Concise, gram-scale synthesis of furo[2,3-b]pyridines with functional handles for chemoselective cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2020.152353

A concise 4-step synthesis of furo[2,3-b]pyridines, with handles in the 3- and 5-positions for palladium mediated cross-coupling reactions, is described. The synthetic route has been optimized, with only one step requiring purification by column chromatography. The route is amenable to scale-up, and was successfully executed on a multi-gram scale. Furopyridines are of growing interest in medicinal chemistry, and this route should enable easy access to the core for structure-activity relationship (SAR) studies.

Full text of DOI:10.1016/j.tetlet.2020.152353

Tetrahedron Letters 61 (2020) 152353
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise, gram-scale synthesis of furo[2,3-b]pyridines with functional
handles for chemoselective cross-coupling
1
1
⇑
Sean N. O’Byrne , Benjamin J. Eduful , Timothy M. Willson, David H. Drewry
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise 4-step synthesis of furo[2,3-b]pyridines, with handles in the 3- and 5-positions for palladium
mediated cross-coupling reactions, is described. The synthetic route has been optimized, with only one
step requiring purification by column chromatography. The route is amenable to scale-up, and was suc-
cessfully executed on a multi-gram scale. Furopyridines are of growing interest in medicinal chemistry,
and this route should enable easy access to the core for structure-activity relationship (SAR) studies.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 1 July 2020
Revised 3 August 2020
Accepted 7 August 2020
Available online 16 August 2020
Keywords:
Furo[2,3-b]pyridines
Heterocycles
Hinge binders
Kinases
Chemoselectivity
Introduction
an FDA approved serine/threonine-protein kinase B-Raf (B-Raf)
inhibitor used in the treatment of melanoma [12]. Azaindoles are
Protein kinases play an essential role in signal transduction and
regulation of cellular activities including metabolism, cell cycle
progression, cell differentiation, and apoptosis [1]. Deregulation
of kinase function has been implicated in cancers, immunological,
neurological, metabolic, and infectious diseases [2]. Chromosomal
mapping of the kinome links 244 kinases to a disease loci or cancer
amplicon, emphasizing the potential of therapeutics in this area
[3]. Kinases are an extremely important group of drug targets, sec-
ond only to G-protein coupled receptors [4,5]. To date 54 kinase
inhibitor have been approved by the FDA and more than 200 are
in clinical trials worldwide [6–8].
The majority of kinase inhibitors bind to the ATP-binding site, a
deep cleft between the N- and C- lobes of the protein’s catalytic
domain [4]. Most inhibitors bind the active conformation of kinase
(type 1), although a significant portion bind to the inactive state
(type 2). Other inhibitor types include allosteric inhibitors (type
3), substrate-directed inhibitors (type 4) and covalent inhibitors
(type 5) [9].
excellent hinge binders, making two hydrogen bonds with the
kinase hinge region. Unfortunately, inhibitors with multiple hinge
binding interactions may suffer from poor selectivity across the
kinome, leading to off-target toxicity [10,11,13].
One strategy to change a kinase inhibitor’s selectivity profile is
to use isosteric replacements, which can elicit changes in binding
affinity between closely related kinases [14]. There is strong evi-
dence to support that modification of the hydrogen bond interac-
tions between a kinase inhibitor and the enzyme’s hinge region
can improve selectivity without sacrificing potency [11]. An iso-
stere of azaindole, the furo[2,3-b]pyridine core (3), has been gain-
ing traction as a hinge-binding template useful for the synthesis of
kinase inhibitors. The furopyridine core contains an electron-defi-
cient pyridine ring and an electron-rich furan ring. Furopyridines
are relatively uncommon in natural compounds, with the most
prominent examples being furochinoline alkaloids (4) isolated
from the Rutaceae plant family and furomegistine I and II (5 and
6) alkaloids isolated from the bark of Sarcomelicope megistophylla
(Fig. 1) [15,16].
