Asymmetric construction of dihydrobenzofuran-2,5-dione derivatives via desymmetrization of p-quinols with azlactones

Article abstract of DOI:10.1039/C8CC08985J

The desymmetrization of p-quinols through a chiral bisguanidinium hemisalt catalyzed enantioselective Michael addition/lactonization cascade reaction with azlactones was reported. 3-Amino-benzofuran-2,5-diones containing a chiral amino acid residue were achieved with up to 99% ee and >19?:?1 dr. An exploration of the structure of the catalyst bisguanidinium was undertaken, revealing a bifunctional catalytic model.

Full text of DOI:10.1039/C8CC08985J

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Asymmetric construction of dihydrobenzofuran-
2,5-dione derivatives via desymmetrization
of p-quinols with azlactones†
Cite this: Chem. Commun., 2019,
55, 87
Received 12th November 2018,
Accepted 15th November 2018
Lihua Xie,
Shunxi Dong,
Qian Zhang, Xiaoming Feng
and Xiaohua Liu
*
DOI: 10.1039/c8cc08985j
rsc.li/chemcomm
The desymmetrization of p-quinols through a chiral bisguanidinium
hemisalt catalyzed enantioselective Michael addition/lactonization
cascade reaction with azlactones was reported. 3-Amino-benzofuran-
2,5-diones containing a chiral amino acid residue were achieved with
up to 99% ee and 419 : 1 dr. An exploration of the structure of
the catalyst bisguanidinium was undertaken, revealing a bifunctional
catalytic model.
The dihydrobenzofuran-2,5-dione skeleton and its analogues
frequently occur in bioactive natural products, such as paeoni-
lactone B, rezishanone A, fumimycin, and sorbicillactone A
and B (Scheme 1a).1 Alkaloid sorbicillactone A, isolated from
sponge-derived microorganisms, showed anti-leukemic activity
without notable cytotoxicity.2 It is the first sorbicillinoid containing
an amino acid residue and could be obtained by biotechnological
production.3 For the asymmetric chemical construction of these
polyfunctionalized scaffolds, the intramolecular 1,4-addition
of 2,5-cyclohexadienone provides a straightforward process
(Scheme 1b).3 For instance, Harned’s group utilized stereoselective
cyclization of cyclohexadienone tethered to the activated methylene
group to get the bicyclic lactone.4 A similar strategy was employed
Scheme 1 Representative natural products bearing a benzofuran-2,5-
dione backbone and the synthesis strategies for dihydrobenzofuran-2,5-
dione skeletons.
for concise construction of sorbicillactone A and 9-epi-diastereomer Our group has utilized chiral guanidine catalysts to promote
after several transformations.5 Lu’s group discovered a Rauhut– several cascade reactions of azlactone for the synthesis of hydro-
Currier reaction of allenonate to afford bicyclic a-allenic coumarin and oxazoline bearing an amino substituent.8d–h We
g-butyrolactone in excellent enantioselectivity.6 Nevertheless, these proposed an intermolecular 1,4-conjugate addition/lactonization
processes could not directly introduce an amide substituent at the cascade between para-quinols9 and azlactones, which allows the
C3 position as shown in the structures in Scheme 1a.
concomitant formation of contiguous stereocenters including
Azlactones are important amino acid precursors which have an amino acid residue (Scheme 1c). Herein, we utilized chiral
been used to synthesize different natural and unnatural amino bisguanidinium hemisalt for the desymmetrization of cyclo-
acid derivatives as well as others.7 Nucleophilic addition/ hexadienone10 via enantioselective nucleophilic addition of azlac-
lactonization cascade or cycloaddition of azlactone has been tone, following the lactonization with the 6-hydroxyl group, giving
designed for the construction of various heterocyclic compounds.8 3-amino-benzofuran-2,5-diones in good yield with high diastereo-
and enantioselectivity. It provides a straightforward access to the
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
key chiral structure of the natural product sorbicillactone.
We started our investigation by studying the desymmetrization
of p-quinol 1a with azlactone 2a, using bifunctional chiral guani-
College of Chemistry, Sichuan University, Chengdu 610064, China.
