Stereodivergent Synthesis of Chromanones and Flavanones via Intramolecular Benzoin Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01767

The strategy of stereodivergent reactions on racemic mixtures (stereodivergent RRM) was employed for the first time in intramolecular benzoin reactions and led to the rapid access of chromanones/flavanones with two consecutive stereocenters. The easily separable stereoisomers of the products were obtained with moderate to excellent enantioselectivities in a single step. Catechol type additives proved crucial in achieving the desired diastereo- and enantioselectivities.

Full text of DOI:10.1021/acs.orglett.6b01767

Letter
pubs.acs.org/OrgLett
Stereodivergent Synthesis of Chromanones and Flavanones via
Intramolecular Benzoin Reaction
Genfa Wen,† Yingpeng Su,† Guoxiang Zhang,‡ Qiqiao Lin,‡ Yujin Zhu,§ Qianqian Zhang,§
and Xinqiang Fang*,‡
†College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, 730070, China
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter,
University of Chinese Academy of Sciences, Fuzhou, 350100, China
§College of Chemistry, Fuzhou University, Fuzhou, 350116, China
S
* Supporting Information
ABSTRACT: The strategy of stereodivergent reactions on
racemic mixtures (stereodivergent RRM) was employed for the
first time in intramolecular benzoin reactions and led to the
rapid access of chromanones/flavanones with two consecutive
stereocenters. The easily separable stereoisomers of the
products were obtained with moderate to excellent enantiose-
lectivities in a single step. Catechol type additives proved
crucial in achieving the desired diastereo- and enantioselectiv-
ities.
hromanones and flavanones are a class of compounds
be applied.2 Recently, an elegant chiral thiourea catalyzed
Ccontaining the core structure of dihydrobenzopyranone. intramolecular conjugate addition approach for the synthesis of
chromanone related products was developed by Scheidt and co-
workers.3 However, methods that are able to assemble both
diastereoisomers (cis- and trans-) of this class of compounds
remain extremely scarce. In recent years, the strategy of divergent
reactions on racemic mixtures (divergent RRM) has drawn
increasing research interest owing to its capability of readily
assembling molecules with structural diversity.4 We envisioned
that the merger of N-heterocyclic carbene (NHC) catalyzed
benzoin reactions5 and the strategy of stereodivergent RRM
would accomplish the mission of furnishing stereodiversified
chromanone related compounds in an efficient and atom-
economic fashion (Scheme 1).
These molecules have drawn long-term research focus in both
chemical and medicinal communities owing to their ubiquitous
pharmacological properties such as anticancer, anti-HIV,
antibacteria, antiparasitic, etc.1 Besides the chromanones/
flavanones with only one stereocenter, there remains a large
amount of these compounds bearing two stereogenic centers. In
many cases, both enantiomers and/or diastereoisomers show
bioactivities, and sometimes, they even display different ones
(Figure 1).1
Therefore, addressing the issue of producing both isomers of
these substances in a concise and efficient approach is
extraordinarily significant and urgent. However, a comprehensive
literature survey reveals markedly limited approaches that can
directly build enantioenriched chromanones/flavanones bearing
two consecutive stereocenters. In most cases several steps have to
However, a concomitant challenge in the study of stereo-
divergent RRM is that the inherent substrate preference for the
product stereoselectivity must be overcome.4f As illustrated in
Scheme 2, in a matched case, both the substrate preference and
Scheme 1. Stereodivergent Benzoin Reaction for the
Synthesis of Chromanones/Flavanones
Received: June 17, 2016
Figure 1. Selected examples of chromanones/flavanones.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Challenge of Overcoming Substrate Preference
Table 1. Reaction Conditions Optimization
the catalyst preference favor the formation of chiral product 2;
however, a mismatched pair shows diminished selectivity and
produces not only the catalyst controlled product 3 but also
minor product ent-2 due to the inherent substrate preference,
thereby resulting in the enantioselectivity erosion of product 2.