Although the furopyridine core is only infrequently found in
nature, it is present in several synthetic drug molecules. One of
the earliest reports of the furopyridine core being utilized is in
the HIV protease inhibitor L-754,394 (7) [17]. A recent publication
describes a set of substituted furopyridine derivatives based on 8
with activity against multidrug-resistant Mycobacterium tuberculo-
sis (Fig. 2) [18]. In the kinase field furopyridines have been reported
There are many heterocyclic hinge binding pharmacophores
found in kinase inhibitors, some of which are considered privileged
fragments [10,11]. One versatile example is the 7-azaindole core 1
(Fig. 1) which is employed as the hinge binder in vemurafenib (2),
⇑
Corresponding author.
E-mail address: david.drewry@unc.edu (D.H. Drewry).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2020.152353
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
S.N. O’Byrne et al. / Tetrahedron Letters 61 (2020) 152353
Fig. 1. 1 – The azaindole core; 2 – The B-Raf kinase inhibitor vemurafenib; 3 – The
furo[2,3-b]pyridine core; 4 – The general structure of the furoquinoline alkaloids
isolated from Rutaceae sp.; 5–6: Alkaloids isolated from Sarcomelicope megistophylla
- Furomegistine I and II.
Scheme 1. Reported synthetic routes to the furo[2,3-b]pyridine core.
Fig. 2. 7 – The HIV protease inhibitor L-754,394; 8 – A furo[2,3-b]pyridine which
has activity against multidrug resistant Mycobacterium tuberculosis; 9 – A furo[2,3-
b]pyridine based EGFR inhibitor; 10 – A furo[2,3-b]pyridine based AKT inhibitor.
as inhibitors of B-Raf, lymphocyte-specific protein tyrosine kinase
(Lck), epidermal growth factor receptor (EGFR) (9), insulin-like
growth factor 1 receptor (IGF-1R), and AKT (10) [19–23].
Despite their interesting chemical and biological activities,
there are only a handful of robust synthetic routes to the furopy-
ridine core. Approaches that have been employed in the synthesis
of furopyridines are summarized in Scheme 1. Nucleophilic aro-
matic substitution on 2-halopyridines, followed by subsequent
ring closure, has been utilized in several routes to substituted
furo[2,3-b]pyridines (Scheme 1 – a), d) and e)) [24–27]. An
intramolecular Diels-Alder reaction between a triazine and alkyne
afforded a dihydrofuro[2,3-b]pyridine which was oxidized to the
furo[2,3-b]pyridine with DDQ (Scheme 1 – b)) [28]. There are sev-
eral examples of palladium catalyzed one-pot syntheses of furopy-
ridines in which Sonogashira couplings were followed by Wacker-
type heteroannulations (Scheme 1 – c)) [29]. The most recent
methodology for synthesis of furopyridines was via pyridine N-oxi-
des which yielded 2,3-substituted furo[2,3-b]pyridines (Scheme 1
– f)) [30]. A comprehensive review on the synthesis of furopyridi-
nes has been published by Noravyan and co-workers [31].
Scheme 2. Initial synthetic route to the furo[2,3-b]pyridine core 15. i) EtOH, H2SO4,
80 °C, 16 h, 95%. ii) 1.1 eq. 13, 3.5 eq. NaH, THF, 0–70 °C, 3 h, 88%. iii) 3 eq. KOH,
EtOH, 100 °C, 20 min then aq. HCl, 100 °C, 20 min, 0%.
Our interest in the furo[2,3-b]pyridine core was its use as an
isosteric hinge binding replacement of a promiscuous azaindole
scaffold for the synthesis of a series of kinase inhibitors. We
required rapid access on a multigram scale to the furopyridine core
that allowed subsequent functionalization at the 3- and 5-posi-
tions. Of the synthetic strategies described we decided to utilize
the route described by Morita and Shiotani (Scheme 1 – a)) [24].
Using this methodology and starting with a trisubstituted pyridine
such as 12 should give furopyridine product 13 (Scheme 2). We
Scheme 3. Revised route to the furo[2,3-b]pyridine 19. i) H2SO4, Mg2SO4, tBuOH,
CH2Cl2, rt, 16 h, 92%. ii) 1.1 eq. 17, 3.5 eq.NaH, THF, 0–50 °C, 3 h, 86%. iii) TFA,
CH2Cl2, rt, 16 h. 89%. iv) Tf2O, DIPEA, CH2Cl2, ꢀ10–25 °C, 3 h, 71%.

