (neat): 3409, 1747, 1714, 1668. H NMR
(CDCl3): d 0.17 (s, 6H, Si(CH3)2), 0.92 (s, 1H,
SiC(CH3)3), 1.26, 1.27 (t, 3H, J = 6.96 Hz, OCH2CH3),
1.43 (s, 9H, OC(CH3)3), 2.04–2.22 (m, 2H, C4–H2),
3.41 (br d, 1H, J = 12.10 Hz, C6–H), 3.61 (dd,
J = 4.03, 12.10 Hz, C6–H), 3.82 (d, 1H, J = 17.20 Hz,
CH2CO2Et), 4.08–4.16 (m, 1H, C5–H), 4.18, 4.19 (q,
2H, J = 6.96 Hz, OCH2CH3), 4.27 (t, 1H, J = 4.40 Hz,
C3–H), 4.31 (d, 1H, J = 17.20 Hz, CH2CO2Et), 6.30
(br d, 1H, J = 8.06 Hz, NH). 13C NMR (CDCl3): d
ꢁ5.62, ꢁ5.60 (q, Si(CH3)2), 14.14 (q, OCH2CH3),
18.07 (s, SiC(CH3)3), 25.72 (q, SiC(CH3)3), 28.37 (q,
OC(CH3)3), 34.50 (t, C4), 43.17 (d, C5), 49.04 (t, C6),
54.60 (t, CH2CO2Et), 61.28 (t, OCH2CH3), 68.28 (d,
C3), 79.33 (s, OC(CH3)3), 155.34 (s, urethane C@O),
168.65, 168.97 (s, ester and lactam C@O). FABMS m/
z: 431 (M+1+). HRFABMS: calcd for C20H39N2O6Si
(M+1+): 431.2577. Found: 431.2575.
1.27 (t, 3H, J = 6.96 Hz, OCH2CH3), 1.44 (s, 9H,
OC(CH3)3), 2.15–2.25 (m, 1H, C4–H), 2.52–2.60 (m,
1H, C4–H), 3.30–3.38 (m, 1H, C6–H), 3.56 (s, 3H,
OCH3), 3.60–3.68 (m, 1H, C6–H), 3.90, 4.31 (d, 2H,
J = 17.6 Hz, CH2CO2Et), 4.15–4.25 (m, 1H, C5–H),
4.19 (q, 2H, J = 6.96 Hz, OCH2CH3), 5.37 (br d, 1H,
NH), 5.50–5.56 (m, 1H, C3–H), 7.40–7.65 (m, 5H, Ph).
13C NMR (CDCl3): d 14.08 (q, OCH2CH3), 28.33 (q,
OC(CH3)3), 33.29 (t, C4), 43.07 (d, C5), 48.60 (t, C6),
53.05 (t, CH2CO2Et), 55.51 (q, OCH3), 61.65 (t,
OCH2CH3), 68.70 (d, C3), 80.11 (s, OC(CH3)3), 121.74
(s, CCF3), 124.61 (s, CF3), 127.87, 128.41, 129.71,
131.65 (Ph), 155.09 (s, urethane C@O), 165.60 (s, lactam
C@O), 165.76, 168.63 (s, ester C@O). FABMS m/z: 533
(M+1+).
4.10. (3R,5S)-5-[(tert-Butoxycarbonyl)amino]-1-[(ethoxy-
carbonyl)methyl]-3-[(methanesulfonyl)oxy]piperidin-2-one
11
4.8. (3R,5S)-5-(tert-Butoxycarbonylamino)-1-(ethoxy-
carbonylmethyl)-3-hydroxypiperidin-2-one 9
Methanesulfonyl chloride (0.16 g, 1.39 mmol) was
added dropwise to a solution of 9 (9.40 g, 1.26 mmol)
and Et3N (0.17 g, 1.64 mmol) in CH2Cl2 (20 mL) at
0 ꢁC and the mixture stirred at 0 ꢁC for 6 h. The solvent
was evaporated in vacuo and the residue diluted with
saturated aqueous Na2CO3 (10 mL), and the mixture
was extracted with AcOEt (40 mL). The extract was
washed with brine and dried over Na2SO4. Concentra-
tion of the solvent in vacuo gave a residue, which was
purified by column chromatography (hexane–
AcOEt = 1:3) to give 11 (0.43 g, 88%), as a colorless
TBAF in THF (1.0 M solution, 6.75 mL) was added
dropwise to a stirred solution of 8 (0.97 g, 2.25 mmol)
in THF (20 mL) at room temperature and the mixture
stirred at ambient temperature for 2 h. The reaction
mixture was concentrated, and the residue was purified
by column chromatography (hexane–AcOEt = 1:3) to
give 9 (0.65 g, 92%) as a colorless solid. Recrystallization
from AcOEt–isopropyl ether gave an analytical sample
24
D
of 9 as colorless needles, mp 122–123 ꢁC. ½aꢀ ¼ ꢁ13:4

814
K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
23
oil. ½aꢀ ¼ ꢁ5:1 (c 1.17, MeOH). IR (neat): 3369,
and brine. The organic layer was dried over Na2SO4.
