Enantiodivergent transannular rearrangement of 3-isopropyl-1,4- benzodiazepine-2,5-dione by memory of chirality

Article abstract of DOI:10.1002/ejoc.201100030

An unprecedented reactivity has been introduced to 3-isopropyl-1,4- benzodiazepine-2,5-dione thanks to N-Boc activation. Under basic conditions, a transannular rearrangement occurred by ring contraction to furnish a 3-aminoquinoline-2,4-dione with good to

Full text of DOI:10.1002/ejoc.201100030

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100030
Enantiodivergent Transannular Rearrangement of
3-Isopropyl-1,4-benzodiazepine-2,5-dione by Memory of Chirality
Daniel Farran,[a] Pierre Archirel,[b] Loïc Toupet,[c] Jean Martinez,[a] and
Georges Dewynter*[a]
Keywords: Conformational equilibrium / Enantioselectivity / Lactam activation / Chirality / Rearrangement / Ring
contraction
An unprecedented reactivity has been introduced to 3-iso-
propyl-1,4-benzodiazepine-2,5-dione thanks to N-Boc acti-
vation. Under basic conditions, a transannular rearrange-
ment occurred by ring contraction to furnish a 3-aminoquin-
oline-2,4-dione with good to excellent enantiomeric purity.
Depending on the nature of the base, either enantiomer can
be obtained in a stereocontrolled manner. This enantiodi-
vergent synthesis could be assigned to the conformational
equilibrium of the starting material, which was studied with
the help of DFT calculations.
nucleophiles[4] or ring contraction by transannular re-
arrangement of activated lactams (TRAL) under basic con-
ditions.[5] In continuation of our efforts in this area, we
hoped to extend this latter reaction to larger cyclic dipep-
tides. For this purpose, we chose 1,4-benzodiazepine-2,5-di-
ones (BZDs), a scaffold widely studied in its relation to me-
dicinal chemistry.[6] In this paper, we describe the rearrange-
ment of bis-Boc BZDs to 3-alkyl-3-aminoquinoline-2,4-di-
ones in a stereocontrolled manner and in the absence of any
external chiral source. To the best of our knowledge, there
is no stereoselective pathway to these derivatives, and only
one racemic preparation (by amination of halogenated in-
termediates) exists in the literature.[7] Nevertheless, quinol-
ine-2,4-diones with a quaternary carbon center at C-3 pos-
sess anti-HIV[8] and 5-HT6 serotonin receptor antagonistic
activities.[9] This skeleton is also found in buchapine, a bio-
logically active natural product with therapeutic poten-
tial.[10] In addition, 4-hydroxyquinolin-2-ones, analogous
structures, exhibit a broad scope of pharmacological prop-
erties,[11] including antagonist behaviour at the glycine site
of the N-methyl-d-aspartate receptor[12] and fatty acid syn-
thase inhibition.[13]
Introduction
The development of stereoselective methods allowing the
access to quaternary centers is a key synthetic goal and a
major point of interest for organic chemists. Asymmetric
construction of α,α-disubstituted amino acid derivatives
have particularly been explored because of their biological
properties and their scarce natural occurrence.[1] Conven-
tional synthesis of such compounds requires chiral auxilia-
ries or chiral catalysts. However, during the last decade, the
principle of Memory of Chirality (MOC) emerged as an
elegant entry to these complex targets without the aid of
any additional chiral sources.[2] This concept consists in the
temporary storage of the stereochemical information at a
different site in the intermediate. A significant example of
this approach has been reported by Carlier and co-workers
who exploited the ring flipping of benzodiazepin-2-ones.[3]
We recently published the unprecedented reactivity of
2,5-diketopiperazines (DKPs) bearing tert-butoxycarbonyl
groups (Boc) on the nitrogen atoms, which display the role
of electron-withdrawing activators (Figure 1). Such substi-
tuted lactams led to unusual transformations: enhancement
of the opening ability of carbonyl lactam groups towards