S.N. O’Byrne et al. / Tetrahedron Letters 61 (2020) 152353
3
envisioned that a sequence of saponification of the ester in the 2-
position followed by decarboxylation would provide 5-chlorofuro
[2,3-b]pyridin-3-ol 14. Conversion of the 3-hydroxy functionality
into a triflate would provide us with a di-substituted furopyridine
core compatible with versatile palladium mediated coupling reac-
tions at the 3- and 5-positions.
ing material recovered. Changing the base from potassium to
sodium or lithium hydroxide also failed to afford 15 (Table 1 –
Entry 1). Increasing the equivalents of base and switching solvent
from ethanol to THF, in combination with longer reaction times
for both the hydrolysis and acidification steps, yielded the product
15 in moderate yield (46%) (Table 1 – Entry 2). The reaction was
attempted under acidic conditions, and also with potassium
trimethylsilanolate (Table 1 – Entry 3/4). Although the product
was isolated from several of these reaction conditions conversion
was not quantitative.
Results
Furo[2,3-b]pyridine core synthesis
To further optimise the hydrolysis-decarboxylation reaction, we
decided to switch to an acid labile tert-butyl ester, which we envi-
sioned cleaving efficiently with TFA. The carboxylic acid of 2,5-
dichloronicotinic acid was converted to the tert-butyl ester using
an acid catalyzed dehydration of concentrated sulfuric acid on
magnesium sulfate in the presence of tert-butanol, which mediates
the formation of isobutylene in situ [32]. The conversion of acid 11
to ester 16 proceeded smoothly in excellent yield (92%). A small
excess of tert-butyl 2-hydroxyacetate 17 was deprotonated with
3 equivalents of fresh sodium hydride and utilized in the tandem
SNAr-cyclisation reaction to afford the furo[2,3-b]pyridine 18 in
excellent yield (86%). Gratifyingly, the TFA mediated tert-butyl
ester cleavage and decarboxylation afforded the furo[2,3-b]pyri-
dine 15 in excellent yield (89%). Notably, the three steps from 11
to 15 were conducted on gram scale without the need for column
chromatography at any stage. Conversion of the alcohol 15 to tri-
flate 19 proceeded smoothly. Triflate 19 was synthesized in 71%
yield, with an overall yield of 50% from 11, with only the final step
requiring purification via column chromatography.
Our initial route is described in Scheme 2. 2,5-Dichloronicotinic
acid 11 was converted to the ethyl ester 12 under acidic conditions.
Ethyl 2-hydroxyacetate 13 was then deprotonated to the nucle-
ophilic alkoxide, which undergoes an SNAr reaction to displace
the 2-chloro group of 12 with intramolecular cyclization of the
putative intermediate to afford the furo[2,3-b]pyridine 14.
With the furo[2,3-b]pyridine 14 constructed, the hydrolysis and
decarboxylation steps were attempted. The conditions described
by Morita, aqueous potassium hydroxide in ethanol at reflux, failed
to yield any saponified or decarboxylated product with only start-
Table 1
Conditions and yields for the one-pot hydrolysis-decarboxylation reaction.
Entry
1
Conditions
(i) 3 eq. KOH*, EtOH,100 °C, 20 min,
Yield
0%
(ii) 3 M HCl, 100 °C, 20 min
(i) 10 eq. LiOH, THF, H2O, 60 °C, 16 h
(ii) ii) 3 M HCl, 100 °C, 1 h
2
46%
3
4
6 M HCl, dioxane (1:2), 100 °C, 6 h
(i) KOSiMe3, THF, 60 °C, 16 h,
(ii) ii) 4 M HCl, 1 h, 100 °C
57%
63%
Chemoselectivity testing
*
Generally, aryl triflates are considered to have greater reactivity
than aryl chlorides in palladium catalyzed CAC bond formation.