In the worst case, both enantiomers of the substrate would not
match the chiral catalyst and provide both products with low ee
values.4a This point is also in sharp contrast to conventional
benzoin reactions that lead to products with only one
stereocenter.6
Furthermore, to achieve a successful stereodivergent reaction
in this study, several side reactions such as an intramolecular
aldol reaction (Scheme 3a), a possible dynamic kinetic resolution
Scheme 3. Challenge of Suppressing Side Reactions
(DKR) process (Scheme 3b), a dehydration reaction that forms
4H-chromen-4-one (Scheme 3c), and intermolecular benzoin or
aldol reactions (Scheme 3d) must be suppressed. It is also
noteworthy that the two diastereoisomers obtained in this work
need to be easily separable from each other via flash
chromatography; otherwise, the practicality of this method will
be significantly discounted.4e
With the goal of addressing all the above challenges and
developing a general approach for the synthesis of multiply
substituted chromanones and flavanones in a concise, efficient,
and highly enantioselective manner, we recently conducted the
NHC-catalyzed stereodivergent reaction on racemic aldehyde-
ketones to furnish the title compounds. Herein we report the
results.
Easily available substrate 1a and triazoliums A−D (used
initially by Rovis and Bode groups),7 which have proven
extremely successful in a large range of NHC-catalyzed reactions
including intramolecular benzoin processes,6d,e were selected for
conditions optimization. Not unexpectedly, the initial evaluation
of several triazoliums with different N-aryl substituents induced
very low levels of enantioselectivity, probably because of the
inability to overcome the substrate preference for the product
stereoselectivity (Table 1, entries 1−4). For instance, C6F5-
substituted catalyst A afforded products 2a and 3a with a ratio of
5:1 and low enantioselectivities (10% and 56% ee, respectively,
Table 1, entry 1). Similar results were observed when catalysts B,
C, and D were utilized (Table 1, entries 2−4), with B giving a
a
Reaction conditions: 1a (0.2 mmol), NHC (0.03 mmol), THF (2
b
c
mL), argon protection. Isolated yields based on 1a. Determined via
HPLC analysis on a chiral stationary phase. The absolute configuration
was determined via the single-crystal X-ray structure analysis of 3h
(Scheme 4). cat. = catalyst, addi. = additive, temp = temperature.
slightly better result considering the ee of 3a. We then screened
several bases using B as the catalyst but did not observe the
promotion of ee values (Table 1, entries 5−8). Further screening
of the reaction parameters indicated that decreasing the
temperature to −20 °C can lead to an apparent enhancement
of ee’s (62% and 90% for 2a and 3a, respectively), and a ratio of
1.2:1 (2a versus 3a) was observed (Table 1, entry 9). We then
sought aid from adding additives such as a1−a3, an approach that
has been used by Rovis, Chi, and other groups and proven useful
in improving the yields and ee’s of the products.8 To our delight,
a remarkable enhancement of ee values of both 2a (83% ee) and
B
DOI: 10.1021/acs.orglett.6b01767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3a (96% ee) was furnished when a1 was added, albeit with
moderate conversion (Table 1, entry 10). Various results were
perceived with different additives (Table 1, entries 11 and 12).
Cheerfully, the combination of additives a1 and a2 can increase
the ee values to 82% (2a) and 98% (3a), adjust their ratio to
1.1:1, and maintain almost quantitative conversion (Table 1,
entry 13). Finally a slight change in the ratio of a1 versus a2
resulted in the optimal results (Table 1, entry 14). Although the
exact model of function is not well established to date, we believe
that the catechol-type additives work through H-bonding that
combines both the Breslow intermediate and the carbonyl group
of the ketone moiety.8d Several widely used triazoliums with
different chiral skeletons were also tested but did not deliver
better results (Table 1, entries 15−17).
With the optimal conditions established, we first examined a
variety of substrates with different substituents to evaluate the
synthetic potential of accessing chromanones. As shown in
Scheme 4, variations on the substitution pattern of the aromatic
ketone moiety were possible. For example, substrates with
additional electron-donating Me or OMe groups at the para-
position were tolerated well, providing the corresponding
diasteroisomers in excellent yields and with good to excellent
enantioselectivities (Scheme 4, 2b/3b and 2c/3c). Similarly,
electron-withdrawing groups such as F or Cl groups had little
effect on the yields and ee values (Scheme 4, 2d/3d, 2e/3e, and
2f/3f). Substrates with different substituents on the formyl
phenyl ring were also surveyed and proved amenable under the
standard conditions, delivering the chromanones in an almost
1:1 ratio and without any erosion of the enantioselectivities
(Scheme 4, 2g/3g, 2h/3h9, and 2i/3i). Ketones with α-ethyl or
propyl groups were also evaluated, and the corresponding 3j and
3k can be delivered with excellent enantioselectivities; however,
moderate ee values were detected for 2j and 2k and the ratios of
2j/3j and 2k/3k changed to about 2:1 in both cases, indicating an
increased substrate preference when sterically more bulky
substituents were introduced. Replacement of the aromatic
substituents with an aliphatic methyl group at the ketone moiety
had no significant influence on the outcomes, with the
enantioselectivities retained, albeit with a moderate total yield
(Scheme 4, 2l/3l). Moreover, the methodology proved
compatible with substituents of Me, Cl, or F at the formyl
units, releasing both isomers with excellent enantioselectivities
(Scheme 4, 2m/3m, 2n/3n, and 2o/3o).
