A novel approach for the asymmetric synthesis of (3S,4R)-3-amino-4-alkyl-2-piperidinones: Conformationally constrained dipeptides

Article abstract of DOI:10.1016/S0040-4039(01)01847-0

A straightforward method is developed for the synthesis of enantiopure (3S,4R)-3-amino-4-alkyl-2-piperidinone derivatives, six-membered lactam-bridged dipeptides, via highly diastereofacial selective 1,4-addition of organocuprate to the chiral oxazolidine

Full text of DOI:10.1016/S0040-4039(01)01847-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8483–8484
A novel approach for the asymmetric synthesis of
(3S,4R)-3-amino-4-alkyl-2-piperidinones: conformationally
constrained dipeptides
Ce´line Flamant-Robin, Qian Wang and N. Andre´ Sasaki*
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
Received 24 July 2001; revised 2 October 2001; accepted 3 October 2001
Abstract—A straightforward method is developed for the synthesis of enantiopure (3S,4R)-3-amino-4-alkyl-2-piperidinone
derivatives, six-membered lactam-bridged dipeptides, via highly diastereofacial selective 1,4-addition of organocuprate to the
chiral oxazolidine a,b-unsaturated ester 1 as the key step. © 2001 Elsevier Science Ltd. All rights reserved.
Lactams have been considered to be a useful type of
conformational constraint in peptide backbones. Incor-
poration of such lactams into pharmacologically impor-
tant peptides may provide useful information regarding
the bioactive conformation, enhance biological potency
and/or increase metabolic stability relative to
unmodified original peptides. This concept has led
numerous groups to develop lactam-bridged dipeptides
as conformationally constrained mimics of peptide
derivatives.1 However, in order for the use of these
mimetics in peptide synthesis to be practical, certain
criteria are to be met. For instance, (i) synthetic route
provides enantiomerically pure lactams, (ii) a sub-
stituent that represents the side chain of the former
amino acid residue is attached at the specific position of
a lactam ring, (iii) the nitrogen atom of a lactam is the
part of an amino acid so that the extension of the
peptide chain can be continued. For the five-membered
lactam-bridged dipeptides, two groups have developed
general synthetic methodologies that satisfy the above
criteria.2 On the other hand, surprisingly, only a few
laborious syntheses have been reported to obtain the
six-membered analogs to the best of our knowledge3
(Fig. 1).
tiomerically pure (3S,4R)-3-amino-4-alkyl-2-piperidi-
none derivatives, d-lactam-bridged dipeptides.
Thus, the a,b-unsaturated ester 1 with E configuration
was obtained according to the methods known in the
literature.4 The 1,4-addition of dimethylcuprate to the
chiral oxazolidine a,b-unsaturated ester 1 in the pres-
ence of trimethylsilyl chloride provided the single
diastereoisomer, syn-2, in 94% yield with excellent
diastereofacial selectivity.5,6 Reduction of
LiAlH4 followed by Swern oxidation gave the aldehyde
2 with
3 in 94% yield (two steps). The aldehyde 3 was then
treated with L-phenylalanine methyl ester in the pres-
ence of NaBH(OAc)3 to provide the amine 47 in 90%
yield. It is worthy to note that in this reductive amina-
tion, the use of THF instead of dichloroethane as
solvent and the free amine in lieu of the hydrochloric
salt of the methyl ester of L-phenylalanine afforded the
optimal yield. The protection of the amine with Cbz
group followed by treatment with Jones’ reagent gave
the acid 6 in 76% yield (two steps). Transformation of
the acid 6 into the pentafluorophenol ester and subse-
quent catalytic hydrogenolysis led to the lactam 78 in
58% yield (two steps) (Scheme 1).
In this report, we describe the preliminary result of our
straightforward approach for the synthesis of enan-
Keywords: peptidomimetics; 3-amino-4-alkyl-2-piperidinone; d-lac-
tam-bridged dipeptide.
* Corresponding author. Fax: +330169077247; e-mail: andre.sasaki@
icsn.cnrs-gif.fr
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01847-0

