Asymmetrie synthesis of y-chloro-α,β-diaminoand β,y-aziridino-α-aminoacylpyrrolidinesand -piperidines via stereoselective Mannich-type additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines

Article abstract of DOI:10.3762/bjoc.8.239

The asymmetric synthesis of new chiral γ-chloro-α,β- diaminocarboxylamide derivatives by highly diastereoselective Mannich-type reactions of N-(diphenylmethylene)glycinamides across chiral α-chloro-N-p-toluenesulfinylaldimines was developed. The resulting

Full text of DOI:10.3762/bjoc.8.239

Asymmetric synthesis of γ-chloro-α,β-diamino-
and β,γ-aziridino-α-aminoacylpyrrolidines and
-piperidines via stereoselective Mannich-type
additions of N-(diphenylmethylene)glycinamides
across α-chloro-N-sulfinylimines
Gert Callebaut1,§, Sven Mangelinckx1,¶, Pieter Van der Veken2,
Karl W. Törnroos3, Koen Augustyns2 and Norbert De Kimpe*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2124–2131.
1Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium, Tel: +32 (0)9 264 59 51.
Fax: +32 (0)9 264 62 21, 2Department of Medicinal Chemistry,
University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
and 3Department of Chemistry, University of Bergen, Allégt. 41,
N-5007 Bergen, Norway
doi:10.3762/bjoc.8.239
Received: 20 September 2012
Accepted: 08 November 2012
Published: 05 December 2012
Associate Editor: J. N. Johnston
Email:
© 2012 Callebaut et al; licensee Beilstein-Institut.
License and terms: see end of document.
Norbert De Kimpe* - norbert.dekimpe@UGent.be
* Corresponding author
§ Aspirant of the “Institute for the Promotion of Innovation through
Science and Technology – Flanders (IWT-Vlaanderen)”.
¶ Postdoctoral Fellow of the Research Foundation (FWO).
Keywords:
asymmetric synthesis; diaminoacid derivatives; Mannich-type
addition; N-sulfinylimines; stereoselectivity
Abstract
The asymmetric synthesis of new chiral γ-chloro-α,β-diaminocarboxylamide derivatives by highly diastereoselective Mannich-type
reactions of N-(diphenylmethylene)glycinamides across chiral α-chloro-N-p-toluenesulfinylaldimines was developed. The resulting
(SS,2S,3S)-γ-chloro-α,β-diaminocarboxylamides were formed with the opposite enantiotopic face selectivity as compared to the
(SS,2R,3R)-γ-chloro-α,β-diaminocarboxyl esters obtained via Mannich-type addition of analogous N-(diphenylmethylene)glycine
esters across a chiral α-chloro-N-p-toluenesulfinylaldimine. Selective deprotection under different acidic reaction conditions and
ring closure of the γ-chloro-α,β-diaminocarboxylamides was optimized, which resulted in Nα-deprotected syn-γ-chloro-α,β-di-
aminocarboxylamides, N-sulfinyl-β,γ-aziridino-α-aminocarboxylamide derivatives, a trans-imidazolidine, and an Nα,Nβ-depro-
tected syn-γ-chloro-α,β-diaminocarboxylamide.
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Introduction
In recent years, non-proteinogenic diaminocarboxylic acids
have gained a lot of attention among organic chemists and
biochemists [1-3]. This is due to the fact that these diaminocar-
boxylic acids are present as key structural fragments in bio-
logically active compounds, and some are also bioactive as the
free diaminocarboxylic acid derivative [1-6]. For example, α,γ-
diaminoacylamides are known for their high potency and selec-
tivity as dipeptidyl peptidase (DPP) inhibitors [7-9].
