Concise synthetic strategy toward cyclic α,α-disubstituted α-amino acids bearing a δ-nitrogen atom: Chiral 1-substituted 4-aminopiperidine-4-carboxylic acids

Article abstract of DOI:10.1016/j.tet.2004.11.004

A concise synthetic strategy toward cyclic α,α-disubstituted α-amino acids, 1-substituted 4-aminopiperidine-4-carboxylic acids have been developed. The synthetic route is a reductive amination of dimethyl bis(dioxolanemethyl)malonate with various amines,

Full text of DOI:10.1016/j.tet.2004.11.004

Tetrahedron 61 (2005) 593–598
Concise synthetic strategy toward cyclic a,a-disubstituted
a-amino acids bearing a d-nitrogen atom: chiral 1-substituted
4-aminopiperidine-4-carboxylic acids
*
Makoto Oba, Masakazu Tanaka, Yukiko Takano and Hiroshi Suemune
*
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Received 20 August 2004; revised 30 October 2004; accepted 4 November 2004
Available online 24 November 2004
Abstract—A concise synthetic strategy toward cyclic a,a-disubstituted a-amino acids, 1-substituted 4-aminopiperidine-4-carboxylic acids
have been developed. The synthetic route is a reductive amination of dimethyl bis(dioxolanemethyl)malonate with various amines, followed
by Curtius rearrangement. This synthetic route is capable of synthesizing 4-aminopiperidine-4-carboxylic acids bearing a bulky substituent
and optically active ones bearing a pendent chiral substituent, by the change of condensed amines.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
could not be easily prepared by the known synthetic route
from 4-piperidone,7 or from heterospirocyclic azirines as
synthons (Fig. 1).8
a,a-Disubstituted a-amino acids are non-proteinogenic
amino acids,1 and attract many synthetic, peptide, and
medicinal chemists because of their characteristic properties
such as biological activities, conformational restriction of
side-chains, and the stable secondary structure of their
peptides.2 We have already reported an asymmetric
synthesis of a-methylated and a-ethylated a,a-disubstituted
a-amino acids,3 and conformational study of their peptides.4
Besides acyclic a-alkylated a,a-disubstituted a-amino
acids, cyclic a,a-disubstituted a-amino acids (1-amino-
cycloalkanecarboxylic acid; Acnc), in which the side-chain
of the amino acids construct a cycloalkane-ring, have been
reported.1b,5 Among cyclic a,a-disubstituted a-amino acids,
4-aminopiperidine-4-carboxylic acid (Pip), which is an
achiral a-amino acid bearing a d-nitrogen atom, has been
focused upon because of the anti-microbial activity of its
helical peptides.6 However so far, the Pip derivatives have
just been synthesized from piperidone derivative, by the
Strecker, or Bu¨cherer–Bergs methods.7 Herein, we describe
a new concise synthetic route for various achiral and chiral
1-substituted 4-aminopiperidine-4-carboxylic acids. Some
of them, especially chiral a,a-disubstituted a-amino acids
are a new class of optically active cyclic a,a-disubstituted
a-amino acids bearing a pendent chiral center, and they
Figure 1. Acyclic and cyclic a,a-disubstituted a-amino acids.
2. Results and discussion
2.1. Synthetic strategy for Pip derivatives
At first, we envisaged that cyclic a,a-disubstituted a-amino
acids (Pip derivatives) could be prepared from a bis-
(formylmethyl)glycine derivative (ii) by reductive
condensation with various amines. Also, it was thought
that the dialdehyde (ii) could be prepared from protected
intermediate (i). Unfortunately, several attempts to prepare
the intermediate (i) from the protected glycines by
bisalkylation failed. Next, we thought that cyclic diester
intermediate (iv) could be converted into the Pip derivatives
by Curtius rearrangement, and diester (iv) may be prepared
by a reductive condensation of dimethyl bis(formylmethyl)-
malonate (iii) and amines. Preparation of the intermediate
(iii) was thought to be easier than that of glycine (ii) because
the alkylated dimethyl malonate seemed to be stable
(Scheme 1).
Keywords: Cyclic a,a-disubstituted a-amino acid; Piperidine; Curtius
rearrangement; Unnatural amino acid; Chiral amino acid.
* Corresponding authors. Tel.: C81 92 642 6604; fax: C81 92 642 6545
(M.T.); (H.S.); e-mail addresses: mtanaka@phar.kyushu-u.ac.jp;
suemune@phar.kyushu-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.004

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M. Oba et al. / Tetrahedron 61 (2005) 593–598
afforded a Boc-protected 1-cyclopentyl-Pip-OMe Boc-4a in
51% yield, and with 9-fluorenemethanol yielded a Fmoc-
protected 1-cyclopentyl-Pip-OMe Fmoc-4a in 59% yield
(Table 1).
Table 1. Preparation of various cyclic a,a-disubstituted a-amino acid; Pip
derivatives 4
Entry Amine
Dienamine 2
% yield
Diester 3
% yield
Cbz-protected
Pip-OMe 4
% yield
1
2
3
4
5
6
a
b
c
d
e
f
2a: 57
2b: 55
2c: 36
2d: 60
2e: 41
2f: 56
3a: 73
3b: 80
3c: 82
3d: 67
3e: 86
3f: 76
Cbz-4a: 50
Cbz-4b: 40
Cbz-4c: 50
Cbz-4d: 41
Cbz-4e: 61
Cbz-4f: 30
Scheme 1. Synthetic strategy for the Pip derivatives.
