Homo-Freidinger lactams: Stereoselective synthesis of 4-aminopiperidin-2-one derivatives from aspartic acid

Article abstract of DOI:10.1055/s-1998-1786

Starting from aspartic acid a stereoselective synthesis of enantiomerically pure 4-aminopiperidin-2-ones which can serve as conformationally restrained β-amino acid equivalents in peptidomimetics is described. The synthesis is based on the regioselective

Full text of DOI:10.1055/s-1998-1786

August 1998
SYNLETT
885
Homo-Freidinger Lactams: Stereoselective Synthesis of 4-Aminopiperidin-2-one Derivatives
from Aspartic Acid
Klaus Weber and Peter Gmeiner*
Institut für Pharmazie und Lebensmittelchemie der Universität Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany
Fax: +49(9131)852585; E-mail: gmeiner@pharmazie.uni-erlangen.de
Received 20 April 1998-06-23
Abstract: Starting from aspartic acid a stereoselective synthesis of
enantiomerically pure 4-aminopiperidin-2-ones which can serve as
conformationally
restrained
ß-amino
acid
equivalents
in
peptidomimetics is described. The synthesis is based on the
regioselective functionalization of the 1,4-bis-electrophile 2b and a
diastereoselective introduction of various side chain equivalents into the
lactam α-position of 4b,c.
Conformationally locked peptide surrogates have been utilized
extensively in the design and development of enzyme inhibitors or
1-4
neuroreceptor ligands.
This strategy afforded valuable information
regarding the elucidation of the biologically active conformation of
peptides and led to drug candidates with remarkable affinity, selectivity
5
and metabolic stability. Among the numerous developments in this
field, incorporating the α-amino carboxamide moiety of a peptide
6-10
backbone into a Freidinger lactam (I) has proven very successful.
On
the other hand, ß-amino acid derived substructures and the investigation
11-13
of ß-peptides led to interesting peptidomimetics.
As far as we
know, a combination of these two strategies was not reported yet.
As part of our efforts on the synthesis of enantiopure ß-amino acid
14,15
derivatives,
here we report the first stereoselective synthesis of 4-
aminopiperidin-2-ones as lactam-bridged analogs with a ß-amino
carboxamide substructure (Homo-Freidinger lactams, II). Applying this
approach, our initial results on lactam-constrained mimetics of the
16
dopamine receptor modulating peptide Pro-Leu-Gly-NH
presented.
are
2
Since 4a should serve as a versatile building block, introduction of
substituents representing ß-amino acid side chains was envisioned. This
should be done by N-protection, deprotonation of the lactam α-position
and subsequent reaction with representing electrophiles. We evaluated
Boc and, alternatively, benzyl as protecting groups for the lactam
The synthesis of a N-protected 4-aminopiperidine in enantiomerically
pure form was planned starting from natural aspartic acid (1). Taking
advantage of our recently described methodology we were able to
function. Thus, deprotonation of the lactam 4 followed by addition of
functionalize regioselectively the dibenzyl protected aminobutanediol
23
Boc O or BnBr afforded 4b and 4c, respectively. For the introduction
2
17-20
2a.
Thus, activation of 2a by MesCl gave the bis-electrophile 2b
24
of the Boc group reaction of 4a with Boc O in the presence of DMAP
2
which could be transformed into the azido nitrile 3a by subsequent
turned out to be the more convenient and higher yielding alternative. C-
alkylation in position 3 was accomplished by deprotonation of 4b with
LDA and subsequent trapping with MeI at -78°C. The reaction
proceeded with high diastereoselectivity. Only the trans isomer 5a could
substitution with LiCN and NaN . Due to an activating anchimeric
3
participation of the dibenzylamino group the leaving group in position 1
is exclusively displaced by the nucleophile which is added first. The
formation of regioisomers was not observed. Chemoselective reduction
of the azide functionality in the presence of the nitrile group was
25
be detected by NMR spectroscopy of the crude reaction product. After
purification by flash chromatography the methylation product 5a, which
21
accomplished under Staudinger conditions giving the amino nitrile 3b
2
26
represents a conformatively restricted equivalent for ß -homoalanine,
in 81 % yield. Alternatively, a more direct preparation of 3b is possible
was isolated in 75% yield. Analogously, deprotonation and methylation
of the N-benzyl protected lactam 4c resulted in exclusive formation of
trans configured isomer 5b. Since the methylation of 4b proceeded in
higher yield and enabled the performance of a selective cleavage of
either N-substituents we chose the orthogonally protected lactam 4b for
22
when liquid NH is used as the “second nucleophile” instead of NaN .