E-mail: liuxh@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
† Electronic supplementary information (ESI) available. CCDC 1836787, 1866762,
dine catalysts developed by our group due to their applicability in a
variety of azlactone-involved transformations.8d–h Despite the base
1847525 and 1851705. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8cc08985j
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Table 1 Optimization of the reaction conditionsa
compounds in the field of pharmaceuticals, agrochemicals
and, other areas,13 we incorporated the trifluoromethyl group
into p-quinol 1b. The reaction of 1b with azlactone 2a under
identical reaction conditions revealed that it performed the
reaction well, affording the corresponding product 3ba in
75% yield and 99% ee (entry 10). Interestingly, high yield with
excellent enantioselectivity could be obtained even when the
catalyst loading was reduced to 2.5 mol% and the amount of
azlactone lowered to 1.5 equivalent (entries 12 and 13).
To further showcase the utility of this organocatalytic
desymmetrization strategy, we next made efforts focused on
azlactones, which bring different amino acid scaffolds into the
dihydrobenzofuran-2,5-dione skeletons (Table 2). It was found
that desymmetrization reaction triggered by 1,4-conjugate addition/
lactonization of azlactones with 4-trifluoromethyl substituted
p-quinol 1b performed well, delivering enantioenriched 3-amino
substituted dihydrobenzofurandione with three contiguous
stereogenic centres in good results. Initial investigation was
conducted with azlactones 2b–2k derived from different amino
acids. The azlactones synthesized from 2-amino-4-phenylbutanoic
acid (2b), alanine (2c), leucine (2d), methionine (2e), and trypto-
phan (2f) tolerated the reaction well in the presence of 10 mol% of
the catalyst BG-1ÁHBPh4. The desired lactone derivatives (3bb–3bf)
were produced in 67–91% yield and 93–99% ee (entries 2–6). The
electronic properties and position of the substituents on the
aromatic rings of phenylalanine-derived azlactones 2g–2k had no
influence on the enantioselectivity (98–99% ee), but a significant
effect on the reactivity (64–99% yield) (entries 7–11). Furthermore,
it showed that azlactones 2l–2w bearing aryl, heteroaryl, or alkyl
substituents at the C2 position were suitable substrates to provide
the desired dihydrobenzo-furandiones 3bl–3bw in excellent
enantioselectivity (95–99% ee) and moderate to good yield
(57–90% yield) (entries 12–23). The tolerance of a number of
amino acid residues at the C3-position of the lactones 3 might
Entry
Cat. (x mol%)
1
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
G-1 (10)
G-2 (10)
G-3 (10)
G-4 (10)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
17
24
11
22
23
33
64
50
71
75
80
98
94
À5
À10
À11
40
41
46
86
99
99
99
G-5 (10)
BG-1 (10)
BG-1ÁHBArF (10)
8d
9d
10d
11d
12d
13d,e
BG-1ÁHBArF4 (10)
4
BG-1ÁHBPh4 (10)
BG-1ÁHBPh4 (10)
BG-1ÁHBPh4 (5)
BG-1ÁHBPh4 (2.5)
BG-1ÁHBPh4 (2.5)
99
98
98
a
Unless otherwise noted, the reactions were carried out with guanidine
(2.5–10 mol%), 1 (0.10 mmol), and 2a (2.0 equiv.) in (1.0 mL) at 30 1C for
b
c
d
24 h. Isolated yield. Determined by HPLC analysis. At À10 1C for
72 h. 2a (1.5 equiv.). (HBArF = HB[3,5-(F3C)2C6H3]4).
e
4
sensitivity that cyclohexadienones generally exhibit,11 the cascade present an impressive array of promising biological properties.
reaction occurred in the presence of different chiral guanidine- Furthermore, the catalyst was applied to the reaction of para-
amides,12 which afforded the desired 3-amino-dihydrobenzofuran- aryl substituted quinols. The reaction was sluggish for p-quinols
2,5-dione 3aa in high diastereoselectivity (Table 1, entries 1–7). (1c–1e) at the previously optimized reaction condition, but several
Single guanidine-amides G1–G3 bearing distinct amino acid back- byproducts were detected after elevation of the reaction temperature
bones accelerated the reaction in low yield and enantioselectivity to 30 1C. Products 3ca–3ea with phenyl, 4-cyanophenyl, and
(entries 1–3). When guanidines G4 and G5 with an additional 4-bromophenyl could be isolated in 29–47% yield, but the
sulfonamide substituent were used, the enantioselection reversed enantioselectivity remained satisfactory. To demonstrate the
and the ee value increased a lot (entries 4–5). Switching to practicality of the transformations, we carried out a gram-scale
bisguanidine BG-1 improved the yield and enantioselectivity synthesis of the product 3ba. In the presence of 2.5 mol% of the
slightly (entry 6). To our delight, the bisguanidinium hemisalt chiral catalyst BG-1ÁHBPh4, 2.5 mmol of 1b and 3.75 mmol of
BG-1ÁHBArF enabled the reaction in 64% yield and 86% ee azlactone 2a reacted well to afford the desired adduct 3ba in
4
(entry 7). This indicates that the formation of a guanidinium 92% yield (0.9876 g) with 98% ee.