DPP IVs are proteases that specifically cleave off N-terminal
dipeptides and are involved in the degradation of incretin
hormones, including glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is
Figure 1: DPP inhibitors.
involved in the regulation of glucose homeostasis through stim- tions of N-(diphenylmethylene)glycine esters across a chiral
ulation of insulin secretion, inhibition of glucagon release, and α-chloro-N-p-toluenesulfinylimine [20], which belongs to the
delay of gastric emptying. It has been demonstrated that the useful class of α-halo-imines [21-26]. However, transformation
presence of intravenous GLP-1 increases insulin secretion as a of γ-chloro-α,β-diaminocarboxyl esters into the corresponding
response to elevated glucose levels, and as such, GLP-1 can carboxylic acids, en route to further coupling to carboxyl-
offer therapeutic benefits for patients with type 2 diabetes. amides, has proven to be unsuccessful, probably due to compet-
Unfortunately, therapeutic application of GLP-1 is problematic itive reactions such as the formation of α,β-diamino-γ-butyro-
due to the lack of oral activity and the rapid degradation by lactones [20].
plasma DPP IV. Therefore, DPP IV inhibitors could offer a
solution to this problem, as they can extend the duration of The results discussed within the present paper demonstrate the
action of GLP-1 and prolong the beneficial effects [10-12]. synthesis and elaboration of chiral syn-γ-chloro-α,β-diaminocar-
boxylamide derivatives with excellent diastereoselectivity. In
Besides DPP IV, a few related enzymes are present in the order to develop potential DPP inhibitors, the ring closure and
family of DPPs, with DPP II, DPP8, DPP9 and FAP being the deprotection of the α-amino functionality of the synthesized
most important regarding the therapeutic potential, when γ-chloro-α,β-diaminocarboxylamides were explored as well.
focusing on the inhibitory potency and selectivity [10-12]. In
the research focused on DPP II and DPP IV inhibitors, it has Results and Discussion
been found that the α,γ-diaminoacylpiperidine, (S)-2,4- The stereoselective synthesis of chiral γ-chloro-α,β-diaminocar-
diaminobutanoylpiperidine, is a lead compound in the develop- boxylamides was performed by using a Mannich-type addition
ment of a large series of highly potent and selective DPP II of glycine amides 4 across chiral α-chloro-N-sulfinylaldimines
inhibitors [7-9] (Figure 1). Next to the α,γ-diaminoacylpyrrol- 3.
idines and –piperidines, which exhibit a DPP inhibitory effect,
some β-aminocarboxylamides, such as sitagliptin, are also Initially, the chiral α-chloro-N-sulfinylaldimines 3, including
known as DPP inhibitors [13]. Sitagliptin is a commercialized the new imines 3b and 3c derived from 2-chloro-2-ethylbutanal
oral antihyperglycemic drug of the DPP IV inhibitor class [14]. (1b) and 1-chlorocyclohexanecarboxaldehyde (1c), respective-
ly, were efficiently prepared by condensation of α-chloroalde-
As α,γ-diaminocarboxylamides, as well as β-aminocarboxyl- hydes 1 with (S)-(+)-p-toluenesulfinamide (2) in dichloro-
amides, are known for their activity as DPP inhibitors, an methane in the presence of Ti(OEt)4 (Scheme 1) [27].
increasing interest to study the DPP inhibitory potency of analo-
gous α,β-diaminocarboxylamides exists [15]. The synthesis of The synthesis of N-(diphenylmethylene)glycinamides 4 was
chiral α,β-diaminocarboxylic acid derivatives by asymmetric performed starting from N-Boc glycine, in accordance with
Mannich-type addition of enolates across activated imines, e.g., literature procedures [28,29]. Based on our previously reported
N-sulfinylimines [16-20], is one of the most common and versa- Mannich-type addition of glycine esters across chiral α-chloro-
tile methods in organic chemistry and is continuously under N-p-toluenesulfinylaldimine 3a [20], the influence of the base
development [1-3]. Recently, our research group elaborated the (LiHMDS or LDA) used for the deprotonation of glycine
asymmetric synthesis of new chiral γ-chloro-α,β-diaminocar- amides 4 on the syn- or anti-selectivity of the Mannich-type
boxyl esters by highly diastereoselective Mannich-type reac- addition was investigated (Scheme 2).
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boxylamides syn-5 (dr > 99:1) was determined by a combina-
tion of 1H NMR, 13C NMR and HPLC analysis in which no
signals from other diastereomers could be detected.
