Diastereoselective synthesis of novel aza-diketopiperazines via a domino cyclohydrocarbonylation/addition process

Article abstract of DOI:10.1039/c4cc03660c

Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino acids. The strategy is based on a Rh(i)-catalyzed hydroformylative cyclohydrocarbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03660c

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Diastereoselective synthesis of novel
aza-diketopiperazines via a domino
cyclohydrocarbonylation/addition process†
Cite this: Chem. Commun., 2014,
50, 9657
Received 14th May 2014,
Accepted 3rd July 2014
Pierre Regenass, Jean-François Margathe, Andre Mann, Jean Suffert, Marcel Hibert,
´
Nicolas Girard* and Dominique Bonnet*
DOI: 10.1039/c4cc03660c
www.rsc.org/chemcomm
Herein, we report an unprecedented, short and diastereo-selective
synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds
starting from amino acids. The strategy is based on a Rh(I)-catalyzed
hydroformylative cyclohydrocarbonylation of allyl-substituted aza-
DKP, followed by a diastereoselective functionalization of the plat-
form. This methodology allows the synthesis of novel bicyclic and
tricyclic aza-DKP scaffolds incorporating six- or seven-membered
rings, with potential applications in medicinal chemistry.
Scheme 1 Strategy towards novel N-heterocyclic aza-DKP scaffolds 6.
and in the solid-phase.2b In the present work, we report a
The diketopiperazine (DKP) moiety found in several natural diversity-oriented, efficient and stereoselective synthesis of
products has been extensively studied in medicinal chemistry.1 novel bicyclic and tricyclic scaffolds 6 derived from aza-DKP.
However, the corresponding aza-DKP platform remains under- To access such structures, we have explored a strategy based on
explored.2 This class of heterocycles can be viewed as a con- cyclohydrocarbonylation (CHC)4 of allyl aza-DKP 4, followed by
strained dipeptidomimetic DKP analogue (Fig. 1). As reported an acid-catalyzed diastereoselective nucleophilic addition on
for aza-peptides,3 the replacement of one Ca-stereogenic center the resulting enamide 5 (Scheme 1). This strategy involves for
by a planar nitrogen atom could have a profound impact on the first time the catalytic hydroformylation of a newly reported
both the chemical and biological properties of DKP and could 1,2,4-triazine-3,6-dione system.2a,b The scope, limitations and
offer new potential for drug discovery and chemical biology.
diastereoselectivity of the approach have been carefully studied,
Recently, we have described a convenient access to original resulting in the preparation of enantiomerically pure scaffolds
2,4,5-trisubstituted-1,2,4-triazine-3,6-diones, both in solution with potential applications in medicinal chemistry.
To investigate the applicability of the CHC reaction to aza-
DKP systems, we initially prepared a set of allyl-substituted
precursors 4a–g and 4k,l according to our previously described
procedure.2b The amino acids were converted into amino esters
which were alkylated by reductive amination. The resulting
secondary amines 2a–g and 2k,l as well as the proline deriva-
tives 2h–j and 2m were reacted with bis(trichloromethyl)-
carbonate (BTC) and allyl or homoallyl t-butyl carbazate 1a or
1b, obtained in one step from commercially available t-butyl
carbazate (see ESI† for a detailed procedure). The crude semi-
carbazides 3a–m were then treated in TFA/water (95 : 5) for 1 h,
resulting in the consecutive semi-carbazide deprotection and
cyclization. This led to allyl derivatives 4a–m, in 27% to 77%
yields from amines 2a–j, the lower yields being obtained with
the most sterically hindered R1 and R2 substituents (Table 1,
entries 3 and 4). Noteworthily, the preparation of aza-DKP 4i
and 4m (from L-hydroxyproline) required hydroxy protection
prior to semicarbazide cyclization (Table 1, entries 9 and 12).
Fig. 1 General structure of diketopiperazines (DKP) and aza-diketo-
piperazines (aza-DKP).
´
´
Laboratoire d’Innovation Therapeutique, UMR7200 CNRS/Universite de Strasbourg,
´
´
Labex Medalis, Faculte de Pharmacie, 74 route du Rhin, 67412 Illkirch, France.
E-mail: nicolas.girard@unistra.fr, dominique.bonnet@unistra.fr
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data for all the compounds. Crystal structures of 5a, 5i,
5k, 6a, 7, trans-isomer of 9 and cis-isomers of 6l and 6j. CCDC 1001769–1001776.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4cc03660c
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Table 1 CHC-based strategy towards novel bicyclic and tricyclic aza-DKP
scaffolds 5a–m
was selected as a metal chelating agent to ensure the formation
of linear rather than branched aldehydes.6 All reactions were
performed under acid catalysis (pyridinium p-toluenesulfonate:
PPTS or camphorsulfonic acid: CSA) to promote cyclization, if
any, into enamide 5 in the same reactor.
