Diastereoselective synthesis of enantiopure differentially protected cis-4,5-diaminopiperidin-2-one through intramolecular transamidation

Article abstract of DOI:10.1016/S0040-4039(02)02418-8

The diastereoselective synthesis of enantiopure differentially protected cis-4,5-diaminopiperidin-2-one was achieved by means of conjugate addition of ammonia to an unsaturated γ-lactam and transamidation reaction with ring expansion as the main steps.

Full text of DOI:10.1016/S0040-4039(02)02418-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9531–9533
Diastereoselective synthesis of enantiopure differentially
protected cis-4,5-diaminopiperidin-2-one through intramolecular
transamidation
Nicole Langlois*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 11 October 2002; revised 24 October 2002; accepted 25 October 2002
Abstract—The diastereoselective synthesis of enantiopure differentially protected cis-4,5-diaminopiperidin-2-one was achieved by
means of conjugate addition of ammonia to an unsaturated g-lactam and transamidation reaction with ring expansion as the main
steps. © 2002 Elsevier Science Ltd. All rights reserved.
During our studies on the synthesis of enantiopure
polysubstituted piperidines,1,2 and piperidin-2-ones,3,4
we developed the first route to cis-4,5-diaminopipe-
ridin-2-ones via an intramolecular Mitsunobu reaction
of hydroxamates, followed by N1ꢀO bond cleavage with
SmI2.3 Compounds of this type were unknown before
and could constitute structural sub-units in interesting
more complex molecules.5 Particularly, the possibility
of orthogonal protections on the amino groups and
their use as peptidomimetics,6,7 make these compounds
attractive as intermediates in the synthesis of conforma-
tionally constrained peptides analogues. Here is
reported a novel access to enantiopure protected cis-
4,5-diaminopiperidinone involving a transamidation of
(4S,5R)-4-acetylamino-5-aminomethylpyrrolidinone 9b
derived from (S)-pyroglutaminol.8
amino group at C-6 was investigated. Thus, looking for
a simple protocol, it was observed that the 6-amino
derivative 2 could be obtained (62%) by stirring a
mixture of unsaturated lactam 1 and 32% NH4OH
solution in a closed flask at 20°C (Scheme 1).10
However, compound 2 was not very stable and slowly
afforded another product 3 on standing at room tem-
perature (Scheme 2). The NMR data of 2 and 3 (Table
1) indicate a change in C-6 substitution. Indeed, the
chemical shifts of H-6 (2: 3.58 ppm, 3: 3.34 ppm) and
C-6 (2: 53.27 ppm, 3: 57.88 ppm) constitute the main
differences, all coupling constants being very similar in
both compounds.
The elementary analysis of adduct 3 (C24H25N3O4)
confirmed by HRMS [(MH)+ at m/z 420.1945] provided
evidence for its dimeric structure. Partial b-elimination
of ammonia and 1,4-addition of one molecule of 2 to
the resulting unsaturated g-lactam could explain its
formation (Scheme 2).
The easy diastereoselective conjugate addition of benzyl-
amine to unsaturated bicyclic lactam 1 in the presence
of water has already been described.9 Taking these
results in account, the direct introduction of a primary
Scheme 1.
* Fax: 33 1 69077247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02418-8

