Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

Article abstract of DOI:10.3762/bjoc.13.214

A new synthesis of the important amino acid 2-aminosuberic acid from aspartic acid is reported. The methodology involves the alternate preparation of (S)-2-aminohept-6-enoate ester as a building block and its diversification through a cross-metathesis reaction to prepare the title compounds. The utility of the protocol is demonstrated through the preparation of three suberic acid derivatives of relevance to the design and the synthesis of peptides of biological relevance.

Full text of DOI:10.3762/bjoc.13.214

Synthesis of 2-aminosuberic acid derivatives as components
of some histone deacetylase inhibiting cyclic tetrapeptides
Shital Kumar Chattopadhyay*§, Suman Sil and Jyoti Prasad Mukherjee
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2153–2156.
Department of Chemistry, University of Kalyani, Kalyani - 741235,
West Bengal, India
doi:10.3762/bjoc.13.214
Received: 03 August 2017
Accepted: 25 September 2017
Published: 17 October 2017
Email:
Shital Kumar Chattopadhyay* - skchatto@yahoo.com
*
Corresponding author
Associate Editor: N. Sewald
§
Fax: +91+33+25828282
©
2017 Chattopadhyay et al.; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
α-amino acid; catalysis; chiral pool; cross metathesis; cyclic peptides
Abstract
A new synthesis of the important amino acid 2-aminosuberic acid from aspartic acid is reported. The methodology involves the
alternate preparation of (S)-2-aminohept-6-enoate ester as a building block and its diversification through a cross-metathesis reac-
tion to prepare the title compounds. The utility of the protocol is demonstrated through the preparation of three suberic acid deriva-
tives of relevance to the design and the synthesis of peptides of biological relevance.
Introduction
α-Aminosuberic acid (Asu) is a component of apicidin F (1, thesis of an orthogonally protected Asu derivative from easily
Figure 1) belonging to an interesting class of cyclic tetrapep- available sources [11] for potential applications remains impor-
tides displaying antimalarial and histone deacetylase inhibitory tant. During the course of our work on the synthesis of amino
(
HDACi) properties [1,2]. It has been suggested [3] that the ter- acids and peptides relevant to HDAC inhibition [12], we re-
minal carbonyl group in members of this family (e.g., in 2) quired orthogonally protected Asu derivatives. Herein we
functionally mimics the C-8 keto group of the acetylated lysine describe an alternate synthesis of the important building block
residue (3) of histones as a part of their biological activity and 2-aminoheptenoic acid and its application to the synthesis of or-
therefore the variation in the carbonyl functionality may have thogonally protected Asu derivatives.
implications in drug design. Moreover, Asu and its congener
2
-aminopimelic acid have been used as ethylenic equivalent of Results and Discussion
a disulfide linkage [4]. Other applications of Asu in peptide Our synthesis started with the preparation of bishomoallyl-
engineering and as a building block are of notable importance glycine derivative 11 (Scheme 1) from the known aspartic acid
[
5,6]. For this, and other reasons, several synthetic routes to Asu derived aldehyde 4 [13]. The latter was converted to its doubly
have been developed [7-9] which often uses chemical or enzy- homologated derivative 8 through four conventional steps viz.
matic resolution of a racemate [10]. However, the chemical syn- HWE-type olefination leading to the unsaturated ester 5, satura-
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Beilstein J. Org. Chem. 2017, 13, 2153–2156.
Figure 1: Biologically active naturally occurring cyclic tetrapeptide HDAC inhibitors.
Scheme 1: Reagents and conditions: (i) Triethyl phosphonoacetate, n-Bu4N+I−, aq K2CO3, rt, 18 h, 86%; (ii) H2, Pd/C, EtOAc, rt, 6 h, 83%; (iii) LAH,
THF, 0 °C to rt, 2 h, 81%; (iv) (COCl)2, DMSO, N-methylmorpholine, CH2Cl2, −78 °C to 0 °C; (v) MePh3PBr, n-BuLi, THF, 0 °C, 3 h, 72% over two
steps; (vi) chromic acid, acetone, 2 h, 73%; (vii) Cs2CO3, CH3I, DMF, 2 h, 88%.
tion of the double bond in the latter to 6, reduction of the ester Having access to the building block 11, we focused on its
moiety in 6 to the alcohol 7 followed by its oxidation. The alde- conversion to the targeted Asu derivatives through cross me-
hyde 8 thus obtained was subjected to a Wittig olefination to tathesis (CM) [20] with conjugated olefins 13a–d (Scheme 2).
obtain the desired alkene 9 in an overall yield of 42% over five In recent years, the cross-metathesis reaction has emerged as a
steps. One-pot deprotection–oxidation [14] of the oxazolidine valuable tool in the preparation of α-amino acids [21-27] and
moiety in 9 proceeded uneventfully to provide N-Boc-2-amino- few useful general guidelines have emerged from these studies.
6
-heptenoic acid (10) in good yield. The latter was smothly pro- Pleasingly, cross metathesis of our building block 11 with tert-