In contrast to the Mannich-type addition of glycine esters across
chiral α-chloro-N-p-toluenesulfinylimine 3a [20], the diastereo-
selectivity of the Mannich-type addition of glycinamides 4
across chiral α-chloro-N-p-toluenesulfinylaldimines 3 was inde-
pendent of the base used. The absolute stereochemistry of
(SS,2S,3S)-γ-chloro-α,β-diaminocarboxylamides syn-5 was
unambiguously determined by means of an X-ray diffraction
analysis of compound syn-5b (Figure 2), in combination with
the analogous NMR chemical shifts (Hα: δ = 4.91–5.20 ppm,
Scheme 1: Synthesis of chiral α-chloro-N-p-toluenesulfinylaldimines 3.
Initially, the Mannich-type addition of glycine amide 4b across Hβ: δ = 3.74–4.05 ppm) and the characteristic vicinal coupling
chiral α-chloro-N-p-toluenesulfinylisobutyraldimine (3a) was constants (3JHα-Hβ = 0–1.1 Hz) of all derivatives syn-5a–f.
performed at −78 °C using 1.1 equiv of LDA. Upon 1H NMR
analysis of the crude reaction mixture, the resulting syn-γ-
chloro-α,β-diaminocarboxylamide syn-5b was formed with an
excellent stereoselectivity (dr > 99:1) but the conversion was
rather low. After crystallization, the syn-adduct syn-5b was
isolated in a low yield of 16%. Repeating the Mannich-type
addition of glycinamides 4 across chiral α-chloro-N-p-toluene-
sulfinylaldimines 3 with 1.1 equiv of LiHMDS resulted also in
the formation of syn-γ-chloro-α,β-diaminocarboxylamides syn-5
with an excellent stereoselectivity (dr > 99:1). Because of the
complete conversion of the substrates under these better reac-
tion conditions (−78 °C, 15 min), the syn-adducts syn-5 could
Figure 2: Crystal structure of syn-γ-chloro-α,β-diaminocarboxylamide
syn-5b.
be isolated in higher yields (41–73%) after recrystallization.
The diastereomeric ratio of these syn-γ-chloro-α,β-diaminocar-
Scheme 2: Synthesis of (SS,2S,3S)-γ-chloro-α,β-diaminocarboxylamides 5. aYield in parentheses results from the use of LDA instead of LiHMDS.
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The vicinal coupling constant 3JHα-Hβ = 0–1.1 Hz for the syn- Reaction of the Z-enolates via a cyclic chelated six-membered
amides 5 has a comparably small value as the observed vicinal chairlike transition-state model TS-6a, would have resulted in
coupling constant 3JHα-Hβ of the closely related syn-γ-chloro- anti-addition products anti-5 in analogy with our previously
α,β-diaminocarboxyl esters (3JHα-Hβ = 1.1 Hz) [20]. Notably, obtained results on the synthesis of (SS,2S,3R)-γ-chloro-α,β-
the (SS,2S,3S)-γ-chloro-α,β-diaminocarboxylamides syn-5 were diaminocarboxyl esters [20]. However, starting from glycin-
obtained with the opposite enantioselectivity as compared to the amides 4, due to the important 1,3-diaxial interaction between
(SS,2R,3R)-γ-chloro-α,β-diaminocarboxyl esters obtained by the haloalkyl group (–CClR2) and the cyclic amine moiety
Mannich-type addition of E-enolates derived from glycine [–N(CH2)n] in this transition state, TS-6a is highly disfavored.
esters across imines 3 [20].
The formation of the (SS,2S,3S)-γ-chloro-α,β-diaminocarboxyl-
amides syn-5 can be explained by a boatlike transition-state
The monosubstituted tertiary amide enolates obtained by depro- model TS-6b involving the (E)-N-p-toluenesulfinylaldimines 3
tonation of N-(diphenylmethylene)glycinamides 4 are expected [32-35]. This less sterically hindered transition state TS-6b,
to have the Z-geometry in which A(1,3) interactions are mini- in which the haloalkyl group (–CClR2) occupies the less
mized and Li-chelation stabilizes the conformation (Scheme 3), hindered pseudoequatorial position, and the corresponding
regardless of the base that was used [30,31].