In our first attempt, we were pleased to obtain cyclized
compound 5a in an excellent 81% yield from allyl compound
4a, thus validating the CHC as a convenient and high yielding
method for bicyclic aza-DKP synthesis (Table 1, entry 1).
Next, the scope and limitations of the reaction were evalu-
ated on allylic aza-DKP 4b–m. In all cases, the expected cyclized
compounds 5 were isolated in yields ranging from 43 to 81%
(Table 1), thus demonstrating the efficiency of the method,
regardless of the nature of R1 and R2 (Table 1, entries 3–5) or of
the configuration of the starting amino acid (Table 1, entry 2).
Noteworthily, CHC still occurred in reasonable yields with
compounds 4f and 4g encompassing nucleophile groups at
R3, which could possibly compete as a ligand for the metal
(Table 1, entries 6 and 7).7
Interestingly, CHC also gave access to tricyclic L-proline-
based aza-DKP 5h, 5i and 5j in good 69%, 73% and 62% yields,
respectively (Table 1, entries 8–10). This scaffold is particularly
appealing for medicinal chemistry as the corresponding DKP is
embedded in the core of several natural product classes used in
targeted cancer therapy.8
These promising results for the synthesis of six-membered
rings prompted us to evaluate CHC as an entry to aza-DKP
fused to a seven-membered ring. Thus, with homoallylic deri-
vative 4k, the CHC reaction proceeded smoothly and 5k was
obtained in moderate yield (34%). Then, we switched from
PPTS to the more acidic CSA, which drives the reaction to
completion and dramatically improves the yield (72%). This
optimized procedure was also applied to the synthesis of
tricyclic L-hydroxyproline-based aza-DPK 5m obtained in
61% yield.
Yield 4 b Yield 5 b
Entry Amino acid
R1
R2
n (%)
(%)
1
2
3
4
5
6
7
8
L-Ala
D-Ala
L-Ile
L-Ala
(S)-Me
(R)-Me
(S)-sec-Bu
(S)-Me
(S)-Bn
(S)-H2N(CH2)4 Bn
(S)-HOCH2
Bn
Bn
Bn
iPea
Bn
1 4a (70)c 5a (81)
1 4b (68)c 5b (79)
1 4c (31)
1 4d (31)
1 4e (49)
1 4f (51)
5c (81)
5d (78)
5e (77)
5f (43)
L-Phe
L-Lys(Boc)
L-Ser(tBu)
L-Pro
Bn
(S)-(CH2)3
1 4g (45)d 5g (57)
1 4h (38)c 5h (69)
9
L-Pro(OBn)
1 4i (29)c,e 5i (73)
10
L-Pro(OpNO2Bn)
1 4j (39)c
2 4k (77)c 5k (72) f
5l (81) f
2 4m (27)c,e 5m (61) f
5j (62)
11
12
L-Ala
L-Ala
(S)-Me
(S)-Me
Bn
pNO2-Bn 2 4l (54)c
13
L-Pro(OBn)
a
b
c
iPe = isopentyl. Isolated yields. Semicarbazide 3 was obtained in
THF/CH2Cl2. Compound 4g was obtained in TFA/water/triisopropyl-
silane (95/2.5/2.5, v/v/v). Cleavage of the benzyl protecting group was
d
e
f
performed prior to CHC. CSA instead of PPTS.
With all these novel structures in hand, we decided to
investigate the functionalization of the diaza-cyclohexene and
diaza-cycloheptene rings in order to extend the molecular
diversity of these novel scaffolds. A first experiment was carried
out by subjecting compound 5a to a CSA acid-catalyzed addi-
tion of MeOH which led to hemiaminal 6a with a high 86%
yield and a good diastereoisomeric ratio (dr) of 93 : 7 (Table 2,
entry 1). The major isomer was readily isolated by preparative
HPLC and was shown to be the C9–C2 trans-isomer by X-ray
diffraction analysis (Fig. 2). This result combined with the axial
position of the methoxy group indicate that the nucleophilic
attack of the acyl iminium intermediate is likely under stereo-
electronic control.9 The out-of-plane substituents associated
with the presence of stereocenters make the aza-DKP scaffold
a promising platform to increase receptor–ligand interactions
and to develop potentially active and selective compounds.10
The diastereoselective addition reaction was then extended
to various enamides. As shown in Table 2, the expected com-
pound was obtained whatever the absolute configuration at Ca
With compounds 4a–m in hand, we explored the CHC using (Table 2, entry 2). The steric hindrance at R2 was found to
syngas (H2/CO) in the presence of a Rh(I) catalyst.5 BiPhePhos impact the selectivity (Table 2, entry 4). In contrast, when a
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Table 2 Diastereoselective acid-catalyzed addition of MeOH on enamide 5
Entry
R1
R2
n
Yieldb (%)
dr (trans/cis)c
1
2
3
4
5
6
(S)-Me
(R)-Me
(S)-sec-Bu
(S)-Me
(S)-H2N(CH2)4
Bn
Bn
Bn
iPea
Bn
1
1
1
1
1
1
6a (86)
6b (83)
6c (65)
6d (74)
6f (61)
6h (65)
93 : 7
92 : 8
499 : 1
97 : 3
96 : 4
4 : 96
(S)-(CH2)3
7
1
6j (59)
4 : 96
Scheme 3 Diastereoselective functionalization of aza-DKP 6a.