Having been successful in the stereodivergent synthesis of
chromanones, we then transferred our focus to flavanones. As
displayed in Scheme 5, although the introduction of an aryl group
a
Scheme 5. Stereodivergent Synthesis of Flavanones
a
Scheme 4. Stereodivergent Synthesis of Chromanones
a
All reactions were run on a 0.2 mmol scale; all yields were of isolated
products; ee values were determined via HPLC analysis on a chiral
stationary phase; in most cases, the dr values are close to the ratio of
b
5/6. Catalyst C (15 mol %), NaOH (1.2 equiv), a1 (0.75 equiv), and
a2 (0.25 equiv) were used for the synthesis of 5f−j and 6f−j.
into substrates such as 4 will increase the enolizability of the
ketone moiety, thereby facilitating an intramolecular aldol
reaction and a dynamic kinetic resolution process, we found
that the optimal conditions used in Scheme 4 worked well in this
range of substrates. For instance, diastereoisomers 5a and 6a
were both isolated with excellent ee values (96% and 92%,
respectively), and substrates equipped with electron-donating
and -withdrawing groups at the formyl units were also
a
All reactions were run on a 0.2 mmol scale; all yields were of isolated
products; ee values were determined via HPLC analysis on a chiral
stationary phase; in most cases, the dr values are close to the ratio of
2/3.
C
DOI: 10.1021/acs.orglett.6b01767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compatible under the standard conditions (Scheme 5, 5b/6b,
5c/6c, 5d/6d, and 5e/6e). Slightly modified conditions were
used for aliphatic ketone substrates to guarantee high
enantioselectivities (Scheme 5, 5f/6f), and the introduction of
substitution groups on both the formyl aryl rings and the phenyl
groups at the α-position of ketones was also possible (Scheme 5,
5g/6g, 5h/6h, 5i/6i, and 5j/6j). The relatively lower total yields
of 5g/6g and 5h/6h were mainly due to the formation of some
side products.
Further transformations based on the products can be realized
through the nucleophilic attack of 2a by a vinyl Grignard reagent
and the two-step dehydroxylation of 3a, releasing corresponding
chromanone 7a10 and 1,2-diol 8a11 without any erosion in ee
values (Scheme 6).
REFERENCES
■
(1) For selected reports, see: (a) Patil, A. D.; Freyer, A. J.; Eggleston, D.
S.; Haltiwanger, R. C.; Bean, M. F.; Taylor, P. B.; Caranfa, M. J.; Breen,
A. L.; Bartus, H. R.; Johnson, R. K. J. Med. Chem. 1993, 36, 4131.
(b) Galinis, D. L.; Fuller, R. W.; McKee, T. C.; Cardellina, J. H., II;
Gulakowski, R. J.; McMahon, J. B.; Boyd, M. R. J. Med. Chem. 1996, 39,
4507. (c) Mbwambo, Z. H.; Kapingu, M. C.; Moshi, M. J.; Machumi, F.;
Apers, S.; Cos, P.; Ferreira, D.; Marais, J. P. J.; Berghe, D. V.; Maes, L.;
Vlietinck, A.; Pieters, L. J. Nat. Prod. 2006, 69, 369.
(2) (a) Khilevich, A.; Mar, A.; Flavin, M. T.; Rizzo, J. D.; Lin, L.;
Dzekhtser, S.; Brankovic, D.; Zhang, H.; Chen, W.; Liao, S.; Zembower,
D. E.; Xu, Z.-Q. Tetrahedron: Asymmetry 1996, 7, 3315. (b) Sekino, E.;
Kumamoto, T.; Tanaka, T.; Ikeda, T.; Ishikawa, T. J. Org. Chem. 2004,
69, 2760. (c) Garcia, J.; Barluenga, S.; Beebe, K.; Neckers, L.;
Winssinger, N. Chem. - Eur. J. 2010, 16, 9767.
