Catalytic enantioselective synthesis of 2-aryl-chromenes

Article abstract of DOI:10.1039/c4sc00423j

An enantioselective Pd-catalyzed 6-endo-trig reaction for the synthesis of 2-aryl-chromenes has been developed. A systematic optimization of a TADDOL-derived ligand set resulted in the identification of a novel monodentate phosphoramidite-palladium catalyst that accesses 2-aryl-2H-chromenes with high yield and enantioselectivity under mild conditions. The products obtained from this method can be transformed into biologically active compounds through functionalization of the chromene alkene. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00423j

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Catalytic enantioselective synthesis of
2-aryl-chromenes†
Cite this: DOI: 10.1039/c4sc00423j
*
Bi-Shun Zeng, Xinyi Yu, Paul W. Siu and Karl A. Scheidt
An enantioselective Pd-catalyzed 6-endo-trig reaction for the synthesis of 2-aryl-chromenes has been
developed. A systematic optimization of a TADDOL-derived ligand set resulted in the identification of a
novel monodentate phosphoramidite–palladium catalyst that accesses 2-aryl-2H-chromenes with high
yield and enantioselectivity under mild conditions. The products obtained from this method can be
transformed into biologically active compounds through functionalization of the chromene alkene.
Received 8th February 2014
Accepted 14th March 2014
DOI: 10.1039/c4sc00423j
www.rsc.org/chemicalscience
Introduction
Chromenes constitute a privileged class of structural motifs
present in a myriad of natural products and medicinally
important agents.1 Given the prevalence of this structural unit,
there has been considerable interest in developing methods for
the generation of the chromene skeleton. While procedures to
access racemic 2-aryl-2H-chromenes are readily available,2 the
difficulty in generating enantioselective variants is under-
scored by the scarcity of documented strategies to produce
these bioactive structures. The construction of enantioen-
riched 2-aryl-2H-chromenes has been recently reported by You
through a Ru-catalyzed ring-closing metathesis reaction of
chiral allyl ethers3 and also by Schaus via the chiral Brønsted
acid (CBA)/Lewis acid-catalyzed addition of aryl boronates to in
situ formed pyrylium ions.4 In addition, Rueping has recently
reported a CBA-catalyzed closure of allylic cations, but this
innovative approach requires substitution at C4.5 Based on our
platform developing new approaches to construct pyran and
related motifs,6 we began investigating substrate/catalyst acti-
vation combinations to access chromenes via an asymmetric
catalytic process. Aer extensive exploration with substrates
such as 1 (not shown), easily accessed from chalcone precur-
sors, the use of either organocatalysis or transition metal
catalysis led to an invariable observation: compounds with
unprotected ortho-substituted phenols were typically unstable
and oen underwent uncatalyzed cyclizations to racemic
chromenes rapidly (eqn (1)).
(1)
With this crucial data in hand and the background reaction a
major hurdle, our reaction design criteria became clear: (a)
promote phenol formation during the course of the reaction, (b)
avoid any background reactions by activating an allylic system
through a chiral metal complex or organocatalytic mechanism,
and (c) promote a 6-endo-trig type closure of the phenol/phen-
oxide with control of the absolute stereochemistry. Based on
this logic, we envisaged that 2-aryl-2H-chromenes could be
constructed through a 6-endo-trig Pd-catalyzed asymmetric
allylic substitution (Fig. 1).7 While Pd-catalyzed allylic alkylation
is a prominent strategy for C–C and C–heteroatom bond
formation,8 to the best of our knowledge there are no reports of
a general asymmetric 6-endo-trig variant.9
Results and discussion
We began our investigation by combining bis-acetate 1a with
potassium carbonate, Pd2(dba)3 and a variety of phosphor-
amiditeligands. Initialsurveyofbidentate ligands, suchasPHOX
or Trost ligand, afforded low reaction conversion and enantio-
selection. Although monodentate phosphoramidites are efficient
chiral ligands in promoting various Pd-catalyzed reactions,10
their application in asymmetric allylic substitutions remains
underdeveloped. Motivated by a recent report from van Leeuwen
and coworkers involving the use of BINOL- and TADDOL-derived
phosphoramidites for Pd-catalyzed intermolecular allylic alkyl-
ations,11 our initial ligand screen included BINOL-, SIPHOS-, and
TADDOL-derived phosphoramidites.12 Our preliminary experi-
ments with BINOL-derived ligand L1a provided chromene 2a in
quantitative yield with an encouraging 69 : 31 enantiomeric ratio
Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road,
Evanston, IL 60208, USA. E-mail: scheidt@northwestern.edu; Fax: +1-847-467-2184
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. CCDC 984483 and 969569. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4sc00423j
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ongoing. We then revisited the effects of the nitrogen substit-
uent. Interestingly, the replacement of the piperidine with a
pyrrolidine resulted in a signicant decrease in enantiose-
lectivity (entry 13), while incorporation of a 7-membered aze-
pane maintained the previously observed 93 : 7 er (entry 14).
