An expedient synthesis of non-racemic N-alkylated pyrrolidin-2,5-diones and piperidin-2,6-diones as peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2016.11.083

In our hands, access to 2 novel peptidomimetic scaffolds, based on N-alkylated pyrroldin-2,5-diones and piperidin-2,6-diones, proved to be much more challenging than anticipated. In this short communication, we disclose the strategies that we explored and

Full text of DOI:10.1016/j.tetlet.2016.11.083

Accepted Manuscript
An expedient synthesis of non-racemic N-alkylated pyrrolidin-2,5-diones and
piperidin-2,6-diones as peptidomimetics
Anne Brethon, Claire Bouix-Peter, Laurence Clary, Jean François Fournier,
Craig S. Harris, Claude Lardy, Didier Roche, Vincent Rodeschini, Sandrine
Talano
PII:
S0040-4039(16)31564-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.083
TETL 48369
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 October 2016
16 November 2016
18 November 2016
Please cite this article as: Brethon, A., Bouix-Peter, C., Clary, L., François Fournier, J., Harris, C.S., Lardy, C.,
Roche, D., Rodeschini, V., Talano, S., An expedient synthesis of non-racemic N-alkylated pyrrolidin-2,5-diones
and piperidin-2,6-diones as peptidomimetics, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.11.083
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An expedient synthesis of non-racemic N-
alkylated pyrrolidin-2,5-diones and
piperidin-2,6-diones as peptidomimetics
Anne Brethon, Claire Bouix-Peter, Laurence Clary, Jean François Fournier, Craig S. Harris, Claude Lardy, Jean-Yves
Ortholand, Didier Roche, Vincent Rodeschini, Sandrine Talano

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
An expedient synthesis of non-racemic N-alkylated pyrrolidin-
2,5-diones and piperidin-2,6-diones as peptidomimetics
Anne Brethon,b Claire Bouix-Peter,a Laurence Clary,a Jean François Fournier,a Craig S.
Harris,a, * Claude Lardy,b Didier Roche,b Vincent Rodeschini,b Sandrine Talanoa
a Galderma R&D, 2400 Route de Colles, 06410 Biot, France
b Edelris, 115 Avenue de Laccasagne, 69003 Lyon, France
Abstract— In our hands, access to 2 novel peptidomimetic scaffolds, based on N-alkylated pyrroldin-2,5-diones and piperidin-2,6-diones,
proved to be much more challenging than anticipated. In this short communication, we disclose the strategies that we explored and our final
route choices to the desired scaffolds with control of both stereocenters. © 2016 Elsevier Science. All rights reserved
During a recent project on an undisclosed target, we needed to find efficient non-racemic routes to pyrrolidin-2,5-dione and
piperidin-2,6-dione central peptidomimetic scaffolds (2)1 from which we could explore the two key vectors to access our
target library 1. Our retrosynthetic analysis drove us to entertain two solutions: 1) Disconnection a, taking us to readily-
available D-aspartic acid and D-glutamic acid precursors 3 relying on an amide coupling reaction with a L-alanine ester
precursor 4 followed by ring closing condensation;2,3 and 2) disconnection b, an unprecedented N-alkylation of the imide
scaffolds 5 either under Mitsunobu4 or classical alkylation conditions5 from commercially-available homochiral D-lactate
derivatives 6 (Figure 1).
Figure 1. Retrosynthetic analysis of key scaffold 1
We decided to focus our initial efforts on disconnection a2,3 which represented the shortest sequence and used readily
available α-amino acids as building blocks thus offering an excellent diversification point (Table 1). Our one-pot 3-step
preparation of the pyrroldin-2,5-dione intermediate (10) started initially from either Cbz or Boc protected L-aspartic acid 7.
Cyclisation to aspartic anhydride 8 in the presence of EDCI proved to be a key step in this 3-step process whereby the
reaction needed to be ran overnight to ensure complete conversion to the anhydride intermediate and limit the formation of
the diamide impurity 11 (Table 1, entries 1-3 v 4-6). The anhydride 8 was subsequently ring-opened6 in situ by nucleophilic
attack of L-alanine tert-butyl ester 9 and the intermediate ring closed7 by adding further EDCI. In the case whereby the amine
group was protected by a Cbz group, only a poor isolated yield of 10 was obtained with complete in situ racemisation (entry
1). From the literature8 and NMR analysis, we proved the epimerization was not occurring during the first step but during the
———
* Craig Harris. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071; e-mail: craig.harris@galderma.com
Keywords: peptidomimetics, N-alkylation, piperidin-2,6-dione