There are only a few reported systems with selectivity for aryl
chlorides over triflates. The first was published by Fu and co-work-
ers in 2000 [33]. Fu used Pd2(dba)3 with the bulky tri-tert-
butylphosphine ligand PtBu3 in THF to obtain selectivity for an aryl
chloride in the presence of an aryl triflate (Scheme 4). Complemen-
tarily, switching to Pd(OAc)2 with the smaller tricyclohexylphos-
phine (PCy3) ligand reversed selectivity favoring reactivity at the
triflate. The selectivity was rationalized by the ligation state of pal-
ladium. PtBu3 forms a mono-ligated palladium species which
favors C-Cl insertion, but the smaller PCy3 forms a bis-ligated spe-
cies which favors C-OTf insertion (Scheme 5).
Substituting with NaOH or LiOH afforded the same result.
Table 2
Conditions utilized towards the chemoselective coupling of furo[2,3-b]pyridine 19.
Conditions Outcome
Pd2(dba)3 (5 mol%), PtBu3 (10 mol%), KF, THF, 70 °C, 16 h SM recoveredy
Pd2(dba)3 (5 mol%), PtBu3 (10 mol%), KF, PhMe, 110 °C, 16 h SM recoveredy
Pd2(dba)3 (5 mol%), PtBu3 (10 mol%), KF, Xylene, 170 °C,
16 h
SM recoveredy
PEPPSI-SiPr (5 mol%), KF, PhMe, 110 °C, 16 h
SM recoveredy
y
Amounts of starting material recovered varied from 0 to 48%.
Table 3
Conditions attempted to selectively couple the triflate or bromide of 26. Yields were calculated after isolation. § All reaction were carried out with 5 mol% of catalyst and 10 mol%
of ligand. /Predicted selectivity is based on the results in the relevant literature. *These conditions resulted in the precipitation of palladium metal in the microwave vial, causing
intense localised heating and shattering of the microwave vial. This happened on two attempts after which safety concerns led us to stop using the microwave reactor for this
reaction. yThe amount of starting material recovered varied from 0 to 71%.
Entry
System§
Conditions
Sel/
26:27:28:29
1
2
3
4
5
6
7
8
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
Pd2(dba)3, PtBu3
PEPPSI-SiPr
THF, KF, rt, 16 h
THF, KF, 70 °C, 16 h
Br
Br
Br
Br
Br
Br
Br
Br
SM recoveredy
37%:<5%:16%:<5%
61%:<5%:14%:<5%
63%:<5%:17%:9%
12%:9%:29%:15%
37%:<5%:36%:6%
*
PhMe, KF, 110 °C, 16 h
Dioxane, KF, 50 °C, 16 h
Dioxane, KF, 100 °C, 16 h
Xylene, KF, 170 °C, 16 h
Xylene, KF, 200 °C, mW, 30 min
THF, KF, rt, 16 h
SM recoveredy
SM recoveredy
SM recoveredy
51%:44%:<5%:<5%
12%:19%:<5%:13%
17%:36%:<5%:<5%
13%:42%:11%:<5%
15%:19%:<5%:<5%
9
PEPPSI-SiPr
PhMe, KF, 110 °C, 16 h
MeCN, KF, rt, 16 h
Br
10
11
12
13
14
15
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
OTf
OTf
OTf
OTf
OTf
OTf
MeCN, KF, 70 °C, 16 h
Dioxane/H2O, KF, 100 °C, 16 h
Dioxane/H2O, KF, rt, 16 h
Dioxane/ H2O KF, 50 °C, 16 h
MeCN, KF, 70 °C, 16 h

4
S.N. O’Byrne et al. / Tetrahedron Letters 61 (2020) 152353
Scheme 4. The chemoselective Suzuki-Miyaura cross-coupling conditions devel-
oped by Fu and co-workers [33]. Chemoselectivity is achieved with the appropriate
palladium and ligand combination.
Scheme 7. Couplings of the furo[2,3-b]pyridine 26 afforded mixtures mono-
substituted 27 and 28, and di-substituted product 29. The conditions and isolated
yields are shown in Table 3.