9532
N. Langlois / Tetrahedron Letters 43 (2002) 9531–9533
Scheme 2.
Table 1. Comparison of relevant chemical shifts (1H, 13C) of 2 and 3 (CDCl3)
l (ppm)
C-2
H-4
C-4
H-5
3.82
3.84
C-5
H-6
3.58
3.34
C-6
H-7
C-7
2
3
87.39
87.21
4.22
3.70
4.24
3.65
70.04
70.34
67.79
65.84
53.27
57.88
2.80
2.62
2.78
2.60
44.52
41.98
pyridine, 20°C, 99% yield);10 thus, the oxaziridine ring
was hydrolyzed selectively and quantitatively by treat-
ment with aqueous trifluoroacetic acid affording 5b.14
Then, compound 5b was converted into N-Boc mesyl-
ate 7b in two steps (67 and 89%, respectively). 5-Azi-
domethyl derivative 8b (NaN3, DMF, 91%) was
reduced in methanol (H2, 10% Pd/C). Under these mild
conditions, complete transamidation occurred directly
affording 10b in 96% yield (Scheme 3).15 In the particu-
lar case of the N-Boc aminomethyl intermediates 9, no
additive base was needed for the ring opening by
intramolecular nucleophilic attack of the primary
amino group. Electrophilic assistance of the solvent,
and activation of the pyrrolidinone carbonyl by the
presence of N-Boc protecting group, account for the
efficiency of the process.
Ring expansion of amino-lactams through transamida-
tion have already been described and applied to the
synthesis of macrocyclic amino-lactams in the ‘Zip’
reaction.11 But until now, the construction of 5-amino-
d-lactams by this route was poorly explored.4,8 For an
efficient transamidation reaction with ring extension,
the presence of electron-withdrawing groups, such as
alkoxycarbonyl residues, on the nitrogen atom was
required to enhance the reactivity of lactam carbonyl.
Azide 8a, prepared from (S)-5-hydroxymethylpyrro-
lidin-2-one 5a (88% overall yield),12 was used as a
model for this purpose. The reduction of the azido
group (H2, 10% Pd/C) was followed by heating in
methanol to complete the formation of the known
(S)-5-(N-Boc)aminopiperidin-2-one 10a (95%).13 In
order to extend the scope of this finding, a similar
sequence was applied to 4-N-acetylamino-5-hydroxy-
methylpyrrolidinone 5b (Scheme 3).
In conclusion, a concise and efficient method has been
developed for the synthesis of 5-aminopiperidin-2-one
10a and differentially N,N%-protected (4S,5R)-4,5-
diaminopiperidin-2-one 10b from (S)-pyroglutaminol in
Accordingly, after a classical N-acylation step, lactam 2
was transformed to the corresponding lactam 4 (Ac2O–
Scheme 3. Reagents and conditions: (a) Ac2O, py, 20°C; (b) CF3CO2H, THF–H2O, rt; (c) MsCl, py, 0°C to rt; Boc2O, DMAP,
CH3CN; (d) NaN3, DMF, 50°C; (e) H2, 10% Pd/C, CH3OH.