3
3
Lactamization of the amino nitrile 3b was induced by HCl/MeOH. The
reaction sequence is highly practical and efficient providing the amino
lactam 4a in 58 % overall yield, based on (S)-aspartic acid (1), as well as
the (R)-configured enantiomer of 4a (ent-4a) when commercially
available (R)-aspartic acid (ent-1) is used as the starting material.
2
further alkylation reactions. Thus, the lactam bridged ß -
homophenylalanine derivative 5c could be obtained from 4b in
diastereomerically pure form when benzyl bromide was used as an

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electrophile (yield: 85 %). Furthermore, highly diastereoselective
introduction of an allyl, propynyl or TMS-propynyl substituent could be
accomplished. Thus, deprotonation of 4b and subsequent reaction with
allyl iodide, propynyl bromide as well as TMS-propynyl bromide
27
resulted in formation of the products 5d, 5e and 5f, respectively.
Electrophilic fluorination employing NFSI (N-fluorobenzene
28
sulfonimide) afforded the α-fluoro lactam 5g. In all cases, the
electrophilic attack at the enolate occurs exclusively from the bottom
29
side (re). Obviously, the si-face is strongly shielded by the sterically
demanding dibenzylamine substituent. Structural analysis of the
1
alkylation products was performed by H NMR spectroscopy when
diagnostic coupling constants and NOEs indicate
a half-chair
conformation and an equatorial disposition for both the dibenzylamine
and the introduced substituents.
The incorporation of the described Homo-Freidinger lactams into
conformationally restricted mimetics of the dopamine receptor
16, 30
modulating peptide Pro-Leu-Gly-NH
and their investigation for
2
biological activity are currently investigated in our laboratories. Using
the (S)-configured building block 4a as an representative example the
preparation of such a tripeptide surrogate is reported. Thus, N-
deprotonation of the aminopiperidinone 4a by KH and subsequent
reaction with ethyl bromoacetate led to formation of the N-alkylation
product 6a incorporating a Gly subunit. Coupling of the amino function
with Pro was accomplished by hydrogenolytic N-debenzylation and
subsequent DCC/HOBT induced acylation of the primary amine 6b
with Cbz-Pro. Finally, aminolysis of the ester functionality of the
coupling product 7a afforded 7b which could be readily N-deprotected
to give the lactam-restricted Pro-Leu-Gly-NH analog 7c in good
2
overall yield.
relationship studies of conformationally restrained dopamine receptor
modulating peptide mimetics will be reported shortly.
Acknowledgments: This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie. Dr.
R. Waibel is acknowledged for NMR studies and helpful discussions.
Tanks are also due to Mrs. E. Tigla for skillful technical assistance.
References and Notes
(1) Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303.
(2) Beck-Sickinger, A.G. In Methods in Molecular Biology,
Neuropeptide Protocols; Irvine, G.B.; Williams, C.H., Ed.;
Humana Press: Totowa, NJ, 1997; p 61.
In conclusion, an efficient and practical approach to enantiomerically
pure 4-aminopiperidin-2-ones including 3-substituted derivatives and
their application as peptidomimetics with Homo-Freidinger lactam
substructure is presented. Further investigations on structure activity
(3) Vacca, J.P.; Condra, J.H. Drug Discovery Today 1997, 2, 261.