(3) (a) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
129, 3830. (b) Farmer, R. L.; Scheidt, K. A. Chem. Sci. 2013, 4, 3304.
(c) McDonald, B. R.; Nibbs, A. E.; Scheidt, K. A. Org. Lett. 2015, 17, 98.
(4) (a) Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368. (b) Jana,
C. K.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6542. (c) Miller, L. C.;
Ndungu, J. M.; Sarpong, R. Angew. Chem., Int. Ed. 2009, 48, 2398.
(d) Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M. L. J. Am.
Chem. Soc. 2010, 132, 12422. (e) Langlois, J. B.; Alexakis, A. Angew.
Chem., Int. Ed. 2011, 50, 1877. (f) Miller, L. C.; Sarpong, R. Chem. Soc.
Rev. 2011, 40, 4550.
Scheme 6. Products Derivatizations
(5) For selected reviews of NHC catalysis including benzoin reactions,
see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(b) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (c) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (d) Marion, N.;
́
Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
(e) Moore, J.; Rovis, T. Top. Curr. Chem. 2009, 291, 77. (f) Biju, A. T.;
Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (g) Vora, H. U.;
Rovis, T. Aldrichimica Acta 2011, 44, 3. (h) Bugaut, X.; Glorius, F. Chem.
Soc. Rev. 2012, 41, 3511. (i) Hopkinson, M. N.; Richter, C.; Schedler,
M.; Glorius, F. Nature 2014, 510, 485. (j) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307.
(6) (a) Hachisu, Y.; Bode, J. W.; Suzuki, K. Adv. Synth. Catal. 2004, 346,
1097. (b) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2006, 2431.
(c) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006,
45, 1463. (d) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew.
Chem., Int. Ed. 2006, 45, 3492. (e) Takikawa, H.; Suzuki, K. Org. Lett.
2007, 9, 2713. (f) Jia, M.-Q.; You, S.-L. ACS Catal. 2013, 3, 622.
(7) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298. (b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.
(c) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088.
(d) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094. For
detailed studies on the effect of N-aryl groups in NHCs, see: (e) Collett,
C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.; O’Donoghue, A. C.;
Smith, A. D. Chem. Sci. 2013, 4, 1514. (f) Collett, C. J.; Massey, R. S.;
Taylor, J. E.; Maguire, O. R.; O’Donoghue, A. C.; Smith, A. D. Angew.
Chem., Int. Ed. 2015, 54, 6887.
(8) (a) Filloux, C. M.; Lathrop, S. P.; Rovis, T. Proc. Natl. Acad. Sci. U. S.
A. 2010, 107, 20666. (b) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc.
2011, 133, 10402. (c) Chen, X.; Fang, X.; Chi, Y. R. Chem. Sci. 2013, 4,
2613. (d) Reddi, Y.; Sunoj, R. B. ACS Catal. 2015, 5, 1596.
(9) CCDC 1483359 (3h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(10) The configuration of 7a was assigned to be trans through
comparing its coupling constant with the known compound: Draper, R.
W.; Hu, B.; Iyer, R. V.; Li, X.; Lu, Y.; Rahman, M.; Vater, E. J.
Tetrahedron 2000, 56, 1811.
In summary, the first stereodivergent intramolecular benzoin
reaction on racemic aldehyde-ketone substrates was developed
and applied in the synthesis of chromanones/flavanones bearing
two consecutive stereocenters. Chromatographically separable
stereoisomers of this series of compounds were obtained with
moderate to excellent enantioselectivities in a concise approach.
The protocol also highlights the use of catechol type additives in
overcoming the substrate preference and eventually assisting the
diastereo- and enantioselective control of both isomers. Further
study on the access of useful synthons and natural products
through the combination of stereodivergent RRM with benzoin
reactions is in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01767.
Experimental procedures, optimization details, data for all
new compounds, NMR and HPLC spectra (PDF)
X-ray structure of 3h (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xqfang@fjirsm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) The absolute configuration of the newly formed stereogenic
center was assigned by analogy to the similar report; see: Yamamoto, K.;
Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Chem. - Eur. J. 2003, 9,
3242.
This work was supported by the Fujian Institute of Research on
the Structure of Matter (FJIRSM), NSFC (21402199 and
21502192) and the Chinese Recruitment Program of Global
Experts. We thank Professor Daqiang Yuan at FJIRSM for
crystallographic analysis.
D
DOI: 10.1021/acs.orglett.6b01767
Org. Lett. XXXX, XXX, XXX−XXX