salt can tune the conformation of the bisguanidine-amide,
It is noteworthy that only one diastereomer was detected
creating a suitable chiral environment for activation and dis- in the catalytic asymmetric version in the investigated cases.
crimination of the substrate. The enantioselectivity of the reaction Performing an X-ray crystallography analysis of the major
increased to 99% ee after the reaction temperature dropped from enantiomer of the product 3aa allowed us to confirm both
30 1C to À10 1C, although the reactivity decreased (entry 8). the cis-fused ring system and trans-position between the amide
Furthermore, the identified catalyst BG-1ÁHBPh4 with variation substituent and C6-proton (Fig. 1). X-ray analysis of the product
of the counter anion was more effective in terms of reactivity, 3bc confirmed its stereo-arrangement.15 The relative configuration
and the desired product 3aa was obtained in 71% yield with of the three chiral centers is consistent with that in the natural
99% ee (entry 9). In view of the importance of fluoro-containing product sorbicillactone. Previously, Harned and coworkers utilized
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Table 2 Substrate scope of azlactones 2a and para-aryl substituted
quinols 1d
Entry Cat. (mol%) R1, R2
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
2.5
10
10
10
10
10
5
5
5
5
5
5
2.5
2.5
2.5
5
5
10
10
10
10
10
10
Bn, C6H5
Phenethyl, C6H5
Me, C6H5
iBu, C6H5
2-(Methylthio)ethyl, C6H5 3be, 67
1H-Indol-3-yl, C6H5
4-Chlorobenzyl, C6H5
4-Bromobenzyl, C6H5
4-Methylbenzyl, C6H5
3-Methylbenzyl, C6H5
3-Methoxybenzyl, C6H5
Bn, 4-EtC6H4
3ba, 94
3bb, 75
3bc, 76
3bd, 77
98
99
93
99
94
94
99
99
99
99
98
99
99
95
97
99
97
99
99
99
99
99
99
3bf, 91
3bg, 99
3bh, 83
3bi, 66
3bj, 73
3bk, 64
3bl, 82
3bm, 87
3bn, 90
3bo, 86
3bp, 74
3bq, 77
3br, 73
3bs, 72
3bt, 72
3bu, 67
3bv, 57
3bw, 60
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Bn, 4-MeC6H4
Bn, 4-BrC6H4
Bn, 4-ClC6H4
Fig. 1 ORTEP representation of the X-ray crystal structure of the catalyst
BG-1ÁHBPh4 and proposed model for the cascade reaction.
Bn, 4-MeOC6H4
Bn, 3,5-(Me)2C6H3
Bn, 2-naphthyl
Bn, 1-adamantyl
Bn, 2-furyl
Bn, 2-thienyl
Bn, cyclopentyl
Bn, cyclohexyl
a
Unless otherwise noted, the reactions were carried out with BG-1ÁHBPh4
(2.5–10 mol%), 1b (0.10 mmol), and 2 (1.5 equiv.) in CH2Cl2 (1.0 mL) at
À10 1C for 72 h. b Isolated yield. c Determined by HPLC and SFC analysis.
d The reactions were carried out with BG-1ÁHBPh4 (10 mol%), 1 (0.10 mmol),
and 2a (1.5 equiv.) in CH2Cl2 (1.0 mL) at 30 1C for 72 h.