N. Langlois / Tetrahedron Letters 43 (2002) 9531–9533
9533
1
very mild conditions. This methodology could be
extended to 5-hydroxymethylpyrrolidin-2-ones bearing
various other substituents in 3 and 4 positions and to
their N1-sulfonyl analogues.
1.50, CHCl3); H NMR (300 MHz, CDCl3, l=0: TMS):
7.37 (m, 5H, H-Ar), 6.60 (m, 1H, NH), 6.28 (s, 1H, H-2),
4.37 (1H), 4.31 (m, 1H, H-6), 3.86 (m, 2H), 2.85 (dd, 1H,
J
7a,7b=16.6, J7a,6=8.9 Hz, Ha-7), 2.73 (dd, 1H, J7a,7b=
16.6, J7b,6=9.8 Hz, Hb-7), 1.96 (s, 3H, COCH3); 13C
NMR (75.0 MHz, CDCl3): 174.29 (CO), 170.76 (CO),
138.23 (qC, Ar), 128.86, 128.58, 126.01 (CH, Ar), 87.09
(C-2), 71.32 (C-4), 66.41 (NCH), 50.03 (NCH), 40.15
(C-7), 22.87 (COCH3). Anal. calcd for C14H16N2O3: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.61; H, 6.34; N,
10.71%.
References
1. Langlois, N.; Calvez, O. Synth. Commun. 1998, 28, 4471–
4477.
2. Calvez, O.; Chiaroni, A.; Langlois, N. Tetrahedron Lett.
11. (a) Kramer, U.; Guggisberg, A.; Hesse, M.; Schmid, H.
Angew. Chem., Int. Ed. Engl. 1977, 861–862; (b) Kramer,
U.; Schmid, H.; Guggisberg, A.; Hesse, M. Helv. Chim.
Acta 1979, 62, 811–815; (c) Wasserman, H. H.; Mat-
suyama, H.; Robinson, R. P. Tetrahedron 2002, 58, 7177–
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1998, 39, 9447–9450.
3. Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 41,
8285–8288.
4. Langlois, N. Org. Lett. 2002, 185–187.
5. Fukuyama, T.; Li, L.; Laird, A. A.; Frank, R. K. J. Am.
Chem. Soc. 1987, 109, 1587–1589.
12. Ackerman, J.; Matthes, M.; Tamm, C. Helv. Chim. Acta
1990, 73, 122–132.
13. Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36,
8205–8208.
14. Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. Tetra-
hedron Lett. 1997, 38, 5891–5894.
6. Weber, K.; Gmeiner, P. Synlett 1998, 885–887.
7. Lehmann, T.; Michel, D.; Gla¨nzel, M.; Waibel, R.;
Gmeiner, P. Heterocycles 1999, 51, 1389–1400.
8. Preliminary communication: Langlois, N. IXth Confer-
ence, French–American Chemical Society, June 2–6,
2002, Saint-Malo, France.
15. Preparation of 10b: 5-Azidomethyl derivative 5b (53.0
mg, 0.178 mmol) in MeOH (1.0 mL) was stirred under H2
(1 atm) in the presence of 10% Pd/C (9.0 mg) for 48 h.
The catalyst was filtered on Celite® and washed with
MeOH. The solution was evaporated under reduced pres-
sure affording 10b (46.4 mg, 96%) after crystallization by
addition of CH2Cl2: mp 123–126°C; [h]2D5=−63.5 (c 0.62,
MeOH); IR: 3430, 3407, 3318, 3005, 1697 (sh), 1669,
1505 cm−1; MS (ESI): 294 [(MNa)+, 100%)], 272 (MH)+,
248, 216; 1H NMR (300 MHz, CDCl3): 7.21 (m, 1H,
NHCOCH3), 6.64 (m, 1H, NH), 5.98 (m, 1H, NHCO2),
4.38 (m, 1H, H-4), 4.05 (m, 1H, H-5), 3.63, 3.23 (2 br dd,
2H, H2-6), 2.83, 2.31 (2 br dd, 2H, H2-3), 2.01 (s, 3H,
COCH3), 1.44 (s, 9H, t-Bu); 13C NMR (75.0 MHz,
CDCl3): 171.50 (CO), 170.33 (CO), 156.46 (NCO2), 80.38
(qC, t-Bu), 48.12, 47.13, 43.68 (C-4, C-5, C-6), 28.32
(CH3, t-Bu), 23.11 (COCH3).
9. Langlois, N.; Calvez, O.; Radom, M. O. Tetrahedron
Lett. 1997, 38, 8037–8040.
10. Preparation of 2 and 4: To a solution of unsaturated
lactam 1 (504 mg, 2.5 mmol) in THF (2.5 mL) was added
NH4OH (32% solution, 5.0 mL) and the mixture was
stirred at rt until complete conversion. After dilution with
CH2Cl2, the organic phase was washed twice with water,
dried over MgSO4 and evaporated to dryness. The
residue could be purified by chromatography on silica gel
(eluent: CH2Cl2–MeOH 93:7) to afford the compound 2
(62%), or directly acylated with Ac2O (0.46 mL) in pyri-
dine (5.7 mL) at rt for 18 h. Then, the mixture was cooled
to 0°C, and methanol (4 mL) was added. After being
stirred for 0.5 h, the solvents were evaporated under
reduced pressure and the product was purified by chro-
matography on silica gel (eluent: CH2Cl2–MeOH 96:4)
giving rise to 4 (398 mg, 61% for two steps): [h]2D5=+92 (c