Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ0)

Article abstract of DOI:10.3762/bjoc.10.135

A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ₀) has been accomplished. This synthetic route allows for an efficient preparation of 4-substituted analogues with

Full text of DOI:10.3762/bjoc.10.135

Stereoselective synthesis of carbocyclic analogues
of the nucleoside Q precursor (PreQ0)
Sabin Llona-Minguez*1,2 and Simon P. Mackay*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1333–1338.
1Strathclyde Institute of Pharmacy & Biomedical Sciences, University
of Strathclyde, 165 Cathedral Street, Glasgow, G4 0RE, United
Kingdom and 2Science for Life Laboratory, Division of Translational
Medicine & Chemical Biology, Department of Medical Biochemistry &
Biophysics, Karolinska Institutet, Stockholm, S-171 21, Sweden
doi:10.3762/bjoc.10.135
Received: 02 March 2014
Accepted: 23 May 2014
Published: 11 June 2014
Email:
Associate Editor: S. Bräse
Sabin Llona-Minguez* - sabin.llona.minguez@scilifelab.se;
Simon P. Mackay* - simon.mackay@strath.ac.uk
© 2014 Llona-Minguez and Mackay; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
diol synthesis; nucleoside; PreQ0; stereoselective amine synthesis;
triol synthesis
Abstract
A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor
(PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4-substituted analogues with interesting
three-dimensional character, including chiral cyclopentane-1,2-diol and -1,2,3-triol derivatives. This unusual substitution pattern
provides a useful starting point for the discovery of novel bioactive molecules.
Introduction
7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are of PreQ0 originates from guanosine 5’-triphosphate (GTP, 4)
commonly found in nature playing a variety of roles such as [7] (Figure 1) and involves four steps via a tetrahydropterine
building blocks of nucleic acids and tRNA, metabolites or intermediate.
antimetabolites [1]. Deazapurine ribonucleosides also show
interesting pharmacological profiles including antibacterial, The pyrrolo[2,3-d]pyrimidine core is a privileged scaffold for
antiviral and anticancer properties [2-4]. Nucleoside Q the development of kinase inhibitors; an inspection of the medi-
precursor (PreQ0) 1 is a common precursor in the biosynthesis cinal chemistry literature reveals >200 publications in the field.
of queuosine (Q, 2) and archaeosine (G+, 3), two hyper-modi- Additionally, PreQ0 meets all the criteria dictated by the “2-0”
fied nucleosides present in the tRNA of prokaryote/eukaryote rule of kinase-likeness proposed by Aronov et al. [8]. It is likely
and euryarchaeota, respectively [5,6]. In turn, the biosynthesis that compounds derived from PreQ0 display kinase activity.
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Beilstein J. Org. Chem. 2014, 10, 1333–1338.
Figure 1: Biosynthetic pathway leading to nucleosides queuosine and archaeosine.
7-Deazapurine nucleoside chemistry has been the subject of
extensive study [1] and several syntheses of the PreQ0 base or
ribonucleoside [9-16] and queuosine [17] have been reported in
the literature. Despite this long-lasting interest, examples of
purine-based nucleosides containing a sugar or carbosugar
motif at the 4-position of the heterocyclic core (systematic
numbering) are scarce in the chemical literature and the
methods available generally lack experimental information,
making them unsatisfactory [18-25]. Inspired by the cyclopen-
tane-1,2,3-triol motif present in noraristeromycin 5 (Figure 2),
Figure 2: Chemical structure of noraristeromycin.
an IκB kinase inhibitor with antiviral and anti-inflammatory
activity [26,27], we decided to investigate a synthetic route that
would allow for the incorporation of carbocyclic systems with in PreQ0 after activation and subsequent nucleophilic aromatic
interesting three-dimensional character at the 4-position of substitution. This convergent synthesis allowed us to prepare
PreQ0 as part of our fragment-based kinase inhibitor library diverse chiral amine building blocks and react them with a
generation programme.
common halo-purine intermediate to obtain the desired final
products. The pyrrolo[2,3-d]pyrimidine core of PreQ0 was
furnished following a method described by Klepper et al. [13]
Results and Discussion
Our retrosynthetic approach introduces the diversity point at a (Figure 3). The two step process started with the formylation of
late stage and takes advantage of the heterocyclic lactam present chloroacetonitrile with methyl formate. The resulting volatile
Figure 3: Synthesis of PreQ0 and chloro-intermediate 9. Reagents and conditions: (a) Methyl formate, NaOMe, PhMe, 3 h, 0 °C; (b) 2,6-diamino-
pyrimidin-4(3H)-one, NaOAc, H2O, 17 h, 100 °C, 60% (over two steps); (c) PivCl, pyridine, 2 h, 85 °C, 64%; (d) POCl3, DMA, BnEt3NCl, MeCN, 1 h,
90 °C, 35%.