tected as its methyl ester using methyl iodide in the presence of butyl acrylate (13a) proceeded quickly in the presence of
cesium carbonate to provide the desired 2-aminoheptenoic acid Grubbs’ 2nd generation catalyst [(1,3-bis(2,4,6-trimethyl-
derivative 11. Several syntheses of this important amino acid phenyl)-2-imidazolidinylidene)dichloro(phenylmethyl-
have appeared which include Lubell’s palladium-catalyzed ally- ene)(trichlorohexylphosphine)ruthenium, 12] in refluxing
lation [15], Riera’s asymmetric epoxidation protocol [16], dichloromethane and the product 14a was obtained in good
Rich’s enolate amination [17] and Hruby’s asymmetric alkyl- yield. The corresponding reaction of 11 with benzyl acrylate
ation [18] of a chiral nickel complex among others. Moreover, (13b) proceeded with similar facility, yield and isomeric com-
many of these studies have also reported an elegant use of this position. Although the cross-metathesis reaction with α,ß-unsat-
unsaturated amino acid [19]. Our simple protocol involves the urated esters and ketones have been extensively studied, the
use of less sophisticated reagents and catalysts and the use of corresponding reactions with amides and anilides are less docu-
easily available starting materials; it proceeds in an overall yield mented [28]. An elegant solution to one of this problems is the
of 27% over seven high yielding simple steps.
use of acryloyl chloride as CM partner followed by functionali-
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Beilstein J. Org. Chem. 2017, 13, 2153–2156.
Scheme 2: Reagents and conditions: (i) Grubbs’ catalyst 12 (2.5 mol %), DCM, reflux, 2 h, 14a, 83%; 14b, 90%; 14c, 88% ; (ii) H2, Pd/C, MeOH, rt, 2
h, 15a, 79%; 15b, 82%; 15c, 90%.
zation of the cross product [29]. To our delight, the reaction of (1 mL) was added dropwise under an argon atmosphere. The re-
1
1 with anilide 13c proceeded well under our developed condi- sulting reaction mixture was then heated to reflux for 2 h. The
tions and the CM product was obtained as a single isomer (E-). reaction mixture was allowed to cool to room temperature and
Only a few successful reports on cross metathesis with then concentrated in vacuo. The residue was subjected to
Weinreb’s amide of acrylic acid, and N-alkylated acrylamides column chromatographic purification over silica gel using an
are known [30-33]. However, all attempts of CM reaction of 11 appropriate mixture of ethyl acetate in hexane to provide the
with the olefin 13d proved to be futile, a major problem being coupled product as colorless viscous liquid.
the inadequate solubility of the olefin in the reaction solvents
(S,E)-1-tert-Butyl 8-methyl 7-(tert-butoxy-
tried, e.g., dichloromethane, dichloroethane, benzene, toluene
etc. The solubility problem may be avoided by dilution and in- carbonylamino)oct-2-enedioate (14a)
creasing the temperature but the reaction is too slow to be use- Colourless liquid. Yield: 148 mg, 83%; [α]D25 +12.60 (c 1.00,
ful. The CM product 14a was then hydrogenated to obtain the CHCl3); IR (neat): 3363, 2978, 2933, 1715, 1652, 1505, 1367,
known Asu derivative 15a [34] under conventional conditions. 1164 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.81 (td, J = 6.8,
Similarly, the known N-Boc-L-Asu-OH (15b) [35] was ob- 15.6 Hz, 1H), 5.74 (d, J = 15.6 Hz, 1H), 5.10 (d, J = 7.6 Hz,
tained by hydrogenation of the benzyl ester 14b with concomi- 1H), 4.31 (m, 1H), 3.74 (s, 3H), 2.23–2.17 (m, 2H), 1.81 (m,
tant saturation of the double bond. The conversion of 14c into 1H), 1.65 (m, 1H), 1.58–1.48 (m, 11H), 1.44 (s, 9H) ppm; 13C
1
5c proceeded without events.
NMR (100 MHz, CDCl3) δ 173.2, 165.9, 155.3, 146.7, 123.6,
0.1, 79.9, 53.1, 52.3, 32.2, 31.4, 28.3, 28.1, 23.8 ppm; HRMS
(TOF–MS ES+) m/z: [M + Na]+ calcd for C18H31NNaO6,
8
Conclusion
In conclusion, we have developed a modestly diversified syn- 380.2049; found, 380.2056.
thesis of important Asu derivatives through an alternate prepa-
ration of the building block 11 of proven utility in the design
Supporting Information
and synthesis of peptidomimetics. A cross-metathesis reaction
has been utilized to create the diversification on the template 11
Supporting Information File 1
in order to obtain orthogonally protected Asu derivatives. More-
over, the Asu derivative 15a has been demonstrated to be use-
ful in the preparation of a plethora of HDAC inhibitors [34].
The methodology may therefore find application in the synthe-
sis of related targets and may complement to the existing litera-
ture. The work will be continued to explore syntheses of other
Asu derivatives using the developed methodology.
Experimental details and analytical data of all new
compounds as well as copies of their 1H and 13C NMR
spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-214-S1.pdf]
Acknowledgements
We are thankful to CSIR, New Delhi, for funds (02/0164/13/
Experimental
General procedure for cross metathesis
EMR-II), and fellowship to two of us (JPM, SS).
This was carried out in a manner as described in [36]. Grubb’s
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