[a] Institut des Biomolécules Max Mousseron, UMR CNRS 5247,
Université Montpellier 1, Université Montpellier 2,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
E-mail: dewynter@univ-montp2.fr
[b] Laboratoire de Chimie-Physique, UMR 8000, Université Paris
Sud,
Bât 349, 91405 Orsay Cedex, France
[c] Groupe Matière Condensée et Matériaux, UMR 6626,
Université Rennes 1,
Figure 1. General structures of 1,4-bis(tert-butoxycarbonyl)piper-
azine-2,5-dione and 1,4-bis(tert-butoxycarbonyl)-1,4-benzodiazep-
ine-2,5-dione.
Campus de Beaulieu, 35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100030.
Eur. J. Org. Chem. 2011, 2043–2047
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Farran, P. Archirel, L. Toupet, J. Martinez, G. Dewynter
SHORT COMMUNICATION
1
careful examination of the H NMR spectrum. At room
Results and Discussion
temperature, only one set of peaks was observed in CDCl3.
3
1,4-Benzodiazepine-2,5-diones were prepared according The coupling constant J3-H,12-H was measured to be
to a typical procedure by treatment of isatoic anhydride 11.1 Hz, a large value consistent with a trans relationship.
with an appropriate α-amino acid ester.[14] Investigations In addition the 12-H chemical shift was recorded at δ =
were conducted on compound (3S)-1 with an isopropyl 1.04 ppm, an upfield shift meaning that this proton is lo-
group at C-3. The insertion of Boc groups on the nitrogen cated in the cone-shaped shielding zone due to the aromatic
atoms was carried out by using our previously reported pro- ring. Furthermore, nOe experiments clearly confirmed that
tocol for the DKP series.[5a] The corresponding bis-Boc this latter hydrogen atom is close to those belonging to the
BZD (3S)-2 was generated in good yield, and – according aromatic moiety. All these observations suggest that, at
to chiral HPLC analyses – no racemisation occurred during room temperature and in solution, bis-Boc BZD 2 adopts
this step (Scheme 1). Surprisingly, despite of our efforts, we a conformation in which the isopropyl group is oriented in
were not able to isolate other diprotected BZDs, all pseudoaxial position.
attempts leading to N1-Boc or N,N,O-tris-Boc products (see
the Supporting Information).
As expected, in the presence of lithium hexamethyldisil-
azide (LiHMDS), we observed a ring contraction of BZD
With compound (3S)-2 in hand, the dynamic equilibrium (3S)-2, leading to 3-aminoquinoline-2,4-dione (3R)-3 in
due to the presence of (P) and (M) conformational enantio- good yield and with excellent enantioselectivity (Scheme 1).
mers was investigated by DFT/PCM calculations at the Removal of the Boc groups was easily achieved by using
B3LYP/SDD level of theory.[15,16] This study revealed that trifluoroacetic acid, and subsequent treatment with bro-
the conformer with the isopropyl group in pseudoaxial po- moacetic anhydride afforded derivative 5. The configuration
sition is the most stable one, probably because of less steric of the quaternary stereogenic carbon center was thus unam-
hindrance between the isopropyl and the N4-Boc groups biguously determined by X-ray diffraction crystal analysis
(Scheme 2). In addition, the barrier height for the conver- of the major isomer 5, enantioenriched by recrystallisation
sion of the (P) to the (M) conformer was calculated to be (Figure 2).[18] At this stage, it is interesting to note that Jua-
22.2 kcal/mol. These results are in agreement with a pre- risti et al. have already reported 3-alkylation of 1,4-benzodi-
vious report, which mentions the importance of the size of azepine-2,5-diones bearing alkyl chains on the nitrogen
the N1-substituent for the inversion barrier.[17] Some insight atoms in the presence of a strong base, but did not observe
into the conformation in solution can be gleaned from a any rearrangement.[19]
Scheme 1. Stereocontrolled transannular rearrangement of an activated BZD derived from l-valine.