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Beilstein J. Org. Chem. 2014, 10, 1333–1338.
and unstable chloroaldehyde 6 was used without further purifi- yield over two steps. Next, we introduced the two hydroxy
cation. Cyclocondensation of 6 with 2,4-diamino-4-hydroxy- groups trans- to the amine moiety using an Upjohn dihydroxy-
pyrimidine afforded 1 regiospecifically with no detectable for- lation. Freshly-prepared aqueous OsO4 stock solutions were
mation of the undesired 6-substituted-furo[2,3-d]pyrimidine 7. required to obtain good yields in this step. The reaction
Direct chlorination of 1 in a moderate scale (1 g) using POCl3 proceeded smoothly and the 1H NMR spectra of the crude reac-
proved to be very low yielding [28]. It remains unclear if this tion mixture showed a 96:4 ratio of cis- to trans-isomers. After
was due to the poor solubility of PreQ0 or to the presence of column chromatography the isolated diol 12 showed a dia-
unprotected amino functionalities. In order to overcome this stereomeric purity of >99% by 1H NMR. The dibenzoate 13
issue, the exocyclic amine was protected [14] (Figure 3). The was obtained in good yield following standard acylation condi-
resulting pivalamide 8 proved to be more soluble than 1 and the tions [31]. Final removal of the two benzyl groups was accom-
subsequent halogenation step was accomplished in the presence plished in excellent yield using catalytic hydrogenation [30],
of a phase transfer catalyst, affording the desired chloro-inter- using EtOAc as a co-solvent to improve the substrate solubility.
mediate 9 in fair yield. In our hands, nucleophilic aromatic Amine 14 was coupled with 9 and the pivalamide and benzoate
substitution on 9 using amines of diverse nature usually groups were cleaved in the one-pot procedure previously
proceeds smoothly and allows for a clean pivalamide deprotec- described to afford 15, the (1RS,2SR,3RS)-3-aminocyclopen-
tion [29]. For this reason we decided to couple the chiral amines tane-1,2-diol derivative of PreQ0.
of interest and remove protecting groups in a one-pot procedure.
Adapting a protocol developed by Springthorpe et al. [32], we
First we investigated a more synthetically accessible then investigated a route to prepare the enantiopure
(1RS,2SR,3RS)-3-aminocyclopentane-1,2-diol core. Our (1S,2R,3S,4R)-4-aminocyclopentane-1,2,3-triol analogue of
previous experience in coupling diols and triols at high PreQ0 16 (Figure 5). The first step is a Tsuji–Trost allylation of
temperatures with chloro-intermediate 9 showed that more than sodium di-tert-butyliminodicarboxylate. The reaction proceeded
one unprotected alcohol functionality leads to complex reaction with an overall retention of configuration as expected and the
mixtures and very low yields of isolated products [29], hence 1H NMR spectra of the crude reaction mixture only showed the
we protected all hydroxy groups as esters. We chose the desired diastereomer 17. Several known catalytic systems were
benzoate protecting group to generate UV–visible intermedi- tested [29]: Pd(PPh3)4/PPh3 in THF/DMF [33], Pd2(dba)3/
ates and because its ease of cleavage under basic conditions diphos in THF/DMF [34], Pd2(dba)3/dppf in THF [35]. The first
would converge with the final pivalamide deprotection step. We set of conditions proved to be the most successful, although
adapted this protecting group strategy to Bond’s synthetic route addition of DMF was required to improve the solubility of the
since it was the most concise and diastereospecific available reactants. It is worth noting that this reaction proved to be
[30] (Figure 4). The process started with a Wohl–Ziegler allylic extremely sensitive to the presence of moisture and oxygen. The
bromination of cyclopentene. The volatile and unstable allylic bulky nature of the nucleophile used aided in the diastereose-
halide 10 was immediately reacted with excess N,N-dibenzyl- lectivity of the following syn-dihydroxylation. Using the
amine and the resulting allylic amine 11 was obtained in good Upjohn conditions previously described we obtained the desired
Figure 4: Synthesis of 15, a (1RS,2SR,3RS)-3-aminocyclopentane-1,2-diol derivative of PreQ0. Reagents and conditions: (a) NBS, (PhCO2)2, CCl4,
1 h, 90 °C; (b) NH(Bn)2, CCl4, 12 h, rt, 70% (over two steps); (c) OsO4, NMO, acetone/H2O, 4 h, rt, 72%, 96% ds; (d) BzCl, pyr, 24 h, 0 °C to rt, 84%;
(e) H2 (1 atm), Pd(OH)2, EtOH/EtOAc, 16 h, rt, 98%; (f) 9, Et3N, n-BuOH, 16 h, 130 °C; (g) KOH, n-BuOH/EtOH, 16 h, 80 °C, 42%.
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Beilstein J. Org. Chem. 2014, 10, 1333–1338.