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C. Flamant-Robin et al. / Tetrahedron Letters 42 (2001) 8483–8484
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CHO
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4
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vi
Cbz
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N
N
BocN
BocHN
Ph
CO2Me
Ph
CO2H
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CO2Me
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5
6
vii , viii
6. Spectral data for 2 (two rotamers): [h]D=+18 (c 2,
CHCl3), lit. [h]D=+19.8 (c 2.18, CHCl3) (Ref. 5a); 1H
NMR (CDCl3, 250 MHz): l 0.95 (d, 3H, J=6.7 Hz), 1.26
(t, 3H, J=7.2 Hz), 1.45–1.63 (m, 15H), 1.96–2.20 (m, 1H),
2.46–2.56 (m, 2H), 3.77–3.96 (m, 3H), 4.14 (q, 2H, J=7.2
Hz); 13C NMR (CDCl3, 62.5 MHz): l 14.3, 16.5, 16.7,
22.7, 24.0, 26.3, 26.9, 28.4, 32.6, 33.0, 36.5, 37.1, 60.3, 61.2,
64.2, 80.0, 94.0, 94.3, 152.5, 173.2; MS (ESI) m/z 316
[M+H]+, 338 [M+Na]+, 653 [2M+Na]+. Anal. calcd for
C24H38N2O5: C, 60.93; H, 9.27; N, 4.44. Found: C, 60.84;
H, 9.51; N, 4.31.
7. Spectral data for 4 (two rotamers): [h]D=+29 (c 3.3,
CHCl3); 1H NMR (CDCl3, 300 MHz): l 0.83 (d, 3H,
J=7.2 Hz), 1.17–1.25 (m, 1H), 1.47 (s, 12H), 1.55–1.68 (m,
4H), 1.80–2.05 (m, 1H), 2.35–2.49 (m, 1H), 2.68 (dt, 1H,
J=5.1, 10.8 Hz), 2.94 (d, 2H, J=7.2 Hz), 3.51 (t, 1H,
J=7.2 Hz), 3.63 (s, 3H), 3.76–3.89 (m, 3H), 7.15–7.31 (m,
5H); 13C NMR (CDCl3, 75 MHz): l 16.3, 22.8, 24.3, 26.3,
26.9, 28.4, 32.0, 33.3, 33.7, 39.7, 46.4, 51.5, 61.9, 63.1, 64.5,
65.0, 79.5, 79.8, 93.6, 94.0, 126.6, 128.3, 129.1, 137.3,
152.5, 152.9, 175.0; MS (ESI) m/z 435 [M+H]+, 457 [M+
Na]+, 473 [M+K]+. Anal. calcd for C24H38N2O5: C, 66.33;
H, 8.81; N, 6.45. Found: C, 66.09; H, 8.84; N, 6.47.
8. Spectral data for 7: [h]D=−59 (c 2.8, CHCl3); 1H NMR
(CDCl3, 300 MHz): l 1.00 (d, 3H, J=5.1 Hz), 1.20–1.44
(m, 10H), 1.65–1.86 (m, 2H), 2.98–3.27 (m, 3H), 3.31–3.42
(dd, 1H, J=5.6, 14.4 Hz), 3.65–3.72 (m, 4H), 4.98–5.11
(m, 2H), 7.21–7.38 (m, 5H); 13C NMR (CDCl3, 75 MHz):
l 18.8, 28.2, 29.3, 34.0, 34.2, 43.8, 52.2, 57.2, 58.9, 79.3,
126.7, 128.5, 128.7, 136.8, 156.4, 170.3, 170.8; MS (CI) m/z
391 [M+H]+; HRMS calcd for C21H31N2O5 (M+1):
391.2232. Found: 391.2243.
N
BocHN
Ph
CO2Me
O
7
Scheme 1. Reagents and conditions: (i) Me2CuLi, Me3SiCl,
THF, −78°C to rt, 94%; (ii) LiAlH4, THF, rt, 2 h, 98%; (iii)
(COCl)2, DMSO, CH2Cl2, −78°C, Et3N, 96%; (iv) L-phenyl-
alanine methylester, NaBH(OAc)3, THF, rt, 15 h, 90%; (v)
CbzCl, Na2CO3, THF/H2O: 3/1, rt, 1 h, 85%; (vi) Jones’
reagent, acetone, 0°C to rt, 1 h, 89%; (vii) C6F5OH, EDC,
CH2Cl2, 0°C to rt, 1 h, 74%; (viii) H2, 10% Pd/C, MeOH, 3 h,
79%.
In conclusion, we have developed a concise method for
the synthesis of enantiomerically pure six-membered
lactam-bridged dipeptides that can be incorporated into
biologically important peptides. Further work is in
progress in order to obtain analogs of the lactam 7 with
various substituents at the C-4 position of the piperidi-
none moiety.
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