Scheme 2. Conformational equilibrium of bis-Boc BZD (3S)-2. Erel = relative energy with respect to the most stable conformation.
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Rearrangement of 3-Isopropyl-1,4-benzodiazepine-2,5-dione
Figure 2. ORTEP representation of (3R)-5.
We propose for this unusual transformation a mechanism enantiomeric ratio (Entry 5). The use of NaH gave worse
very similar to the TRAL in the DKP series.[5a,5c] Under results (Entry 6), and potassium tert-butoxide appeared as
basic conditions, the resulting enolate attacks the activated a moderate reagent (Entry 7), whereas a significant im-
lactam carbonyl group to promote an oxy anion with an provement was obtained with 4-(dimethylamino)pyridine
aziridine moiety, which opens to furnish the desired product (DMAP, Entry 8). It is noteworthy that good enantiomeric
(Scheme 3). This can be related to the Chan reaction,[20]
a
excess can be achieved with these three bases, although the
base-induced rearrangement of an acyloxyacetate to a 2- temperature was relatively high for this type of reaction. A
hydroxy-3-oxo ester, and the N Ǟ C acyl migration of an similar observation has previously been made in a cycliza-
acyclic imide,[21] two rare tools used in the total syntheses tion process by MOC for the synthesis of quaternary amino
of aplasmomycin,[22] boromycin,[23] rapamycin,[24] diazon- acids.[27]
amide A[25] and taxol.[26]
However, the most exciting finding is undoubtedly the
In order to explore this original reactivity, bis-Boc BZD fact that starting from an enantiopure benzodiazepine, it is
2 was subjected to other bases (Table 1). Attempts carried possible to obtain stereospecifically both enantiomers of
out with stronger lithiated bases, such as lithium diiso- the quinoline by changing the nature of the base. With
propylamide (LDA, Entry 1) or n-butyllithium (nBuLi, En- LiHMDS, the rearrangement proceeds preferentially with
try 2), were unsuccessful and led to complex mixtures of inversion of configuration, whereas retention of configura-
compounds difficult to analyse. KHMDS provided the de- tion is observed with other bases (for example: Entry 3 vs.
sired quinoline-2,5-dione in excellent yield and with good Entry 5). A plausible explanation could be found in the
Scheme 3. Possible mechanism to explain the observed stereoselectivity of the reaction. Base: KHMDS, NaH, tBuOK, DMAP; R =
SiMe3; S = solvent.
Eur. J. Org. Chem. 2011, 2043–2047
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Farran, P. Archirel, L. Toupet, J. Martinez, G. Dewynter
SHORT COMMUNICATION
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data for all com-
pounds and details on the DFT calculations for (3S)-2.
Table 1. Effects of base on the stereochemical course of the re-
arrangement of 2.
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Entry
2
Base
T [°C] 3, yield [%][a,b] Enantiomeric ratio[c]
1
2
3
4
5
6
7
8
(3S)
(3S)
LDA
nBuLi
–78
–78
–, 0
–, 0
–
–
(3S) LiHMDS –78
(3R) LiHMDS –78
(3S) KHMDS –78
(3S)
(3S) tBuOK
(3R) DMAP
(3R), 75
(3S), 76
(3S), 87
(3S), 5
(3S), 52
(3R), 84
93:7
7:93
19:81
17:83
28:72
86:14
NaH
0
0
20
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Conclusions
We have described the extension of the TRAL reaction
to a seven-membered ring, 3-isopropyl-1,4-benzodiazepine-
2,5-dione, leading to the first enantioselective synthesis of
3-aminoquinoline-2,4-dione, a valuable scaffold with phar-
macological potential. The stereochemistry of the re-
arrangement depends on the base used. Studies are cur-
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vergent synthesis. We also envision to expand the scope of
the TRAL to activated lactams included in macrocycles.
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Eur. J. Org. Chem. 2011, 2043–2047

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Received: January 10, 2011
Published Online: February 21, 2011
Eur. J. Org. Chem. 2011, 2043–2047
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