2.2. Preparation of achiral Pip derivatives
a: cyclopentylamine; b: n-hexylamine; c: 1-adamantanylamine; d: (S)-
phenylethylamine; e: (S)-(C)-2-aminobutane; f: (1R,2R,3R,5S)-(K)-iso-
pinocampheylamine.
Bisalkylation of dimethyl malonate by treatment with
KOtBu and 2-bromomethyl-1,3-dioxolane in DMSO at
80 8C afforded a bis(dioxolanemethyl) diester 1 in 47%
yield (Scheme 2).
2.3. Preparation of optically active Pip derivatives
The aforementioned strategy was applied to the synthesis of
optically active cyclic a,a-disubstituted a-amino acids 4d–f
in which asymmetric carbons exist in the appendant
substituent of amines. So far, no such chiral cyclic a,a-
disubstituted a-amino acids have been designed, nor
synthesized in optically active form. The crude dialdehyde
prepared from 1 was condensed with chiral amines
(S)-phenylethylamine d, (S)-2-aminobutane e, and
(1R,2R,3R,5S)-(K)-isopinocampheylamine f to give
dienamines 2d (60%), 2e (41%), and 2f (56%), respectively.
Hydrogenation of 2d–f afforded the corresponding cyclic
diesters 3d–f in 67, 86 and 76% yields. Partial hydrolysis of
the diesters, followed by Curtius rearrangement with DPPA9
afforded optically active 1-substituted Pip-OMe 4d–f. Work
up with benzyl alcohol gave Cbz-protected Pip-OMe Cbz-
4d (41%), Cbz-4e (61%), and Cbz-4f (30%), and with
t-BuOH produced a Boc-protected 1-(S)-phenylethyl-Pip-
OMe Boc-4d (43%). Furthermore, work up with
concentrated HCl afforded an N-terminal free amine H2N-
1-(S)-phenylethyl-Pip-OMe H2N-4d in 40% yield. The
HPLC analysis of Cbz-(S)-4d using a chiral column
indicated that no epimerization occurred in the synthetic
sequences, and the enantiomeric excesses of Cbz-(S)-4d
was O99% ee. Hydrolysis of the ester in Cbz-Pip-OMe 4d
afforded a C-terminal free cyclic a,a-disubstituted a-amino
acid Cbz-protected 1-(S)-phenylethyl-Pip-OH 5d (quant.).10
Scheme 2. Synthetic scheme of various Pip derivatives.
The dioxolane group in 1 could be deprotected by 10%
aqueous HCl to give a dialdehyde, which seemed to be
unstable to purification by column chromatography on silica
gel. Thus, the crude dialdehyde was subjected to the next
reaction without purification. The deprotection of the
dioxolane group, followed by condensation of the
dialdehyde with cyclopentylamine, n-hexylamine, or
1-adamantanylamine afforded cyclic dienamines 2a
(57%), 2b (55%), and 2c (36%), respectively. The isolated
dienamines 2a–c were subjected to hydrogenation with
Pd-C to afford the desired cyclic diesters 3a–c in 73, 80 and
82% yields. Hydrolysis of the diester 3a–c with aqueous
NaOH gave monocarboxylic acids, and subsequent Curtius
rearrangement using diphenylphosphoryl azide (DPPA),9,3
followed by quenching with benzyl alcohol afforded
Cbz-protected 1-cyclopentyl-Pip-OMe Cbz-4a (50%), 1-n-
hexyl-Pip-OMe Cbz-4b (40%), and 1-adamantanyl-Pip-
OMe Cbz-4c (50%), respectively. Work up with t-BuOH
3. Conclusion
We succeeded in developing a concise synthetic route
toward cyclic a,a-disubstituted a-amino acids bearing a
d-nitrogen atom. By using amines, it is possible to
synthesize various 1-substituted 4-aminopiperidine-4-
carboxylic acid derivatives. In particular, this strategy can
be applied to the synthesis of optically active cyclic a,a-
disubstituted a-amino acids bearing a pendent chirality,11
which have not been designed nor synthesized so far.
Application of the synthetic route to the combinatorial
chemistry, and the use of cyclic a,a-disubstituted a-amino

M. Oba et al. / Tetrahedron 61 (2005) 593–598
595
acids having a pendent chiral moiety for the synthesis of
peptide-foldamers12 are currently underway in our group.
FAB(C)HRMS calcd for C15H24NO4 ([MCH]C)
282.1705, found 282.1710.
4.1.4. 1-Adamantanyl-4,4-bis(methoxycarbonyl)-1,4-
dihydropyridine (2c). Compound 2c was prepared from 1
and adamantanylamine in a manner similar to that described
for the preparation of 2a. 2c: 36%. Colorless crystals; mp
155–156 8C (recryst from CHCl3); IR (KBr) 2911, 2852,
4. Experimental
4.1. General
1
1734, 1674, 1595 cmK1; H NMR (400 MHz, CDCl3) d
1H NMR spectra were determined at 270, 400 or 500 MHz.
Infrared spectra were recorded on a NICOLET AVATAR-
320 spectrometer. EIMS, FABMS, EI(C)HRMS and
FAB(C)HRMS spectra were taken on a JEOL HMS 610H
or JEOL SX102 spectrometer.
6.45 (d, JZ8.3 Hz, 2H), 4.72 (d, JZ8.3 Hz, 2H), 3.72
(s, 6H), 2.14 (br s, 3H), 1.80 (br d, JZ2.4 Hz, 6H), 1.68
(br d, JZ12.1 Hz, 3H), 1.61 (br d, JZ12.1 Hz, 3H)
FAB(C) HRMS calcd for C19H26NO4 ([MCH]C)
332.1862, found 332.1860.