8
9
(S)-Me
(S)-Me
Bn
pNO2Bn
2
2
6k (62)
6l (55)
37 : 63
37 : 63
hemiaminals 6k and 6l in still good yields (62 and 55%,
respectively) but with a lower dr (37 : 63), likely due to greater
flexibility of the seven-membered ring.13 As aforementioned for
6h and 6j, the X-ray diffraction analysis of 6l revealed that the
major isomer was the C9–C2 cis-isomer.
a
b
c
iPe = isopentyl. Isolated yields. Diastereomeric ratio was deter-
mined by 1H NMR or HPLC analysis of the crude reaction mixtures.
Looking for a further improvement in the access to novel
aza-DKP platforms, a domino CHC/acid-catalyzed MeOH addi-
tion sequence was envisaged (Scheme 2).14 To this end, N-allyl
substituted triazinedione 4a was submitted to a CHC reaction
in the presence of PPTS in MeOH/THF (10 : 1) and led to
compound 6a in 74% yield and a good stereoselectivity
(93 : 7). Thus, compound 6a is readily attainable in a three-
step process only from simple N-benzyl amino ester 2a in a 52%
overall yield. This result highlights the efficiency of our strategy
to provide a rapid access to novel N-heterocyclic scaffolds.
Finally, to further enlarge the molecular diversity of novel
aza-DKP platforms and access to diversity-oriented chemical
libraries, we envisaged the incorporation at C9 of functional
groups able to react with commercially available building
blocks. Hence, trans-isomer 6a was reacted either with TMSN3
or with TMSCN, both in the presence of BF3ÁOEt2 (Scheme 3).15
Thus, azide 7 was obtained in good yield (88%) and dr (495 : 5).
Nitrile 9 was also isolated in excellent yield (92%) but with a
lower dr (68 : 32). Again, for both compounds, the major isomer
was shown to be the C9–C2 trans-isomer (X-ray structure
analysis, ESI†).
Fig. 2 X-ray structures of compounds 6a and 6j.
hindered group was introduced at R1, only one diastereomer
was detected by 1H NMR and HPLC analyses of the crude
material (Table 2, entry 3). The diastereoselective addition
was also found compatible with the presence of a nucleophilic
primary amine at R1 (Table 2, entry 5). Interestingly, when the
addition was performed on tricyclic proline derivatives 5h and
5j (Table 2, entries 6 and 7), desired hemiaminals 6h and 6j
were also obtained in good yields (65% and 59%, respectively)
but with an inverted dr in favor of the cis-isomer (4 : 96), as
demonstrated by X-ray diffraction analysis of 6j (Fig. 2). The
inversion of dr for proline-based substrates compared to other
amino acids was previously reported for the 2,5-diketo-
piperazine system.11,12 Finally, the addition performed on
seven-membered rings 5k and 5l led to the corresponding
Besides, hydrolysis of the major isomer under acidic condi-
tions led to carboxylic acid 10, able to react with amino
building-blocks. Azide 7 was reduced with H2/Pd in the
presence of di-tert-butyl dicarbonate to provide tBoc-protected
compound 8 (86%). To further extend the chemical diversity of
aza-diketopiperazines, compound 7 could also be engaged in
Cu(I)-catalyzed azide–alkyne cycloaddition reactions.16
Starting from the amino acid pool, we have developed a
diastereoselective approach for the preparation of a diverse
range of N-heterocyclic scaffolds derived from aza-DKP. Indeed,
this rapid and flexible method enables the efficient conversion
of N-allyl substituted aza-DKP into newly reported bicyclic or
tricyclic scaffolds containing six- or seven-membered rings by a
Scheme 2 Domino cyclohydrocarbonylation/addition reaction.
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amino or carboxylic functions which paves the way to the
preparation of diversity-oriented libraries.
This work was supported by the Centre National de la
´
Recherche Scientifique, the Universite de Strasbourg (UDS)
and the LABEX Medalis (ANR-10-LABX-0034). Dr Denis Heissler
is kindly acknowledged for helpful discussions and for his
comments on the manuscript. We are grateful to Cyril Antheaume
and Barbara Schaeffer for NMR experiments (Service Commun
d’Analyse, UDS).
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9660 | Chem. Commun., 2014, 50, 9657--9660
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