2
Tetrahedron Letters
second cyclocondensation step that we propose was due to the base abstraction of the proton α to the amine protecting group.
We overcame the epimerisation issue by switching to a more hindered Boc group (entries 2-6). However, extension of this
methodology to the more hindered L-valine analogue afforded the desired product in just 48% yield with a disappointing d.r.
of 82/18 (entry 6) that we believe was due to the elevated temperature necessary to complete the cyclisation step.
Table 1. General one-pot route developed to access the pyrrolidin-2,5-dione scaffold 10
Entry Protecting
Group
R
Solvent
Yield
(%)
d.r.
(NMR)
Conditions
(PG)
1) DIPEA (1.5 eq.), EDCI (1.25 eq.), 2 h, r.t.
2) H-Ala-OtBu.HCl, DIPEA (1.5 eq.), 1.5 h, r.t.
3) EDCI (1.25 eq.), HOBt (1.1 eq.), 16 h, r.t.
1) H-Ala-OtBu.HCl, HOBt (2.2 eq.), EDCI (1.2 eq.), DIPEA
(3.0 eq.), 30 min., r.t.
1
2
3
4
5
6
Cbz
Boc
Boc
Boc
Boc
Boc
Me
Me
Me
Me
Me
iPr
DCM
DCM
DCM
DCM
DCM
DCM
17
9
50/50
> 95/5
> 95/5
~90/10
> 95 / 5
82/18
2) EDCI (1.3 eq.), 4 h, r.t.
1) EDCI (1.25 eq.), 20 min followed by
H-Ala-OtBu.HCl, DIPEA (1.0 eq.), 2 h, r.t.
2) EDCI (1.3 eq.), HOBt (1.5 eq.), 16 h, r.t.
1) EDCI (1.1 eq.), 16 h, r.t.
2) H-Ala-OtBu.HCl, DIPEA (1.0 eq.), 4 h, r.t.
3) EDCI (1.5 eq.), HOBt (1.5 eq.), DIPEA (1.0 eq.), 16 h, r.t.
1) EDCI (1.25 eq.), 16 h, r.t.
2) H-Ala-OtBu.HCl, DIPEA (2.0 eq.), 2 h, r.t.
3) EDCI (1.3 eq.), HOBt (1.5 eq.), 16 h, r.t.
1) EDCI, THF, DCM, 16 h, r.t.
12
48
58
48
2) H-Val-OtBu.HCl, DIPEA, r.t.
3) EDCI, HOBt, r.t.-30 °C, 3 h, 48%
Boc = tert-Butyloxycarbonyl; Cbz = benzyloxycarbonyl; EDCI = N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; HOBt
= 1-hydroxybenzotriazole hydrate; DCC = N,N'-Dicyclohexylcarbodiimide; DIPEA = N,N-Diisopropylethylamine; Ala = L-alanine
In parallel, we started the synthesis of piperidin-2,6-dione analogue 17 using a similar approach as used for 10 starting from
Z-D-Glu-OH (12).9 Therefore, cyclisation to the intermediate anhydride 13 proceeded in quantitative yield. Nucleophilic
ring-opening of anhydride 13 with the chosen tert-butyl amino acid ester afforded consistently a ~7/3 inseparable mixture of
amide products 14 and 15, respectively, in almost quantitative yield (Scheme 1, Table 2). The subsequent cyclocondensation
step was very sensitive to steric hindrance (Table 2) α to the reacting amide bond.9 Only acceptable yields of 17 were
achieved from the glycine derivative (Table 2, entry 1) under thermal conditions. After screening numerous reaction
conditions for the alanine derivative (entries 2,3), we finally identified suitable cyclisation conditions under microwave
irradiation to afford the desired piperidin-2,6-dione intermediate 17 albeit in average yields with the unwanted pyrrolidin-2-
one by-product 16. Moreover, the desired piperidin-2,6-dione intermediates 17 were also obtained as an inseparable mixture
of epimers at C-3 in 11 to 67% yield depending on steric hindrance α to the amide moiety (Table 2, entries 2,3 vs 4,5).