Scheme 2 Transformation and X-ray crystal structure of the products.
the corresponding double salt,16 special arrangement of BG-1ÁHBPh4
the intramolecular addition of a tethered malonate to construct the reveals some differences. The two intramolecular hydrogen-
lactone ring (Scheme 1b, left process) following installation of bonds disappear after one equivalent of HBPh4 is incorporated.
the amide nitrogen, but the 9-epi-sorbicillactone A was gotten as Accordingly, the relative position of the substituents tethered
the major diastereomer.14 Our intermolecular strategy provides to the amide units changes. The two phenyl groups rotate to
a direct route for the diastereo- and enantioselective introduction the anti-position, releasing the steric hindrance in the gauche
of the amide unit into the lactone structure. The products have conformation in BG-1. The rotation leads to the existence of three
a variety of synthetic handles for subsequent derivatization. equidirectional hydrogen bonds, including two NH of amides and
Bromination of 3aa followed by elimination formed vinyl bromide one NH of guanidinium. The bulky Ph4BÀ anion locates nearby the
4aa, allowing the incorporation of a variety of functional groups guanidinium unit through electrostatic attraction, creating steric
though cross-coupling. Indeed, epoxide 5ba was yielded as a single hindrance at the top side. The imine-nitrogen of the basic guanidine
diastereomer bearing five contiguous stereocenters by using tert- unit turns inside towards the hydrogen-bond-network.
BuNH2 as the catalyst of epoxidation (Scheme 2). The absolute
configuration of the epoxide was determined by X-ray crystallography guanidine catalyst, a detailed confirmation of a catalyst–sub-
analysis.15 strate adduct was not possible. We probed 1H NMR (see the
Due to the instability of the two reactants in the presence of
To gain some insights into this cascade process, we obtained ESI† for details) of a commixture of catalyst and substrates 1b
the X-ray crystal structure of the chiral catalyst BG-1ÁHBPh4. and 2a. A significant upfield shift of the CH resonance on
Fig. 1 shows the actual three-dimensional architecture of the quinol 1b, and the benzyl CH2 resonance and C4-H resonance
bisguanidinium hemisalt. In comparison with the information on azlactone 2a by approximately 0.05–0.15 ppm is observed.
obtained from X-ray crystal structures of bisguanidine BG-1 and This indicates the multiple intermolecular H-bonding between
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the bisguanidinium salt and substrates in the transition state. Notes and references
When 4-MeO substituted cyclohexadienone was used instead
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of p-quinol 1b, the corresponding Michael reaction did not
occur. This indicates that the synergic lactonization step might
accelerate the initial conjugation addition step. With these
experimental observations in hand, we proposed a bifunctional
catalyst model that is consistent with the significant levels of
diastereo- and enantioselectivity. Fig. 1 shows catalyst–substrate
interaction with the guanidinium hemisalt maintaining its con-
formation as the crystal. The basic guanidine unit accelerates the
enolization of azlactone, contacting the formed intermediate as a
hydrogen-acceptor; meanwhile the vicinal amide bonds to the
other oxygen atom via H-bonding. The guanidinium salt and
neighboring amide provide double hydrogen-bonds to contact
the carbonyl group of p-quinol 1a. An intermolecular conjugate
addition between azlactone and p-quinol might take place via a
Re–Re face contact. The phenyl group and cyclohexyl group
underneath raise steric hindrance to discriminate the para-
substituents of p-quinol, thus desymmetrization of p-quinol
occurs. Next, the OH group attacks the carbonyl group of the
azlactone, performing lactonization to give 3-amino-benzofuran-2,5-
dione (3R,3aS,7aS)-3aa.
In summary, we have developed a highly diastereo- and
enantioselective addition/lactonization of azlactones to p-quinols.
The generation of 3-amino-benzofuran-2,5-diones bearing three
stereogenic centers serves to synthesize potential biologically active
compounds for building non-natural sorbicillactone A homologue
libraries. Our results include the study of azlactones derived from
different amino acids and aldehydes, and prochiral p-quinols
containing different para-substituents, revealing mechanistic con-
sequences. From the examination of the crystal structure of the
bisguanidinium hemisalt, we also disclosed that the catalyst works
as a bifunctional catalyst and bonds the reactants through multiple
hydrogen-bonds. The catalytic principle may be extended equally
well to other classes of asymmetric organocatalysis. Further
application of these kinds of catalysts to other reactions is
underway.
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We thank Prof. Zhihua Mao of SiChuan University for single
crystal analysis. We appreciate the National Natural Science
Foundation of China (No. 21625205, 21332003), and National
Program for Support of Top-Notch Young Professionals for
financial support.
˜
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1851705 (5bc)†.
Conflicts of interest
There are no conflicts to declare.
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