4.1.1. Dimethyl 2,2-bis(1,3-dioxolan-2-ylmethyl)malo-
nate (1). A mixture of dimethyl malonate (4.33 mL,
37.9 mmol) and KOtBu (5.10 g, 45.4 mmol) in DMSO
(100 mL) was stirred at room temperature for 1 h. Then,
2-bromomethyl-1,3-dioxolane (4.7 mL, 45.4 mmol) was
added, and the mixture was stirred at 80 8C for 12 h. The
solution was cooled to room temperature, and then
KOtBu (5.10 g, 45.4 mmol) was added, and stirred for 1 h.
2-Bromomethyl-1,3-dioxolane (4.7 mL, 45.4 mmol) was
added again, and the solution was stirred at 80 8C for
12 h. The solution was diluted with H2O, extracted with
EtOAc, and dried over MgSO4. Removal of the solvent
afforded an oily residue, which was purified by column
chromatography on silica gel (40% EtOAc in hexane) to
give 1 (5.25 g, 47%) as colorless crystals: mp 36–37 8C; IR
4.1.5. 1-[(1S)-Phenylethyl]-4,4-bis(methoxycarbonyl)-
1,4-dihydropyridine (2d). Compound 2d was prepared
from 1 and (S)-phenylethylamine in a manner similar to that
described for the preparation of 2a. 2d: 60%. A colorless oil;
[a]2D8ZK7.53 (c 0.95, CHCl3); IR (neat) 2978, 2954, 2902,
1
1739 cmK1; H NMR (270 MHz, CDCl3) d 7.22–7.37 (m,
5H), 6.18 (d, JZ8.0 Hz, 2H), 4.77 (d, JZ8.0 Hz, 2H), 4.45
(q, JZ6.9 Hz, 1H), 3.73 (s, 6H), 1.56 (d, JZ6.9 Hz, 3H);
EI-MS m/z 302 (MCCH), 6), 289 (51), 273 (24), 245 (83),
199 (70), 185 (74), 139 (93), 97 (93), 59 (100);
FAB(C)HRMS calcd for C17H20NO4 ([MCH]C)
302.1392, found 302.1397.
4.1.6. 1-[(1S)-1-Methylpropyl]-4,4-bis(methoxy-car-
bonyl)-1,4-dihydropyridine (2e). Compound 2e was
prepared from 1 and (S)-2-aminobutane in a manner similar
to that described for the preparation of 2a. 2e: 41%. A
colorless oil; [a]2D5ZC12.5 (c 0.94, CHCl3); IR (neat) 2967,
2877, 1737, 1677, 1599 cmK1; 1H NMR (400 MHz, CDCl3)
d 6.11 (d, JZ7.7 Hz, 2H), 4.72 (d, JZ7.7 Hz, 2H), 3.73 (s,
6H), 3.06 (m, 1H), 1.43–1.53 (m, 2H), 1.16 (d, JZ6.7 Hz,
3H), 0.86 (t, JZ7.4 Hz, 3H); FAB(C)HRMS calcd for
C13H20NO4 ([MCH]C) 254.1392, found 254.1388.
(KBr) 2955, 2891, 1738 cmK1 1H NMR (500 MHz,
;
CDCl3) d 5.02 (t, JZ4.8 Hz, 2H), 3.89–3.93 (m, 4H),
3.78–3.82 (m, 4H), 3.71 (s, 6H), 2.45 (d, JZ4.8 Hz,
4H); EI-MS m/z 305 (MC, 1), 273 (2), 215 (2), 73 (100);
FAB(C)HRMS calcd for C13H21O8 ([MCH]C) 305.1236,
found 305.1241.
4.1.2. 1-Cyclopentyl-4,4-bis(methoxycarbonyl)-1,4-di-
hydropyridine (2a). A solution of 1 (1.0 g, 3.29 mmol) in
10% aqueous HCl (20 mL) and THF (20 mL) was stirred at
room temperature for 12 h. The solution was neutralized
with powdered NaHCO3, and then cyclopentylamine
(280 mg, 3.29 mmol) in THF (5 mL) was added. After
being stirred at room temperature for 3 h, the solution was
extracted with EtOAc, and dried over MgSO4. Removal of
the solvent afforded an oily residue, which was purified by
column chromatography on silica gel (15% EtOAc in
hexane) to give 2a (497 mg, 57%) as colorless crystals: mp
41–42 8C; IR (KBr) 2955, 2874, 1734, 1676, 1599,
4.1.7.
1-[(1R,2R,3R,5S)-Isopinocampheyl]-4,4-bis-
(methoxycarbonyl)-1,4-dihydropyridine (2f). Compound
2f was prepared from 1 and (1R,2R,3R,5S)-(K)-isopino-
campheylamine in a manner similar to that described for the
preparation of 2a. 2f: 56%. Colorless crystals; mp 80–81 8C
(recryst from CHCl3–MeOH); [a]2D3ZK22.5 (c 0.70,
CHCl3); IR (KBr) 2985, 2972, 2935, 2893, 1733, 1675,
1
1596 cmK1; H NMR (400 MHz, CDCl3) d 6.26 (d, JZ
8.1 Hz, 2H), 4.77 (d, JZ8.1 Hz, 2H), 3.73 (s, 6H), 3.48 (td,
JZ7.6, 10.1 Hz, 1H), 2.40 (m, 1H), 2.32 (m, 1H), 2.01 (m,
1H), 1.90 (m, 1H), 1.75–1.83 (m, 2H), 1.23 (s, 3H), 1.04 (d,
JZ7.1 Hz, 3H), 1.00 (s, 3H), 0.92 (d, JZ10.1 Hz, 1H);
FAB(C)HRMS calcd for C19H28NO4 ([MCH]C)
334.2018, found 334.2019. Anal. Calcd for C19H27O4N:
C, 68.44; H, 8.16; N 4.20. Found: C, 68.21; H, 8.16; N, 4.20.