Tetrahedron Letters
3
Scheme 1. First generation of conditions employed to prepare piperidin-2,6-dione analogue 17. Conditions: a) DCC, THF,
r.t., quant.; b) amino acid t-Bu ester. HCl (see Table 2), DIPEA, THF, r.t., 1-4 h; c) see Table 2
Table 2. Selected examples prepared using Scheme 1
16 (%)
17 (%) [e.r.]
Entry
R
% Yield (Step b)
Conditions (Step c)
1
2
3
4
5
H
90
99
CDI, DMF, 50 °C, 4 h
CDI, DMF, 70 °C, 24 h
CDI, DMF, 153 °C, MW, 15 min
CDI, DMF, 70 °C, 24 h
CDI, DMF, 153 °C, MW, 15 min
-
67 [N/A]
32 [76:24]
52 [1:1]
-
CH3
CH3
i-Pr
i-Pr
33
28
24
26
96
11 [1:1]
N/A = Not analysed
Scheme 2 Synthesis of the Boc analogue 22. Reagents and conditions: a) Allyl bromide, K2CO3, DMF, r.t., 93%; b) Boc2O,
DMAP, MeCN, r.t., 99%; c) Pd(PPh3)4, N-Me-aniline, THF, r.t., 94%; d) tert-butyl L-alaninate, HATU, DIPEA, DMF, r.t.,
96%; e) H2 (1 atm), Pd(OH)2/C cat., EtOH, r.t., 96%; f) LiOH, THF-H2O, r.t., 99%; g) CDI, DMF, 153 °C, microwave
irradiation, 13%
With these results in hand and based on our exploration for pyrroldin-2,5-dione series, we assumed that we could solve the
problem of epimerization at C-3 during cyclisation by changing the protecting group from Cbz to a more hindered Boc group.
Therefore, Z-D-Glu(OMe)-OH (18) was protected as the allyl ester by alkylation with allyl bromide and Boc protection of the
Z-carbamate moiety proceeded in excellent yield to afford 19.11 Deprotection of the allyl ester using
tetrakis(triphenylphosphine)palladium (0) followed by HATU coupling afforded the dipeptide precursor 20. Hydrogenolysis
of the Cbz group followed by saponification of the methyl ester moiety afforded the cyclisation precursor 21. Unfortunately,
application of the optimised cyclocondensation conditions successfully employed for the pyrroldin-2,5-dione series, resulted
in a very poor isolated chemical yield and a 1:1 mixture of epimers at C-3 (Scheme 2)
After the disappointing results obtained for the piperidin-2,6-dione series using the cyclocondensation approach, we changed
our retrosynthetic strategy to study direct N-alkylation of the pre-formed piperidin-2,6-dione cycle4,5 with homochiral
alkylating agents. Surprisingly, after inspection of the literature, there were few references supporting the N-alkylation of
piperidin-2,6-dione under classical conditions5 or under Mitsunobu conditions.4 Moreover, there are no references using
homochiral alkylating substrates. As most of the literature supported the use of Mitsunobu conditions for achiral alcohols, we
initiated our exploration in this chemical reactivity space (Table 3).
Table 3. Selected results from Mitsunobu screening