Figure 5: Synthesis of 16, a (1S,2R,3S,4R)-4-aminocyclopentane-1,2,3-triol derivative of PreQ0. Reagents and conditions: (a) Pd(PPh3)4, PPh3, NaH,
NH(Boc)2, THF/DMF, 1 day, 50 °C, 42%; (b) OsO4, NMO, acetone/H2O, 1 day, rt, 83%; (c) BzCl, pyr, 17 h, 0 °C to rt, 74%; (d) 4 M HCl in 1,4-
dioxane, 16 h, 0 °C to rt, 76%; (e) 9, Et3N, n-BuOH, 16 h, 130 °C; (f) KOH, n-BuOH/EtOH, 16 h, 80 °C, 33%.
triol 18 in good yield and excellent diastereoselectivity (>99% of phenylboronic acid to cyclohexenone [39]. The resulting
by 1H NMR after column chromatography) [30]. Tri-benzoate ketone 25 was reduced to the axial [40,41] and equatorial [40]
19 was subsequently obtained in good yield using the standard alcohols 26 and 27 with excellent diastereoselectivity thanks to
benzoylation conditions [31]. Final removal of the two BOC steric control of the hydride source. After column chromatog-
protecting groups using 4 M HCl in 1,4-dioxane yielded amine raphy both alcohols showed a diastereomeric purity of >99% by
20 as the hydrochloride salt. Amine 20 was coupled with 1H NMR. Mitsunobu reaction on the secondary alcohols using
chloro-intermediate 9 and the remaining four protecting groups DEAD or DIAD did not provide the desired azides [42,43] nor
were cleaved in a one-pot procedure under basic conditions, did a one-pot Appel reaction/nucleophilic substitution/
generating the desired triol 16.
Staudinger reaction protocol involving a double inversion of
configuration [44]. Mesylation of 26 and 27 lead to intermedi-
To extend into hydrophobic chemical space around our PreQ0 ates 28 and 29 [45], which were subsequently reacted with
analogues, we prepared two novel derivatives containing the sodium azide inverting the stereochemistry as required [46]. A
unusual 3-arylcyclohexylamine chiral motif present in 21 and final transfer hydrogenation of 30 and 31 yielded the desired
22. Zhou et al. had reported an asymmetric synthesis leading to amines rapidly and with excellent yields [47]. Amines 23 and
the cis-3-arylcyclohexanamines with reasonable diastereoselect- 24 were reacted with chloro-intermediate 9 and the pivalamide
ivity [36], but since initially we did not require an enantioselect- groups were cleaved under basic hydrolysis conditions to yield
ive synthesis and the Zhou method employed rather expensive 21 and 22.
reagents, we investigated a simpler and cheaper route to access
both cis- and trans-isomers. We envisioned a stereoselective Conclusion
synthesis that would potentially allow for the introduction of In conclusion, a concise and stereoselective synthesis of novel
diverse aryl groups at the 3-position of the cyclohexane ring cyclopentyl and cyclohexyl analogues of PreQ0 has been devel-
using commercially available arylboronic acids as building oped to expand our fragment-based kinase library. This syn-
blocks, and Pd catalysis to form the new C–C bond, followed thetic protocol involves asymmetric syntheses of hydroxy-
by a highly diastereoselective ketone-to-amine conversion. protected (1RS,2SR,3RS)-3-aminocyclopentane-1,2-diol and
Others have reported on similar preparations of 3-phenylcyclo- (1S,2R,3S,4R)-4-aminocyclopentane-1,2,3-triol or cis- and
hexanamines, although with poor diastereomeric control trans-3-arylcyclohexylamines, which are in turn reacted with a
[37,38]. 1-Cyclohex-2-enone provided the two required syn- conveniently PreQ0-derived halo-intermediate and subse-
thetic handles: a sp2 carbon for Pd chemistry and a ketone for quently deprotected in a one-pot fashion. Pharmacological
further derivatization into an amine group (Figure 6). The syn- assessment of these novel PreQ0 derivatives is currently
thesis of cis- and trans-3-arylcyclohexylamines 23 and 24 underway in a variety of kinase-inhibitory studies and will be
started with a Pd(II)-catalyzed Miyaura 1,4-conjugate addition reported in due course.
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Beilstein J. Org. Chem. 2014, 10, 1333–1338.
Figure 6: Synthesis of 21 and 22, 3-arylcyclohexylamine derivatives of PreQ0. Reagents and conditions: (a) PhB(OH)2, Pd(OAc)2, bpy, H2O/THF/
AcOH, 3 days, 60 °C, 98%; (b) K-Selectride, THF, 2 h, −90 °C; then KOH (aq), H2O2, 30 min, rt, 80%, 99% ds; (c) LiAlH4, Et2O, 1,5 h, 0 °C to rt; then
NaOH (aq), 30 min, rt, 76%, 97% ds (d) MsCl, Et3N, THF, 16 h, rt, (trans- 67%, cis- 64%); (d) NaN3, DMF, 2 days, 80 °C, (trans- 56%, cis- 67%); (f)
HCO2NH4, Pd/C, MeOH, 1.5 h, reflux, (trans- 92%, cis- 94%); (g) 9, Et3N, n-BuOH, 16 h, 130 °C; (h) KOH, n-BuOH/EtOH, 16 h, 80 °C, (trans- 38%,
cis- 50%).
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doi:10.1080/00397919608004641
The authors would like to thank Stuart Lang for insightful
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