1
1433 cmK1; H NMR (400 MHz, CDCl3) d 6.16 (d, JZ
8.1 Hz, 2H), 4.74 (d, JZ8.1 Hz, 2H), 3.73 (s, 6H), 3.56
(quintet, JZ7.0 Hz, 1H), 1.85–1.89 (m, 2H), 1.66–1.69 (m,
2H), 1.51–1.60 (m, 4H); FAB(C)HRMS calcd for
C14H20NO4 ([MCH]C) 266.1392, found 266.1392.
4.1.3. 1-Hexyl-4,4-bis(methoxycarbonyl)-1,4-dihydro-
pyridine (2b). Compound 2b was prepared from 1 and
n-hexylamine in a manner similar to that described for the
preparation of 2a. 2b: 55%. A colorless oil; IR (neat) 2953,
4.1.8. 1-Cyclopentyl-4,4-bis(methoxycarbonyl)piper-
idine (3a). A mixture of 2a (213 mg, 0.80 mmol) and 5%
Pd-C (100 mg) in MeOH (10 mL) was vigorously stirred
under H2 atmosphere for 12 h. The Pd-catalyst was filtered
off, and the filtrate was evaporated to leave an oily residue.
Purification by column chromatography on silica gel
(EtOAc) gave 3a (159 mg, 73%) as colorless crystals; mp
59–60 8C (recryst from CHCl3); IR (KBr) 3446, 2963, 2869,
1
2928, 2858, 1736, 1679, 1600 cmK1; H NMR (400 MHz,
CDCl3) d 6.07 (d, JZ7.9 Hz, 2H), 4.71 (d, JZ7.9 Hz, 2H),
3.73 (s, 6H), 3.08 (t, JZ7.2 Hz, 2H), 1.50 (quintet, JZ
6.8 Hz, 2H), 1.26–1.32 (m, 6H), 0.88 (t, JZ6.8 Hz, 3H);

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M. Oba et al. / Tetrahedron 61 (2005) 593–598
1
2806, 1728 cmK1; H NMR (400 MHz, CDCl3) d 3.73 (s,
6H), 2.40–2.46 (m, 5H), 2.17 (t, JZ5.6 Hz, 4H), 1.80–1.86
(m, 2H), 1.63–1.71 (m, 2H), 1.50–1.57 (m, 2H), 1.33–1.42
(m, 2H); 13C NMR (100 MHz, CDCl3) d 171.7, 67.4, 53.2,
52.5, 49.4, 30.8, 30.5, 24.1; FAB(C)HRMS calcd for
C14H24NO4 ([MCH]C) 270.1705, found 270.1705. Anal.
Calcd for C14H24O4N: C, 62.43; H, 8.61; N 5.20. Found: C,
62.59; H, 8.60; N, 5.09.
JZ9.5 Hz, 1H); FAB(C)HRMS calcd for C19H32NO4
([MCH]C) 338.2331, found 338.2328. Anal. Calcd for
C19H31O4N: C, 67.63; H, 9.26; N 4.15. Found: C, 67.59; H,
9.26; N, 4.14.
4.1.14. Methyl 1-cyclopentyl-4-(benzyloxycarbonyl-
amino)piperidine-4-carboxylate (Cbz-4a). A solution of
3a (200 mg, 0.743 mmol) and 0.1 N aqueous NaOH
(7.43 mL, 0.743 mmol) in MeOH (7 mL) was refluxed for
3 h. After removal of MeOH, the aqueous solution was
neutralized with 10% aqueous HCl. Removal of H2O in
vacuo afforded a crude monocarboxylic acid. A solution of
the crude acid, diphenylphosphoryl azide (DPPA,
0.192 mL, 0.89 mmol), Et3N (0.124 mL, 0.891 mmol), and
BnOH (0.092 mL, 0.891 mmol) in benzene (7 mL) was
refluxed for 6 h. After removal of the solvent, the oily
residue was purified by column chromatography (EtOAc) to
afford Cbz-4a (133 mg, 50%) as colorless crystals: mp
78–79 8C (recryst from CHCl3–MeOH); IR (KBr) 3331,
2951, 2870, 2814, 1735, 1715, 1690, 1526 cmK1; 1H NMR
(400 MHz, CDCl3) d 7.29–7.34 (m, 5H), 5.09 (s, 2H), 5.02
(s, 1H), 3.68 (br s, 3H), 2.75–2.85 (m, 2H), 2.50 (quintet,
JZ7.9 Hz, 1H), 2.15–2.30 (m, 4H), 2.01 (m, 2H), 1.84 (m,
2H), 1.63–1.73 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H);
FAB(C)HRMS calcd for C20H29N2O4 ([MCH]C)
361.2127, found 361.2128.
4.1.9. 1-Hexyl-4,4-bis(methoxycarbonyl)piperidine (3b).
Compound 3b was prepared from 2b in a manner similar to
that described for the preparation of 3a. 3b: 80%. A
colorless oil; IR (neat) 2952, 2930, 2857, 2812, 1736 cmK1
;
1H NMR (400 MHz, CDCl3) d 3.73 (s, 6H), 2.41 (br m, 4H),
2.27 (t, JZ7.7 Hz, 2H), 2.16 (t, JZ4.8 Hz, 4H), 1.45
(m, 2H), 1.27–1.30 (m, 6H), 0.88 (t, JZ7.2 Hz, 3H);
FAB(C)HRMS calcd for C15H28NO4 ([MCH]C)
286.2018, found 286.2014.