Li-adduct 7 are stabilized by the interaction between the
Scheme 3: Transition-state model for reaction of the Z-enolate of glycinamides 4 in the Mannich-type addition across chiral α-chloro-N-p-toluene-
sulfinyl aldimines 3.
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Li-cation, the diphenylmethyleneamino group, and the complete based on 1H NMR and LC–MS analysis of the crude
sulfinylimine nitrogen.
reaction mixture. Unfortunately, all attempted purification tech-
niques (column chromatography, preparative TLC, acid-base
The reversal of the enantiotopic face selectivity in the reaction extraction) to remove benzophenone and some other minor
of the N-sulfinylimines 3 with the glycinamides 4, as compared impurities from the crude reaction mixture, failed to provide the
to the reaction with glycine esters, is attributed to the α-coordi- pure N-deprotected syn-β,γ-aziridino-α-aminocarboxylamide
nating ability of the chlorine atom with the lithium of the 9b.
incoming enolate as depicted in transition state TS-6b. The
coordinating α-chloro atom in TS-6b overrides the chelation of Alternatively, the deprotection of the α-amino functionality of
the sulfinyl oxygen (e.g., TS-6a) and allows the sulfinylimine to the synthesized syn-γ-chloro-α,β-diaminocarboxylamides syn-5
react in the conformation wherein the S=O bond and the lone was investigated en route towards the development of potential
pair of electrons on the nitrogen atom are antiperiplanar [36]. DPP inhibitors [7-9]. The syn-γ-chloro-α,β-diaminocarboxyl-
This reversal of stereoselectivity is analogous to results amides syn-5 were treated with 5 equiv of trifluoroacetic acid in
obtained with other N-p-toluenesulfinylimines containing an acetone/water (2:1) for 15 min (Scheme 5).
oxygen atom as α-coordinating group [37-39]. The resulting
syn-addition products syn-5 were subsequently cyclized to the After a basic workup with NH4OH, the α-deprotected syn-γ-
corresponding N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides chloro-α,β-diaminocarboxylamides 10 could be purified by
8 upon treatment with K2CO3 in acetone under reflux in a crystallization or preparative TLC (21–91% yield). The
moderate to very good yield (36–90%, Scheme 4).
obtained result was in accordance with the earlier reported
selective deprotection of a benzophenone imine functionality, in
The conversion of the ring-closure reaction was always the presence of an N-p-toluenesulfinyl moiety, of diamino esters
complete as determined by TLC analysis, but purification of with H3PO4/H2O/THF [17,40].
these N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides 8
by flash chromatography resulted in a considerable loss of In a subsequent step, syn-γ-chloro-α,β-diaminocarboxylamide
product.
10b was chemoselectively cyclized to the corresponding
N-sulfinyl-β,γ-aziridino-α-aminocarboxylamide 11b upon treat-
In order to extend the potential applicability of the synthesized ment with K2CO3 in acetone under reflux in 86% yield. In order
N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides 8 as building to provide access to the Nα,Nβ-deprotected syn-γ-chloro-α,β-di-
blocks in biomedicinal chemistry, some attempts were made to aminocarboxylamides, syn-γ-chloro-α,β-diaminocarboxyl-
remove the N-protective groups of diaminocarboxylamides 8 amides syn-5 were subjected to some alternative acidic depro-
under mild acidic conditions (Scheme 4). In analogy with our tection reactions (Scheme 6).
recently published results on the corresponding aziridino esters
[20], amide 8b was treated with 5 equiv of trifluoroacetic acid In an initial reaction, syn-γ-chloro-α,β-diaminocarboxylamide
in acetone/water (2:1) at rt for 15 min. After a basic workup syn-5b was treated with 10 equiv of trifluoroacetic acid in
with NH4OH, it was concluded that the conversion towards the ethanol at rt [18]. This resulted in trans-imidazolidine 12b
N-deprotected syn-β,γ-aziridino-α-aminocarboxylamide 9b was after basic workup with NH4OH. It is remarkable that the
Scheme 4: Synthesis of N-sulfinyl-β,γ-aziridino-α-amino carboxylic amides 8.
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Scheme 5: α-Deprotection and subsequent ring-closure of syn-γ-chloro-α,β-diamino carboxylic amides syn-5.