Efforts to increase enantioselectivity by utilizing acyclic amines
were ineffective (entry 15). Finally, the incorporation of ethyl
groups at the 3- and 5-position of the aryl ring was explored. We
were pleased to nd that with this ligand (L3k), chromene 2a
was obtained in 71% isolated yield with 95 : 5 er (entry 16).
With selective conditions developed, several bis-acetate
substrates were evaluated (Table 2). The high levels of enantio
selectivity observed for 2a were maintained with extended
aromatic substrates (2b and 2c). Electron-donating groups on
the styrenyl component were also well tolerated, with methyl
substitution in the ortho- or para-positions (2d and 2e, respec-
tively) affording the chromene products in good yield and
excellent enantioselectivity. The electron-rich 3-methoxy
substituted cyclization precursor also performed well in this
reaction, generating chromene 2f (78%, 94 : 6 er).
The incorporation of electron-withdrawing (2g–2l) substitu-
ents around the aromatic ring was also accommodated.
Furthermore, we found that the electronegative uorine
substituent can occupy various positions while maintaining
Fig. 1 Reaction design for 2H-chromenes.
(Table 1, entry 1). Unfortunately, modication of the amine high er. The erosion of enantioselectivity was observed with
constituent to piperidine, dimethylamine, 1-phenylethylamine substrates possessing
triuoromethyl, dichloro, or the
a
(results not shown) or bis[(S)-1-phenethyl]amine (entry 2), was strongly electronegative nitro group (2j–2l), but a uorine
detrimental to both the conversion and enantioselectivity. The substituent was tolerated at various positions (2m and 2n). The
modication of the ligand backbone to SIPHOS-derived ligand electron-donating methoxy group was also accommodated,
(Ra,R,R)-L2 and TADDOL-derived ligand L3a resulted in signi- albeit with a slight decrease in enantioselectivity (2o). Addi-
cantly improved levels of enantioselectivity (entries 3 and 5, tionally, the preparation of chromene 2p indicates that this
respectively). Interestingly, the diastereomer (Sa,R,R)-L2 (entry 4) system tolerates moderate substitution adjacent to the
afforded racemic chromene product, suggesting a mismatch of phenoxide.
stereogenic elements.
The complete conversion of racemic substrates 1 to the
Due to the shortened reaction time with ligand L3a enantioenriched chromenes indicates that a dynamic kinetic
compared to L2 and the opportunity to rapidly evaluate a wide asymmetric transformation (DYKAT) might be operative.13 Since
range of TADDOL-derived ligands, we focused our efforts on the both enantiomers of the starting material must go through a
optimization of this ligand backbone. We began by evaluating a common intermediate, and the unsymmetrical 1,3-disubstituted
variety of N-substituents, including achiral and sterically less allyl substrate precludes racemization through a palladium p–
demanding amine moieties (entry 6–8). In comparison to ligand s–p allyl rearrangement, the generation of an achiral ortho-
L3a, other acyclic amines such as dimethylamine (entry 6) and quinone methide intermediate (4) is proposed to account for
diisopropyl amine (entry 7) resulted in decreased enantiose- the high levels of enantioselectivity observed for the chromene
lectivity, while replacement with the more rigid piperidinyl products (Scheme 1).
substituent afforded chromene 2a with improved selectivity
Our current understanding of the reaction starts with the
(82 : 18 er, entry 8).12d To understand the effects of ligand subjection of either enantiomer of 1a to potassium carbonate
rigidity on engendering enantioselection, the isopropylidene and methanol, which rapidly produces the nucleophilic
acetal of L3 was substituted with an acyclic dimethyl ether phenoxide in situ (Æ3, Path A). This deacylation promotes
motif. With the less rigid L4 as the ligand, chromene 2a was ejection of the secondary acetate to form the achiral trans-o-
furnished with low enantioselectivity (entry 9).
quinone methide (o-QM, 4a).14 A subsequent coordination
The last point of variation of the TADDOL-derived ligands and addition of the chiral palladium complex generates the p
lies in the substitution about the arene rings. The examination allyl intermediate (5) which undergoes intramolecular attack
of various aryl-substituted TADDOL ligands (entry 10–12) of the proximal phenoxide aer bond rotation to achieve the
revealed that enantioselectivity can be enhanced through the proper conformation (6). For this pathway, the rate of o-QM
placement and positioning of methyl groups on the aryl ring, formation is faster than addition of the palladium–ligand
culminating in a 93 : 7 er attained for ligand L3g (entry 12). A complex to Æ3 (or Æ1). If this is not the case, then an alter-
full investigation of this distal effect and the balance between native potential pathway could be operative (Path B). This
electronic and steric parameters on this ligand is currently process involves the generation of diasteromeric p allyl
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Table 1 Optimization of reaction conditions
Table 2 Substrate scopea
Entry Ligand
Ar
NRR1
Timea erb
1
2
L1a
L1b
—
—
N(i-Pr)2
N((S)-CH(Me)(Ph))2 21 h
2 h
69 : 31
57 : 43
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(Ra,R,R)-L2
(Sa,R,R)-L2
L3a
L3b
L3c
L3d
L4
L3e
L3f
L3g
L3h
L3i
L3j
—
—
Ph
Ph
Ph
Ph
Ph
2-Me-C6H4
3-Me-C6H4
3,5-Me-C6H3 N(CH2)5
3,5-Me-C6H3 N(CH2)4
3,5-Me-C6H3 N(CH2)6
3,5-Me-C6H3 N(Me)(Cy)
3,5-Et-C6H3 N(CH2)5
—
—
1 day 79 : 21
1 day 50 : 50
N((S)-CH(Me)(Ph))2 12 h
N(Me)2
74 : 26
60 : 40
65 : 35
82 : 18
53 : 47
85 : 15
90 : 10
93 : 7
2 h
4 h
2 h
3 h
12 h
19 h
38 h
N(i-Pr)2
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
2 day 71 : 29
2 day 93 : 7
19 h
19 h
93 : 7
95 : 5
L3k
a
Time to reach 100% conversion as measured by 1H NMR (500 MHz).