4.1.10. 1-Adamantanyl-4,4-bis(methoxycarbonyl)piper-
idine (3c). Compound 3c was prepared from 2c in a manner
similar to that described for the preparation of 3a. 3c: 82%.
Colorless crystals; mp 68–69 8C (recryst from CHCl3–
MeOH); IR (KBr) 2905, 2849, 1734 cmK1 1H NMR
;
(400 MHz, CDCl3) d 3.72 (s, 3H), 3.71 (s, 3H), 2.62 (br s,
4H), 2.14 (br s, 4H), 2.07 (br s, 3H), 1.67 (br s, 6H), 1.64
(br d, JZ12.0 Hz, 3H), 1.58 (br d, JZ12.0 Hz, 3H);
FAB(C)HRMS calcd for C19H30NO4 ([MCH]C)
336.2175, found 336.2179.
4.1.15. Methyl 1-hexyl-4-(benzyloxycarbonylamino)-
piperidine-4-carboxylate (Cbz-4b). Compound Cbz-4b
was prepared from 3b in a manner similar to that described
for the preparation of Cbz-4a. Cbz-4b: 40%. A colorless oil;
IR (neat) 3348 (br), 2953, 2930, 2857, 1739, 1716,
4.1.11. 1-[(1S)-Phenylethyl]-4,4-bis(methoxycarbonyl)-
piperidine (3d). Compound 3d was prepared from 2d in a
manner similar to that described for the preparation of 3a.
3d: 67%. A colorless oil; [a]2D4ZK15.4 (c 0.30, CHCl3); IR
1
1522 cmK1; H NMR (400 MHz, CDCl3) d 7.30–7.34 (m,
5H), 5.09 (s, 2H), 5.02 (s, 1H), 3.68 (br s, 3H), 2.71 (m, 2H),
2.31 (t, JZ7.7 Hz, 2H), 2.12–2.28 (m, 4H), 2.01 (m, 2H),
1.49 (m, 2H), 1.25–1.36 (m, 6H), 0.88 (t, JZ6.5 Hz, 3H);
FAB(C)HRMS calcd for C21H33N2O4 ([MCH]C)
377.2440, found 377.2445.
(neat) 3026, 2972, 2953, 2811, 1733 cmK1 1H NMR
;
(270 MHz, CDCl3) d 7.21–7.30 (m, 5H), 3.71 (s, 6H), 3.31
(q, JZ6.7 Hz, 1H), 2.31–2.47 (m, 4H), 2.12 (t, JZ5.6 Hz,
4H), 1.32 (d, JZ6.7 Hz, 3H); EI-MS m/z 306 (MCCH, 21),
305 (MC, 14), 291 (59), 290 (100), 228 (52);
FAB(C)HRMS calcd for C17H24NO4 ([MCH]C)
306.1705, found 306.1701.
4.1.16. Methyl 1-adamantanyl-4-(benzyloxycarbonyl-
amino)piperidine-4-carboxylate (Cbz-4c). Compound
Cbz-4c was prepared from 3c in a manner similar to that
described for the preparation of Cbz-4a. Cbz-4c: 50%.
Colorless crystals; mp 112–113 8C; IR (CDCl3) 3438 (br),
2908, 2853, 1736, 1724 cmK1; 1H NMR (400 MHz, CDCl3)
d 7.30–7.39 (m, 5H), 5.09 (s, 2H), 4.95 (br s, 1H), 3.68 (br s,
3H), 2.90 (m, 2H), 2.42 (br t, JZ10.8 Hz, 2H), 1.97–2.18
(m, 7H), 1.73 (br s, 6H), 1.68–1.74 (m, 6H), 1.59 (d, JZ
12.1 Hz, 3H), 1.67 (d, JZ12.1 Hz, 3H); FAB(C)HRMS
calcd for C25H35N2O4 ([MCH]C) 427.2597, found
427.2599.
4.1.12. 1-[(1S)-1-Methylpropyl]-4,4-bis(methoxy-car-
bonyl)piperidine (3e). Compound 3e was prepared from
2e in a manner similar to that described for the preparation
of 3a. 3e: 86%. A colorless oil; [a]2D8ZC9.91 (c 0.91,
CHCl3); IR (neat) 2961, 1736 cmK1; H NMR (400 MHz,
1
CDCl3) d 3.73 (s, 6H), 2.48–2.54 (m, 2H), 2.38–2.46 (m,
3H), 2.10–2.16 (m, 4H), 1.51 (m, 1H), 1.25 (m, 1H), 0.92 (d,
JZ6.6 Hz, 3H), 0.87 (t, JZ7.4 Hz, 3H); FAB(C)HRMS
calcd for C13H24NO4 ([MCH]C) 258.1705, found
258.1710.