Concentration of the solvent in vacuo gave a residue,
which was purified by column chromatography (hex-
D
1739, 1683. 1H NMR (CDCl3):
d 1.29 (t, 3H,
J = 6.96 Hz, OCH2CH3), 1.45 (s, 9H, OC(CH3)3),
2.20–2.32 (m, 1H, C4–H), 2.55–2.62 (m, 1H, C4–H),
3.27 (s, 3H, SO2CH3), 3.37 (dd, 1H, J = 6.96,
12.10 Hz, C6–H), 3.60 (dd, 1H, J = 4.40, 12.10 Hz, C6–
H), 3.88 (d, 1H, J = 17.20 Hz, CH2CO2Et), 4.08–4.20
(m, 1H, C5–H), 4.22 (q, 2H, J = 6.96 Hz, OCH2CH3),
4.28 (d, 1H, J = 17.20 Hz, CH2CO2Et), 5.13 (dd, 1H,
J = 6.96, 8.80 Hz, C3–H), 5.22 (d, 1H, J = 7.70 Hz,
NH). 13C NMR (CDCl3): d 14.13 (q, OCH2CH3),
28.34 (q, OC(CH3)3), 34.91 (t, C4), 39.29 (q, SO2CH3),
43.04 (t, C6), 48.92 (t, C6), 53.36 (t, CH2CO2Et), 61.77
(t, OCH2CH3), 74.14 (d, C3), 80.32 (s, OC(CH3)3),
155.10 (s, urethane C@O), 165.87, 168.36 (s, ester and
lactam C@O). FABMS m/z: 395 (M+1+). HRFABMS
m/z: calcd for C15H27N2O8S (M+1+): 395.1486. Found:
395.1480.
ane–AcOEt = 1:1) to give 1 (0.26 g, 82%) as a colorless
23
D
oil. ½aꢀ ¼ ꢁ20:5 (c 1.60, MeOH). IR (neat): 3320,
1712, 1666. 1H NMR (CDCl3):
d 1.27 (t, 3H,
J = 6.96 Hz, OCH2CH3), 1.44 (s, 9H, OC(CH3)3),
1.98–2.08 (m, 1H, C4–H), 2.39–2.48 (m, 1H, C4–H),
3.26–3.35 (m, 1H, C6–H), 3.59–3.69 (m, 1H, C6–H),
3.99 (br d, 1H, J = 17.20 Hz, CH2CO2Et), 4.04–4.38
(m, 3H, C3–H, C5–H, and CH2CO2Et), 4.18 (q, 2H,
J = 6.96 Hz, OCH2CH3), 5.10 (s, 2H, CO2CH2 Ph),
5.54 (br d, 1H, J = 7.70 Hz, NHBoc), 5.88 (d, 1H,
J = 5.13 Hz, NHCbz), 7.26–7.38 (m, 5H, Ph). 13C
NMR (CDCl3): d 14.11 (q, OCH2CH3), 28.37 (q,
OC(CH3)3), 33.23 (t, C4), 43.71 (d, C5), 48.59 (t, C6),
48.66 (d, C3), 52.59 (t, CH2CO2Et), 61.56 (t,
OCH2CH3), 66.89 (t, CO2CH2Ph), 79.86 (s, OC(CH3)3),
127.99, 128.09, 128.51, 136.36 (Ph), 155.38, 156.29 (s,
urethane C@O), 168.92, 169.93 (s, ester and lactam
C@O). HRMS m/z: 450 (M+1+). HRFABMS:
calcd for C22H32N3O7 (M+1+): 450.2240. Found:
450.2238.
4.11. (3S,5S)-3-Azido-5-[(tert-butoxycarbonyl)amino]-1-
ethoxycarbonylpiperidin-2-one 12
Sodium azide (0.30 g, 4.60 mmol) was added to a solu-
tion of 11 (0.60 g, 1.52 mmol) in DMF (15 mL). The
mixture was heated at 70 ꢁC for 8 h. The reaction mix-
ture was diluted with water (10 mL) and the mixture ex-
tracted with AcOEt (30 mL). The extract was washed
with brine, and then dried over Na2SO4. Concentration
of the solvent in vacuo gave a residue, which was puri-
fied by column chromatography (hexane–AcOEt = 1:1)
Acknowledgements
This work was supported by the Specific Research Fund
of Hokuriku University.
to give 12 (0.50 g, 95%) as
a
colorless oil.
24
½aꢀ ¼ ꢁ123:3 (c 0.63, MeOH). IR (neat): 3332, 2109,
References
D
1747, 1712, 1695. 1H NMR (CDCl3): d 1.29 (t, 3H,
J = 6.96 Hz, OCH2CH3), 1.45 (s, 9H, OC(CH3)3),
1.85–1.96 (m, 1H, C4–H), 2.29–2.39 (m, 1H, C4–H),
3.26 (dd, 1H, J = 5.50, 12 10 Hz, C6–H), 3.65 (dd, 1H,
J = 3.67, 12.10 Hz, C6–H), 3.74 (d, 1H, J = 17.20 Hz,
CH2CO2Et), 4.05–4.14 (m, 1H, C5–H), 4.18–4.28 (m,
3H, C3–H and OCH2CH3), 4.48 (d, 1H, J = 17.20 Hz,
CH2CO2Et), 5.46 (br d, 1H, J = 7.70 Hz, NH). 13C
NMR (CDCl3): d 14.11 (q, OCH2CH3), 28.37 (q,
OC(CH3)3), 32.66 (t, C4), 43.19 (d, C5), 48.47 (t, C6),
53.19 (t, CH2CO2Et), 56.70 (d, C3), 61.74 (t,
OCH2CH3), 80.06 (s, OC(CH3)3), 155.23 (s, urethane
C@O), 167.66, 168.84 (s, ester and lactam C@O).
FABMS m/z: 342 (M+1+). HRFABMS: calcd for
C14H24N5O5 (M+1+): 342.1777. Found: 342.1774.
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temperature under an H2 atmosphere (3 atm). The cata-
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acylation without purification. Triethylamine (0.10 g,
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0 ꢁC for 6 h. The mixture was washed successively with
10% aqueous citric acid, saturated aqueous NaHCO3,

K. Tanaka et al. / Tetrahedron: Asymmetry 16 (2005) 809–815
815
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