a
b
See ESI for details. Yield of isolated product aer chromatography.
Longer reactions did not provide side products. Enantiomeric ratio
Enantiomeric ratio determined by HPLC analysis.
determined by HPLC.
palladium complexes (5a or 5b) from each enantiomer of 3.
While one of these additions would be the “matched” case, a
rapid interconversion between the diasteromeric intermedi-
ates is required so the “mismatched” complex undergoes
smooth conversion to the observed enantiomer (2a) vs. the
undesired isomer (ent-2a). Possible mechanisms for this
involve generation of the achiral o-QM or direct addition of
the palladium complex. For a related system, the possibility
for racemization of the p-allylpalladium complex (such as 5b)
by an intermolecular nucleophilic attack (or anti-addition) of
a Pd(0) has been investigated.15 We currently favor Path A due
to the lack of observed correlation between enantioselectivity
and catalyst concentration, which disfavors Path B. Addi-
tionally, the use of bis-benzoylated substrates (vs. acetates)
proceeds at the approximately the same rate with the similar
levels of er and yield (see ESI† for details). More extensive
investigations of this process are currently underway.
allyl acetate as a substrate surrogate incapable of closure
(Scheme 2). The structure shows that the phosphoramidite
ligand L3g is coordinated to the Pd(II) center through its phos-
phorus center and a single aryl ring.16 This h2-arene stabiliza-
tion results in the observed 1 : 1 phosphoramidite–Pd(II)
complex and supports mono-coordination of a bulky ligand to
the palladium.17
To highlight the potential of this new approach, we pursued
the synthesis of catechin 8, which has demonstrated anti-
staphylococcal activity due to their ability to reverse methicillin
resistance in strains of drug resistant S. aureus.18 Interestingly,
this catechin analog has increased activity compared to the
parent (À)-epicatechin gallate, which bears additional hydroxyl
groups on the catechin core (7). The regioselective hydro-
boration of 2a delivered chromanol 7 with 9 : 1 dr favoring the
desired anti relationship. The esterication of chromanol 7 with
tri-OBn gallic acid chloride followed by hydrogenolysis afforded
8 in 65% yield over the two steps. In a second vignette, the
synthesis of hydroxyavanone 10 was accomplished. The race-
mate of this compound exhibited promising levels of inhibition
of M. tuberculosis H37Rv.19 The application of our methodology
allows access to enantioenriched 10 and could facilitate
We wished to further elucidate the structure of the Pd(II)–L3k
complex and its interaction with the bis-acetate substrate 1a,
but to date have been unable to obtain suitable crystals.
However, X-ray quality crystals of the related Pd(II) complex has
been solved using ligand L3g in conjunction with 1,3-diphenyl
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Scheme
3
Transformation to bioactive flavonoids. Reagents and
conditions: (a) (i) BH3$THF, (ii) H2O2, NaOH; (b) tri-OBn galloyl chlo-
ride, DMAP, Et3N, CH2Cl2; (c) H2, 10% Pd/C, EtOAc; (d) 3 mol% OsO4,
4-methylmorpholine 4-oxide, t-BuOH, H2O; (e) MnO2, CH2Cl2.
Conclusions
We have developed a catalytic enantioselective method for the
synthesis of 2-aryl-2H-chromenes. A ligand structure–selectivity
relationship study resulted in the development of a novel
monodentate phosphoramidite system that enabled the
synthesis of these privileged heterocycles with high yield and
enantioselectivity. Crystallographic analysis provides mecha-
nistic support that aryl ligand–metal interactions provide
unanticipated additional rigidity in competing diasteroemeric
transition states which promotes the high levels of enantiose-
lectivity for the newly formed C–O bond. Investigations
involving the use of these chiral phosphoramidite ligands for
the formation of other heterocycles and detailed mechanistic
studies are underway.
Scheme 1 Proposed reaction pathway.
Acknowledgements
Support was provided by the NIH (P50-GM086145). We thank
Prof. Chad Eichman (Loyola Univ., Chicago) for helpful
discussions. X. Y. thanks NU for a summer undergraduate
research grant (NU-URG).
Notes and references
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BF4. ORTEP at 80% probability with hydrogen atoms and BF4À omitted
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