4.1.17. Methyl 1-[(1S)-phenylethyl]-4-(benzyloxy-car-
bonylamino)piperidine-4-carboxylate (Cbz-4d). Com-
pound Cbz-4d was prepared from 3d in a manner similar
to that described for the preparation of Cbz-4a. Cbz-4d:
41%. A colorless oil; [a]2D5ZK23.2 (c 0.49, CHCl3); IR
4.1.13. 1-[(1R,2R,3R,5S)-Isopinocampheyl]-4,4-bis-
(methoxycarbonyl)piperidine (3f). Compound 3f was
prepared from 2f in a manner similar to that described for
the preparation of 3a. 3f: 76%. Colorless crystals; mp 69–
70 8C (recryst from CHCl3–MeOH); [a]2D4ZK24.2 (c 1.60,
CHCl3); IR (KBr) 2992, 2935, 2873, 1732 cmK1; 1H NMR
(400 MHz, CDCl3) d 3.73 (s, 6H), 2.86 (td, JZ6.4, 9.9 Hz,
1H), 2.51–2.61 (m, 4H), 2.22 (m, 1H), 2.15 (t, JZ5.4 Hz,
4H), 1.98–2.06 (m, 2H), 1.90 (m, 1H), 1.74–1.80 (m, 2H),
1.18 (s, 3H), 1.06 (d, JZ7.1 Hz, 3H), 0.97 (s, 3H), 0.87 (d,
(neat) 3346 (br), 3030, 2952, 2815, 1732, 1710, 1520 cmK1
;
1H NMR (400 MHz, CDCl3) d 7.22–7.37 (m, 10H), 5.02 (s,
2H), 4.91 (br s, 1H), 3.67 (br s, 3H), 3.41 (q, JZ6.4 Hz, 1H),
2.83 (m, 1H), 2.62 (m, 1H), 2.11–2.25 (m, 4H), 2.05 (m,
1H), 1.93 (m, 1H), 1.36 (d, JZ6.4 Hz, 3H); EI-MS m/z 396
(MC, 5), 381 (57), 319 (8), 291 (47), 273 (12), 140 (97), 105

M. Oba et al. / Tetrahedron 61 (2005) 593–598
597
(41), 91 (100); FAB(C)HRMS calcd for C23H29N2O4
([MCH]C) 397.2127, found 397.2126; HPLC analysis:
column, Chiralcel OD 0.46f!25 cm; eluent, 5% iso-PrOH
2.84 (m, 1H), 2.59 (m, 1H), 2.08–2.26 (m, 4H), 1.97 (m,
1H), 1.87 (m, 1H), 1.42 (s, 9H), 1.34 (d, JZ6.6 Hz, 3H);
FAB(C)HRMS calcd for C20H31N2O4 ([MCH]C)
363.2284, found 363.2282.
in hexane; flow rate, 1 mL/min; detection, UV254 nm
;
retention time (tR), Cbz-(G)-4d: 36 and 42 min, Cbz-(S)-
4d: 42 min.
4.1.22. Methyl 1-cyclopentyl-4-[(9-fluorenylmethoxy-
carbonyl)amino]piperidine-4-carboxylate (Fmoc-4a). A
solution of 3a (124 mg, 0.460 mmol)) and 0.1 N aqueous
NaOH (4.60 mL, 0.460 mmol) in MeOH (10 mL) was
refluxed for 3 h. After removal of MeOH, the aqueous
solution was neutralized with 10% aqueous HCl. Removal
of H2O in vacuo afforded a crude monocarboxylic acid. A
solution of the crude acid, DPPA (0.119 mL, 0.553 mmol),
and Et3N (0.077 mL, 0.553 mmol) in benzene (3 mL) was
refluxed for 1 h. Then, 9-fluorenylmethanol (108 mg,
0.553 mmol) was added, and the solution was refluxed for
5 h. After removal of the solvent, the oily residue was
purified by column chromatography (4% MeOH in CHCl3)
to afford Fmoc-4a (121 mg, 59%) as colorless crystals; mp
160 8C (decomp.); IR (KBr) 3371 (br), 2953, 2867, 1729,
1605, 1448 cmK1; 1H NMR (400 MHz, CDCl3) d 7.76 (br d,
JZ7.5 Hz, 2H), 7.59 (br d, JZ7.5 Hz, 2H), 7.40 (br t, JZ
7.5 Hz, 2H), 7.31 (br t, JZ7.5 Hz, 2H), 4.93 (s, 1H), 4.42 (d,
JZ6.5 Hz, 2H), 4.23 (t, JZ6.5 Hz, 1H), 3.68 (br s, 3H),
2.71–2.82 (m, 2H), 2.51 (quintet, JZ8.0 Hz, 1H), 2.11–2.29
(m, 4H), 1.91–2.09 (m, 2H), 1.84–1.86 (m, 2H), 1.65–1.73
(m, 2H), 1.54–1.60 (m, 2H), 1.35–1.44 (m, 2H);
FAB(C)HRMS calcd for C27H33N2O4 ([MCH]C)
449.2440, found 449.2436.
4.1.18. Methyl 1-[(1S)-1-methylpropyl]-4-(benzyloxy-
carbonylamino)piperidine-4-carboxylate (Cbz-4e). Com-
pound Cbz-4e was prepared from 3e in a manner similar to
that described for the preparation of Cbz-4a. Cbz-4e: 61%.
A colorless oil; [a]2D5ZC8.75 (c 1.0, CHCl3); IR (neat)
3350 (br), 2961, 1739, 1715, 1523 cmK1 1H NMR
;
(400 MHz, CDCl3) d 7.31–7.35 (m, 5H), 5.09 (s, 2H),
4.93 (br s, 1H), 3.69 (br s, 3H), 2.60–2.65 (m, 2H), 2.42–
2.51 (m, 2H), 2.36 (m, 1H), 2.10–2.20 (m, 2H), 1.98–2.01
(m, 2H), 1.54 (m, 1H), 1.26 (m, 1H), 0.96 (d, JZ6.6 Hz,
3H), 0.88 (t, JZ7.4 Hz, 3H); FAB(C)HRMS calcd for
C19H29N2O4 ([MCH]C) 349.2127, found 349.2130.