Neufeldt as selective and high yielding in coupling of aryl chlorides
did not prove effective either, with only starting material
recovered.
As we could not find conditions that led to reaction at the chlo-
rine instead of the triflate, we opted to make the bromo analogue
of compound 19. Aryl bromides are often considered to have sim-
ilar reactivity to triflates, but we wanted to investigate if selectivity
for the bromide could be achieved over the triflate. Following the
same route as shown in Scheme 3, the bromo-triflate 26 was syn-
thesized in 62% overall yield.
Initial attempts to couple the bromide utilized Fu’s conditions
of Pd2(dba)3 and PtBu3 in THF at room temperature (Scheme 7
and Table 3). The reaction failed to afford product, and only limited
starting material was isolated after purification. Increasing the
reaction temperature to 70 °C did afford the product 28, but in poor
yield (16%) along with small amounts of 27 and 29. Multiple con-
ditions were subsequently explored, affording various mixtures of
mono- and di-substituted products. Several conditions reported to
selectively couple the triflate over the bromide were also
attempted [33–35] (Table 3), but all failed to give clean reactions.
Scheme 5. Coupling reaction of 19. i) Pd(PPh3)4 (5 mol%), Cs2CO3, dioxane/water
(3:1), 100 °C, 16 h, 92%. ii) 4-methylphenylboronic acid, Pd2(dba)3 (5 mol%), XPhos
(10 mol%), Cs2CO3, dioxane/water (3:1), 100 °C, 16 h, 84%.
Proutiere and Schoenebeck later found that solvent polarity
plays an important role in the selectivity [34]. They demonstrated
that, with the Pd2(dba)3/PtBu3 system, changing from THF to DMF
switched the selectivity from the chloride to the triflate. The non-
polar toluene retained selectivity for the chloride. Most recently,
Neufeldt and co-workers used N-heterocycle carbene ligands to
achieve chemoselectivity in the Pd-catalyzed Suzuki–Miyaura
cross-coupling of chloroaryl triflates [35].
Controlling chemoselectivity in our furopyridine derivative
would be a valuable asset in our medicinal chemistry efforts, so
we set out to investigate conditions that would allow this. Our pri-
mary objective was to first substitute the triflate at the 3-position
followed by the chloro in the 5-position. Effective conditions to
couple aryl triflates had already been utilized in our group using
palladium tetrakis (Pd(PPh3)4) and cesium carbonate. The triflate
of 19 selectively reacted in a Suzuki reaction using Pd(PPh3)4 to
afford the product 23 in 92% yield. The chlorine was subsequently
substituted using a system of Pd2(dba)3/XPhos to efficiently afford
24 in 84% yield (Scheme 6).
Our initial attempts to achieve selectivity for the chlorine over
the triflate used the reported system of Pd2(dba)3/PtBu3 in THF,
either at rt or 70 °C. 4-Acetylphenylboronic acid was used as a cou-
pling partner. We envisioned that the acetyl group could cause a
moderate change in polarity and greatly simplify separation of
products during chromatography, however after 16 h only a low
yield of unreacted starting material was recovered. We next
employed toluene and xylene as solvents to run the reaction at
higher temperatures. Frustratingly use of either solvent yielded
none of the desired product, although <10% of the triflate substi-
tuted product was isolated. Additional aliquots of palladium and
ligand with longer reaction times did not improve the result. The
NHC carbene pre-catalyst PEPPSITM SIPr which was reported by
Discussion
Our initial synthetic route to the furopyridine core 12 was suc-
cessful, although the hydrolysis-decarboxylation to 14 was not as
efficient as anticipated. Under basic conditions, the stability of
the ethyl ester 13 could be due to the ability of the deprotonated
starting material to chelate with the positively charged metal
counter ion, forming a pseudo 6-membered ring (Fig. 3 – 30a/b).
This intermediate is analogous to the acetylacetonate anion (31a/
b), which is commonly used as bidentate ligand in metal com-
plexes [36]. The chelation could hinder nucleophilic attack of
hydroxide into the ester carbonyl group and suppress the saponifi-
cation reaction.