Scheme 6: N-p-toluenesulfinyl-deprotection of syn-γ-chloro-α,β-diaminocarboxylamides syn-5.
N-(diphenylmethylene) group was not removed under these under acidic conditions, in analogy with deprotection reactions
reaction conditions but was trapped by the deprotected β-amino of imidazolidines, imidazolines and oxazolines in the literature
group, as the deprotection of analogous anti-substrates under [16,47,48]. However, in a second reaction, syn-γ-chloro-α,β-
the same reaction conditions led to unprotected anti-α,β- diaminocarboxylamide syn-5a was directly converted into the
diaminocarboxyl esters [18]. This is possibly due to the fact that dihydrochloride of the Nα,Nβ-deprotected syn-γ-chloro-α,β-
solvolysis of the imine functionality with ethanol is not favor- diaminocarboxylamide 13a, by stirring in 0.5 M (aq) HCl/
able and an acid-catalyzed deprotection of the sulfinyl moiety EtOAc (2:1) for 30 min at rt, in a yield of 83%. In this reaction,
will occur first [41,42]. The resulting β-amino deprotected syn- the acid-catalyzed hydrolysis of the benzophenone imine func-
γ-chloro-α,β-diaminocarboxylamide could subsequently ring tionality proceeds readily and prevents the formation of the
close further to trans-imidazolidine 12b, which will be less ster- corresponding trans-imidazolidine.
ically congested than an analogous cis-imidazolidine. In the
literature, comparable non-halogenated trans-imidazolidines Conclusion
were already synthesized by 1,3-dipolar cycloaddition of In conclusion, it was demonstrated that new chiral syn-γ-chloro-
N-benzylidene glycine ester enolates across N-sulfinyl- α,β-diaminocarboxylamides are formed in acceptable to good
aldimines in the presence of a Lewis acid [43]. The trans- yields and with excellent diastereomeric ratios by stereoselec-
stereochemistry of imidazolidine 12b was ensured by the tive Mannich-type reactions of N-(diphenylmethylene)glycin-
vicinal coupling constant 3JH4-H5 = 7.43 Hz and the 1H NMR amides across chiral α-chloro-N-p-toluenesulfinylaldimines.
chemical shift of H4 (3.85 ppm), which were in the same range Notably, a very high syn-diastereoselectivity was obtained in
as for closely related trans-imidazolidines and trans-oxazo- the synthesis of the (SS,2S,3S)-γ-chloro-α,β-diaminocarboxyl-
lidines [43-45]. The trans-imidazolidine 12b is a potential amides with the opposite enantiotopic face selectivity as
building block for foldamers, as the corresponding trans-oxazo- compared to the Mannich-type additions of N-(diphenylmeth-
lidin-2-ones are already applied as such [46]. trans-Imidazoli- ylene)glycine esters across chiral α-chloro-N-p-toluenesulfinyl-
dine 12b could also be used as a precursor of the corresponding aldimines. The synthesized γ-chloro-α,β-diaminocarboxyl-
Nα,Nβ-deprotected α,β-diaminocarboxylamide, by hydrolysis amides were selectively deprotected under acidic conditions,
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Supporting Information
Supporting Information File 1
General experimental conditions, experimental procedures
and data, copies of 1H NMR and 13C NMR spectra for
compounds 3, syn-5, 8, and 10–13.
17.Viso, A.; Fernández de la Pradilla, R.; Flores, A.; García, A.;
Tortosa, M.; López-Rodríguez, M. L. J. Org. Chem. 2006, 71, 1442.
doi:10.1021/jo052077h
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-239-S1.pdf]
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19.Davis, F. A.; Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833.
doi:10.1021/ol063058c
Supporting Information File 2
CIF-file of compound syn-5b.
20.Callebaut, G.; Mangelinckx, S.; Kiss, L.; Sillanpää, R.; Fülöp, F.;
De Kimpe, N. Org. Biomol. Chem. 2012, 10, 2326.
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Acknowledgements
The authors are indebted to the “Institute for the Promotion of
Innovation through Science and Technology, Flanders” (IWT-
Vlaanderen) and the Research Foundation, Flanders (FWO) for
financial support.
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