4.1.19. Methyl 1-[(1R,2R,3R,5S)-isopinocampheyl]-4-
(benzyloxycarbonylamino)piperidine-4-carboxylate
(Cbz-4f). Compound Cbz-4f was prepared from 3f in a
manner similar to that described for the preparation of Cbz-
4a. Cbz-4f: 30%. Colorless crystals; mp 106–107 8C
(recryst from MeOH); [a]2D4ZK21.7 (c 0.89, CHCl3); IR
(KBr) 3356, 2952, 2920, 1735, 1712, 1531 cmK1; 1H NMR
(400 MHz, CDCl3) d 7.31–7.36 (m, 5H), 5.09 (s, 2H), 4.97
(br s, 1H), 3.69 (br s, 3H), 2.90 (td, JZ6.4, 4.5 Hz, 1H), 2.78
(br t, JZ11.4 Hz, 2H), 2.47 (td, JZ10.9, 21.8 Hz, 2H),
2.13–2.25 (m, 3H), 1.92–2.09 (m, 6H), 1.76–1.84 (m, 2H),
1.19 (s, 3H), 1.08 (d, JZ6.9 Hz, 3H), 0.97 (s, 3H), 0.88 (d,
JZ9.6 Hz, 1H); FAB(C)HRMS calcd for C25H37N2O4
([MCH]C) 429.2753, found 429.2758.
4.1.23. Methyl 1-[(1S)-phenylethyl]-4-aminopiperidine-
4-carboxylate (H2N-4d). A solution of 3d (200 mg,
0.655 mmol) and 0.1 N aqueous NaOH (6.55 mL,
0.655 mmol) in MeOH (8 mL) was refluxed for 3 h. After
removal of MeOH, the aqueous solution was neutralized
with 10% aqueous HCl. Removal of H2O in vacuo afforded
a crude monocarboxylic acid. A solution of the crude acid,
DPPA (0.169 mL, 0.786 mmol), and Et3N (0.110 mL,
0.786 mmol) in benzene (5 mL) was refluxed for 2 h.
Removal of the solvent afforded an oily residue, which was
dissolved in 10% aqueous HCl (3 mL), and stirred at room
temperature for 1 h. Then, the solution was diluted with 5%
aqueous NaHCO3, extracted with EtOAc, and dried over
MgSO4. Removal of the solvent and purification by column
chromatography afforded H2N-4d (69 mg, 40%) as a
colorless oil: [a]2D6ZK14.9 (c 1.70, CHCl3); IR (neat)
4.1.20. Methyl 1-cyclopentyl-4-(t-butoxycarbonyl-
amino)piperidine-4-carboxylate (Boc-4a). A solution of
3a (254 mg, 0.943 mmol) and 0.1 N aqueous NaOH
(9.43 mL, 0.743 mmol) in MeOH (10 mL) was refluxed
for 3 h. After removal of MeOH, the aqueous solution was
neutralized with 10% aqueous HCl. Removal of H2O in
vacuo afforded a crude monocarboxylic acid. A solution of
the crude acid, DPPA (0.447 mL, 2.08 mmol), Et3N
(0.158 mL, 1.13 mmol) in t-BuOH (10 mL) was refluxed
for 6 h. After removal of the solvent, the oily residue was
purified by column chromatography (4% MeOH in CHCl3)
to afford Boc-4a (156 mg, 51%) as a colorless oil: IR (neat)
1
3375 (br), 3305 (br), 2951, 2816, 1729, 1600 cmK1; H
1
3354 (br), 2956, 1732, 1716 cmK1; H NMR (400 MHz,
NMR (400 MHz, CDCl3) d 7.21–7.32 (m, 5H), 3.70 (s, 6H),
3.41 (q, JZ6.7 Hz, 1H), 2.60 (m, 1H), 2.42–2.52 (m, 3H),
2.03–2.15 (m, 2H), 1.63 (br s, 2H), 1.48–1.57 (m, 2H), 1.36
(d, JZ6.7 Hz, 3H); FAB(C)HRMS calcd for C15H23N2O2
([MCH]C) 263.1760, found 263.1758.
CDCl3) d 4.68 (br s, 1H), 3.72 (s, 3H), 2.80 (br d, JZ
12.2 Hz, 2H), 2.54 (quintet, JZ7.8 Hz, 1H), 2.29 (m, 2H),
2.18 (dt, JZ3.1, 12.2 Hz, 2H), 1.97 (br d, JZ12.7 Hz, 2H),
1.82–1.89 (m, 2H), 1.64–1.72 (m, 2H), 1.49–1.59 (m, 2H),
1.37–1.45 (m, 2H), 1.43 (s, 9H); FAB(C)HRMS calcd for
C17H31N2O4 ([MCH]C) 327.2284, found 327.2279.
4.1.24. 1-[(1S)-Phenylethyl]-4-(benzyloxycarbonyl-
amino)piperidine-4-carboxylic acid (5d). 0.1 N Aqueous
NaOH solution (1.6 mL) was added to the stirred solution of
Cbz-4d (41 mg, 0.105 mmol) in MeOH (1 mL), and the
whole was refluxed for 6 h. After evaporation of MeOH, the
aqueous solution was washed with hexane, neutralized with
5% aqueous HCl, and the solution was concentrated in
vacuo. The residue was dissolved in MeOH, and filtered.