August 1998
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887
21
1
(4) Blommaert, A.G.S.; Dhôtel, H.; Ducos, B.; Durieux, C.;
Goudreau, N.; Bado, A.; Garbay, C.; Roques, B.P. J. Med. Chem.
1997, 40, 647.
[α]D = -31.3°, (c = 0.9, CHCl ); H NMR (CDCl ): δ(ppm) =
3
3
1.46 - 1.63 (m, 1H, 4-H ), 1.83 - 2.01 (m, 1H, 4-H ), 2.41 (dd, J =
16.8, 6.8 Hz, 1H, 2-H ), 2.58 (dd, J = 16.8, 6.3 Hz, 1H 2-H ), 2.74
a
b
a
b
- 2.81 (m, 2H, 5-H), 3.07 - 3.20 (m, 1H, 3-H), 3.47 (d, J = 13.6 Hz,
2H, NCH Ph), 3.77 (d, J = 13.6 Hz, 2H, NCH Ph), 7.24 - 7.38 (m,
10H, Ar).
(5) Hruby, V.J. Drug Discovery Today 1997, 2, 165.
(6) Freidinger, R.M. J. Org. Chem. 1985, 50, 3631.
(7) Wolf, J.-P.; Rapoport, H. J. Org. Chem. 1989, 54, 3164.
2
2
20
1
(23) 4b: [α]D = -25.7°, (c = 1, CHCl ); H NMR (CDCl ): δ(ppm) =
3
3
(8) Robl, J.A.; Cimarusti, M.P.; Simpkins, L.M.; Weller, H.N.; Pan,
Y.Y.; Malley, M.; DiMarco, J.D. J. Am. Chem. Soc. 1994, 116,
2348.
1.5 (s, 9H, Boc-CH ), 1.79 (dddd, J = 15.8, 11.1, 10.7, 4.8 Hz, 1H
3
5-H ), 2.10 (m, 1H, 5-H ), 2.63 (dd, J = 16.4, 9.8 Hz, 1H, 3-
ax
eq
H
), 2.70 (ddd, J = 16.4, 6.3, 1.3 Hz, 1H 3-H ), 3.14 (m, 1H, 4-
eq
ax
(9) Acton III, J.J.; Jones, A.B. Tetrahedron Lett. 1996, 37, 4319.
H), 3.35 (ddd, J = 13.0, 10.7, 4.3 Hz, 1H, 6-H ), 3.60 (d, J = 13.8
ax
(10) Wolfe, M.S.; Dutta, D.; Aubé, J. J. Org. Chem. 1997, 62, 654; and
Hz, 2H, NCH Ph), 3.65 (d, J = 13.8 Hz, 2H, NCH Ph), 3.85 (ddd,
2 2
references cited therein.
J = 13.0, 4.8, 4.3 Hz, 1H, 6-H ), 7.20 - 7.40 (m, 10H, Ar).
eq
(11) Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.;
(24) Höfle, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem. 1978, 90,
Wiley-VCH: New York, 1997.
602.
20
1
(12) Karle, I.L.; Pramanik, A.; Banerjee, A; Bhattacharjya, S.;
(25) 5a: [α]D = +37.1, (c = 5.5, CHCl ) H NMR (CDCl ): δ(ppm) =
3 3
Balaram, P. J. Am. Chem. Soc. 1997, 39, 9087.
1.31 (d, J = 6.5 Hz, 3H, CH ), 1.50 (s, 9H, Boc-CH ), 1.82 (dddd,
3 3
J = 14.3, 9.6, 9.5, 4.8 Hz, 1H, 5-H ), 2.08 (m, 1H, 5-H ), 2.59
(13) Seebach, D.; Overhand, M.; Kühnle, F.N.M.; Martinoni, B.;
Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79,
913.
ax
eq
(m, 1H, 3-H), 2.65 (m, 1H, 4-H), 3.38 (d, J = 13.8 Hz, 2H,
NCH Ph), 3.53 (ddd, J = 13.0, 9.6, 4.7 Hz, 1H, 6-H ), 3.72 (ddd,
2
ax
J = 13.0, 5.3, 4.8 Hz, 1H, 6-H ), 3.83 (d, J = 13.8 Hz, 2H,
eq
(14) Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717.