Switching to acidic hydrolysis conditions did afford product, but
longer reaction times led to decomposition of the product and
reduction in yield. Potassium trimethylsilanolate proved effective
but capricious, with the yield on repeated reactions proving vari-
able. Switching to the acid labile tert-butyl ester proved to be an
effective strategy to facilitate the hydrolysis-decarboxylation step,
proceeding cleanly in high yield and on multigram scale with TFA.
The conversion of the aryl-alcohol to the triflate proceeded
smoothly to afford the furo[2,3-b]pyridine with handles in the 3-
and 5-positions. The triflate and chloro of 19 could be subjected
to Pd-catalyzed coupling reaction sequentially and chemoselec-
tively, which accomplished our primary objective.
Scheme 6. Attempted chemoselective Suzuki coupling of the chloride of 19.
Reaction conditions are listed in Table 2.

S.N. O’Byrne et al. / Tetrahedron Letters 61 (2020) 152353
5
Acknowledgements
We thank Brandie M Ehrmann and the UNC Department of Chem-
istry Mass Spectrometry Core Laboratory for collecting HR-MS
data. We thank Christopher R.M Asquith for valuable input and
reviewing of the manuscript.
This research was funded in part by the National Cancer Insti-
tute of the National Institutes of Health (D.H.D.) grant number
R01CA218442 and also by the NIH Illuminating the Druggable
Genome
program
(TMW
and
DHD)
grant
number
1U24DK116204-01. The SGC is a registered charity (number
1097737) that receives funds from AbbVie, Bayer Pharma AG,
Boehringer Ingelheim, Canada Foundation for Innovation, Eshel-
man Institute for Innovation, Genome Canada, Innovative Medici-
nes Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen,
Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG,
Ontario Ministry of Economic Development and Innovation, Pfizer,
Takeda, and Wellcome [106169/ZZ14/Z].
Fig. 3. a) The deprotonated species 30 can coordinate a metal counter-ion forming a
pseudo 6-membered ring stabilized by resonance forms. This may hinder the
nucleophilic attack of hydroxide anions, preventing the saponification of the ester.
b) The acetylacetonate (acac-) anion 31 which is often used as a bidentate ligand in
inorganic metal complexes.
Unfortunately, all attempts to switch the chemoselectivity by
coupling the chloride of 19 before the triflate proved futile. The
chlorine group is positioned at the least reactive carbon of the pyr-
idine ring, hindering the oxidative insertion of the active palladium
species. This observation is in line with the predictive model of
regioselectivity developed by Handy and Zhang based on the 1H
NMR chemical shift values [37]. Review of published NMR data
and predicted NMR spectrums indicate the 5-position has the
smallest 1H chemical shift and therefore is often the least reactive.
Switching intermediates to the more reactive bromine did
afford some success, but the yields of bromo-substituted product
were not high enough for this to be an effective method to support
analog synthesis. This approach also led to problems in the
chemoselective coupling of the triflate of 26 over the bromide.
Having a 5-chloro instead of a 5-bromo increased our ability to
achieve selectivity for the triflate in the 3-position. Conditions
which couple the triflate in 19 are indiscriminate when used on
the bromo-triflate analogue 26, resulting in non-selective addition
to the bromine and triflate. Reducing the temperature from 100 °C
to rt or 50 °C did enhance selectivity of the triflate but the yields
were greatly reduced, leading us back to chloro triflate 19 as our
key intermediate.
Literature conditions reported to chemoselectively couple aryl
halides and triflates performed poorly, and is likely reflective of
these challenging furopyridine substrates, which push the current
methodologies for Pd-catalyzed reactions to their limits. Initial
attempts to couple the bromine afforded only starting material.
Changing to higher boiling non-polar solvents, with accompanying
increases in temperature did produce low yields of product. The
most successful condition employed xylene at 170 °C, but only
afforded the isolated product in 36% yield. Longer reaction times
may have improved the yield, but running reactions at 170 °C for
over 24 h did not meet our goal of a practical synthesis.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152353.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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