Evaporation of MeOH afforded an acid 5d (40 mg, quant.)
as a yellowish powder: [a]2D5ZK25.8 (c 0.66, CHCl3); IR
4.1.21. Methyl 1-[(1S)-phenylethyl]-4-(t-butoxycarbonyl-
amino)piperidine-4-carboxylate (Boc-4d). Compound
Boc-4d was prepared from 3d in a manner similar to that
described for the preparation of Boc-4a. Boc-4d: 43%. A
colorless oil; [a]2D6ZK18.2 (c 0.68, CHCl3); IR (neat) 3367
(br), 2975, 2813, 1740, 1705, 1495 cmK1 1H NMR
;
(400 MHz, CDCl3) d 7.30 (d, JZ4.3 Hz, 4H), 7.23 (m,
1H), 4.61 (br s, 1H), 3.71 (s, 3H), 3.38 (q, JZ6.6 Hz, 1H),

598
M. Oba et al. / Tetrahedron 61 (2005) 593–598
1
(KBr) 3307 (br), 1705, 1588 cmK1; H NMR (500 MHz,
CD3OD) d 7.21–7.40 (m, 10H), 5.01 (s, 2H), 3.45 (q, JZ
6.9 Hz, 1H), 2.89 (m, 1H), 2.60 (m, 1H), 2.20–2.35 (m, 2H),
1.90–2.20 (m, 4H), 1.39 (d, JZ6.9 Hz, 3H); FAB(C)MS
m/z 405 ([MCNa]C), 383 ([MCH]C); FAB(C)HRMS
calcd for C22H27N2O4 ([MCH]C) 383.1971 found
383.1952.
Valle, G.; Valente, E.; Bianco, A.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Int, J. Peptide Res. 1996, 47, 231–238. (c) Wolf,
W. M.; Stasiak, M.; Leplawy, M. T.; Bianco, A.; Formaggio,
F.; Crisma, M.; Toniolo, C. J. Am. Chem. Soc. 1998, 120,
11558–11566. (d) Saviano, M.; Iacovino, R.; Benedetti, E.;
Moretto, V.; Banzato, A.; Formaggio, F.; Crisma, M.; Toniolo,
C. J. Peptide Sci. 2000, 6, 571–583. (e) Ohwada, T.; Kojima,
D.; Kiwada, T.; Futaki, S.; Sugiura, Y.; Yamaguchi, K.; Nishi,
Y.; Kobayashi, Y. Chem. Eur. J. 2004, 10, 617–626. (f)
Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
Angew. Chem., Int. Ed. 2004, 43, 5360–5363.
Acknowledgements
This work was partly supported by a Grant-in-Aid for
Scientific Research (C) from Japan Society for the
Promotion of Science, and also supported by a grant from
the Takeda Science Foundation.
6. (a) Yokum, T. S.; Elzer, P. H.; McLaughlin, M. L. J. Med.
Chem. 1996, 39, 3603–3605. (b) Yokum, T. S.; Gauthier, T. J.;
Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997,
119, 1167–1168.
7. Wysong, C. L.; Yokum, T. S.; Moraqles, G. A.; Gundry, R. L.;
McLaughlin, M. L.; Hammer, R. P. J. Org. Chem. 1996, 61,
7650–7651.
¨
8. (a) Strassler, C.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
1997, 80, 1528–1554. (b) Ota, H.; Chyouma, T.; Iso, S.; Satoh,
T. Tetrahedron Lett. 2004, 45, 3903–3907.
References and notes
1. (a) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227.
(b) Cativiela, C.; D. de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 9, 3517–3599 and 2000, 11, 645–732.
2. For recent reviews, see: (a) Wysong, C. L.; Yokum, T. S.;
McLaughlin, M. L.; Hammer, R. P. Chemtech 1997, 26–33. (b)
Benedetti, E. Biopolymers (Peptide Science) 1996, 40, 3–44.
(c) Tanaka, M. J. Synth. Org. Chem. Jpn 2002, 60, 125–136.
(d) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.
Biopolymers (Peptide Science) 2001, 60, 396–419.
9. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203–6205. (b) Ninomiya, K.; Shioiri, T.; Yamada,
S. Tetrahedron 1974, 30, 2151–2157. (c) Evans, D. A.; Wu,
L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow,
J. S. J. Org. Chem. 1999, 64, 6411–6417. (d) Ghosh, A. K.;
Fidanze, S. J. Org. Chem. 1998, 63, 6146–6152. (e) Spino, C.;
Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106–12107.
10. Hydrolysis of the ester in Fmoc-Pip-OMe did not work well.
11. (a) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.;
Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E.
J. Am. Chem. Soc. 2003, 125, 13525–13530. (b) Cheuk,
K. K. L.; Lam, J. W. Y.; Chen, J. C.; Lai, L. M.; Tang, B. Z.
Macromolecules 2003, 36, 5947–5959.
3. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem.
2001, 66, 2667–2673.
4. (a) Imawaka, N.; Tanaka, M.; Suemune, H. Helv. Chim. Acta
2000, 83, 2823–2835. (b) Oba, M.; Tanaka, M.; Kurihara, M.;
Suemune, H. Helv. Chim. Acta 2002, 85, 3197–3218. (c)
Tanaka, M.; Nishimura, S.; Oba, M.; Demizu, Y.; Kurihara,
M.; Suemune, H. Chem. Eur. J. 2003, 9, 3082–3090.
12. (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell,
D. R.; Huang, X.; Barchi, J. J. Jr.; Gellman, S. H. Nature 1997,
387, 381–384. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31,
173–180. (c) Seebach, D.; Matthews, J. L. Chem. Commun.
1997, 2015–2022.
5. (a) Paul, P. K. C.; Sukumar, M.; Bardi, R.; Piazzesi, A. M.;
Valle, G.; Toniolo, C.; Balaram, P. J. Am. Chem. Soc. 1986,
108, 6363–6370. (b) Flippen-Anderson, J. L.; George, C.;