(15) Gmeiner, P. Liebigs Ann. Chem. 1991, 501.
NCH Ph), 7.24 - 7.38 (m, 10H, Ar).
2
2
(26) For an explanation of the term ß , see: Seebach, D.; Hintermann,
(16) Johnson, R.L.; Rajakumar, G.; Mishra, R.K. J. Med. Chem. 1986,
29, 2100.
T. Synlett 1997, 437.
(27) General Procedure for the Reaction of 4b,c with Electrophiles
to give 5a-g: To a solution of 4a,b (1 mmol) in THF (30 ml) was
added LDA (2 ml, 1M in THF) at -78°C. After being stirred for 1
h at -78°C the electrophile (2.5 mmol) was added slowly. The
reaction was kept at -78°C for 1 h. Then, it was allowed to warm
up to RT. After 12 h, the mixture was treated with saturated
(17) Gmeiner, P.; Kärtner, A.; Junge, D. Tetrahedron Lett. 1993, 34,
4325.
(18) Gmeiner, P.; Junge, D.; Kärtner, A. J. Org. Chem. 1994, 59, 6766.
(19) Gmeiner, P.; Kärtner, A. Synthesis 1995, 83.
(20) Gmeiner, P.; Orecher, F.; Thomas, C.; Weber, K. Tetrahedron Lett.
1995, 36, 381.
aqueous NaHCO and extracted with ether. The organic layer was
3
dried (MgSO ) and evaporated and the residue purified by flash
chromatography (petroleum ether / ethyl acetate 4:1) to give 5a-g
in analytically pure form.
4
(21) Gololobov, Y.G.; Zhmurova, I.N.; Kasukhin, L.F. Tetrahedron
1981, 37, 437.
(22) Preparation of 3b from 2a: To a solution of 2a (5.76 g, 20.2 mmol)
(28) Differding, E.; Duthaler, R.O.; Krieger, A.; Rüegg, G.M.; Schmit,
in THF (100 ml) was added Et N (6.13 g, 60.6 mmol) and MesCl
3
C. Synlett 1991, 395.
(4.74 g, 41.4 mmol) at -23°C. After stirring for 30 min the cooled
mixture was filtered into a precooled solution of LiCN (48 ml, 0.5
M in DMF). Then stirring was continued for further 3 h at RT.
1
(29) The diastereomeric purity was determined by
H NMR
spectroscopy (360 MHz) of the crude material. At a signal to noise
13
ratio > 4:1 for the C satellites of the N-benzyl resonances, no
After addition of sat. aq. NaHCO and Et O the org. layer was
3
2
13
signal of any impurity exceeded the intensity of the C satellites,
dried (MgSO ) and evaporated. The residue was dissolved in
4
indicating a diastereoselectivity > 99 %.
MeOH (200 ml) and cooled to -30°C. After addition of liquid NH
3
(100 ml) the mixture was stirred for 4 d at RT. Then sat. aq.
NaHCO and Et O was added and the org. layer was dried
(30) For recent examples of conformationally restrained Pro-Leu-Gly-
NH analogs, see: Baures, P.W.; Ojala, W.H.; Costain, W.J.; Ott,
3
2
2
(MgSO ) and evaporated. The residue was purified by flash
chromatography (petroleum ether - acetone 1:4) to give pure 3b.
M.C.; Pradhan, A.; Gleason, W.B.; Mishra, R.K.; Johnson, R.L. J.
Med. Chem. 1997, 40, 3594 and references cited therein.
4