4
Tetrahedron Letters
Entry
Solvent
[Concentration]
Time (h)
Yield (%)
d.r.
THF
DCM
0.12 M
0.19 M
0.10 M
22
3.5
1
67
78
72
54/46
56/44
71/29
1
2
3
Toluene
From our exploration, we were surprised how difficult it was to control the Mitsunobu alkylation step using commercially-
available tert-butyl (R)-2-hydroxypropanoate. In DCM and THF, good yields were obtained but with an almost 1:1 ratio of
epimers at the C-3 position (Table 3, entries 1,2). Changing the solvent to toluene afforded a similar chemical yield and an
improved d.r. (entry 3) that was still not acceptable for the program. Despite much effort looking at concentration and the
order of addition of Mitsunobu reagents, we were unable to improve on the d.r. and abandoned the Mitsunobu approach.
Next, we turned our attention to screening classical alkylation conditions, using either the mesylate11 or triflate12 (25) of tert-
butyl (R)-2-hydroxypropanoate. Taking into account the variable results achieved under Mitsunobu conditions and the
absence of literature in this chemical space, we carried out a rapid solvent screen using potassium carbonate as the base.
Briefly, despite screening several conditions, no product was observed using the mesylate12 as the alkylating species at room
temperature and all attempts to heat the reaction mixture led to degradation with no traces of desired product (Table 4, entries
1-3). In parallel, we prepared the triflate analogue12 and carried out a solvent screen keeping potassium carbonate as the base.
When the reaction was carried out in DMF, only 5% product was observed by LCMS and attempts to increase the yield by
heating the reaction mixture only led to degradation of the starting piperidin-2,6-dione (entry 4). However, carrying out the
reaction in DCM afforded the desired product in good conversion but with several unidentified close-running by-products
that were difficult to remove using standard chromatographic techniques (entry 5). In MeCN, the starting piperidin-2,6-dione
23 was completely consumed affording an excellent chemical yield albeit with a d.r. of 86:14 (entry 6). Finally, we managed
to improve the d.r. to 98:2 by starting the reaction at 0 °C and adding just 1.05 eq of K2CO3 albeit compromising the isolated
yield to just 53% (entry 7). Attempts to reduce further in situ epimerization by using a weaker base e.g., KHCO3, failed
whereby the starting material did not react (entry 8).
Table 4. Selected results from the conditions’ screening of N-alkylation of 23.
Conditions
Yield (%) [d.r.]
Entry
R
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
K2CO3 (1.3 eq) DMF, r.t. to 90 °C
K2CO3(1.3 eq) MeCN, r.t. to 90 °C
K2CO3 (1.3 eq) Toluene, r.t. to 90 °C
K2CO3 (1.05 eq) DMF, r.t.,16 h
K2CO3 (1.05 eq) DCM, r.t., 22 h,
K2CO3 (1.3 eq) MeCN, r.t., 18 h
K2CO3 (1.05 eq) MeCN, 0 °C to r.t., 24 h
KHCO3 (1.05 eq), MeCN, r.t., 48 h
Deg.
Deg.
Deg.
1
2
3
4
5
6
7
8
5 (N/I)
69 (N/I)
99 [86:14]
53 [98:2]
0
*Deg. = degradation; N/I = Not isolated; Ms = methanesulfonyl; Tf = trifluoromethylsulfonyl
In conclusion, we have evaluated two separate retrosynthetic strategies to successfully prepare N-alkylated pyrrolidin-2,5-
dione and piperidin-2,6-dione scaffolds. Obtention of the latter through a cyclisation protocol afforded poor chemical yields
with a 1:1 mixture of epimers at C-3. This problem was overcome by adopting a novel strategy via N-alkylation of piperidin-
2,6-dione scaffold using triflates derived from homochiral lactate precursors, achieving the desired product in good chemical
yield with minimal in situ epimerisation.

Tetrahedron Letters
5
Supplementary data
Full experimental procedures and supporting LCMS and 1H NMR characterisation data are available for selected compounds
at no extra charge via the on-line version.
References and notes
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Highlights


Efficient routes to novel peptidomimetic scaffolds while minimising in situ racemisation are described
A successful route to prepare N-alkylated chiral pyrrolidin-2,5-dione was found with good chemical and
optical yields

A novel N-alkylation of the piperidin-2,6-dione scaffold from homochiral lactate precursors is revealed