Iridium-Catalyzed Asymmetric Hydrogenation of 2H-Chromenes: A Highly Enantioselective Approach to Isoflavan Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02341

A highly efficient (aS)-Ir/In-BiphPHOX-catalyzed asymmetric hydrogenation of substituted 2H-chromenes and substituted benzo[e][1,2]oxathiine 2,2-dioxides is described. A series of 2H-chromenes and benzo[e][1,2]oxathiine 2,2-dioxides were hydrogenated to give the target products in high yields (92-99%) with excellent enantioselectivities (up to 99.7% ee) using our catalytic system. This reaction provides a direct and efficient method for the construction of chiral benzo six-membered oxygen-containing compounds.

Full text of DOI:10.1021/acs.orglett.7b02341

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Asymmetric Hydrogenation of 2H‑Chromenes: A
Highly Enantioselective Approach to Isoflavan Derivatives
Jingzhao Xia,† Yu Nie,‡ Guoqiang Yang,*,‡ Yangang Liu,† and Wanbin Zhang*,†,‡
‡
†School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient (aS)-Ir/In-BiphPHOX-cata-
lyzed asymmetric hydrogenation of substituted 2H-chromenes
and substituted benzo[e][1,2]oxathiine 2,2-dioxides is de-
scribed. A series of 2H-chromenes and benzo[e][1,2]oxathiine
2,2-dioxides were hydrogenated to give the target products in
high yields (92−99%) with excellent enantioselectivities (up to
99.7% ee) using our catalytic system. This reaction provides a direct and efficient method for the construction of chiral benzo six-
membered oxygen-containing compounds.
he dihydrobenzopyran core is a prevalent structural motif
found in numerous biologically active natural compounds
and pharmaceuticals. The broad range of bioactivities exhibited
by molecules containing this core element has led to their
description as “privileged structures” (Figure 1).1 Among them,
they have several shortcomings: (1) they require an equivalent
of a chiral auxiliary; (2) they suffer from limited starting
material availability; and (3) they are low-yielding. Hence,
exploration of new catalytic strategies for the construction of a
diverse array of enantioenriched chiral dihydrobenzopyran
skeletons is of great importance. Obviously, asymmetric
catalysis is a good solution for these problems. In 2012, List
reported a chiral Brønsted acid-catalyzed asymmetric intra-
molecular addition of phenol to ketene dithioacetals, and (S)-
equol could be prepared from one of the products (Scheme
1c).7 Metz has developed an enantioselective synthesis of
isoflavanones by catalytic dynamic kinetic resolution via Ru-
catalyzed asymmetric transfer hydrogenation (Scheme 1d).8
Asymmetric hydrogenation utilizing metal complexes has
proven to be a powerful tool for the preparation of pure
enantiomers because of its high efficiency, good atom economy,
and minimal environmental impact.9 Since the pioneering work
of Pfaltz and co-workers,10 iridium complexes consisting of
phosphine nitrogen ligands have attracted much attention. The
search for highly enantioselective and efficient reactions has
prompted many chemists to design and develop new catalytic
systems.11 However, despite considerable progress in this field,
efficient and straightforward syntheses of chiral dihydrobenzo-
pyrans have rarely been reported.12 The Zhou group reported a
four-step synthetic route starting from a chiral acid obtained via
Ir-catalyzed asymmetric hydrogenation of α-arylcinnamic acids
using a chiral spiro phosphine−oxazoline (PHOX) ligand
(Scheme 1e).13 4H-Chromene derivatives and a thio analogue
have been hydrogenated with high enantioselectivities using Ir
PHOX-type catalysts.12 The asymmetric hydrogenation of 2H-
chromenes provides a direct and efficient method for the
preparation of isoflavans. We previously developed a class of
axially flexible chiral phosphine−oxazoline ligands that have
T
Figure 1. Representative examples of biologically active compounds
possessing a chromane core.
isoflavans, which are metabolites of soy isoflavanoids, have
received much attention because of their estrogenic activity,
activity toward the estrogen receptor β (ERβ)2 and potential
use in menopausal hormone replacement therapy.3 Although
many synthetic methods for the racemic preparation of
isoflavans have been published,4 examples of the enantiose-
lective synthesis of such compounds are far more rare.5 To the
best of our knowledge, the earliest conventional approaches for
the preparation of this important building block employed
chiral starting materials and required multistep synthetic
sequences (Scheme 1a,b).6 Although these methodologies
provide a variety of routes for the preparation of isoflavans,
Received: July 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Previous Reports and Our Strategy for the
Table 1. Reaction Condition Screening
Enantioselective Synthesis of Isoflavans
b
c
d
entry
solvent
ligand
conv (%)
ee (%)
1
2
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
toluene
CH2Cl2
CHCl3
MeOH
THF
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
62
85
93
98
−68
−
93
98
98
−
94
3
99
4
46
5
NR
16
6
7
>99
>99
messy
NR
NR
>99
8
9
10
11
−
−
98
e
12
CH2Cl2
a
Reaction conditions: 0.24 mmol scale of substrate 1a, substrate/
b
catalyst ratio (S/C) = 100, 2 mL of solvent. When L1−L3 were used,
the axial chirality of the catalyst was aS. Determined by H NMR
c
1
d
spectroscopy. Determined by HPLC using a chiral Daicel column.
e
H2 (10 bar).
been successfully applied in iridium-catalyzed asymmetric
hydrogenations.14 On the basis of our previous studies in this
field, we expected that our catalyst would enable the
asymmetric hydrogenation of 2H-chromenes and provide a
more efficient route for the synthesis of optically pure
dihydrobenzopyrans.
(98% ee; entries 7 and 8). However, reaction with CHCl3 as a
solvent was messy (entry 9). Polar solvents such as MeOH and
THF were also investigated, but no hydrogenation occurred
when these solvents were used (entries 10 and 11). A similar
conversion and enantioselectivity were obtained when the
reaction was conducted at a hydrogen pressure of 10 bar in
CH2Cl2 (entry 12).
We were pleased to discover that the asymmetric hydro-
genation could be conducted with our (aS)-Ir/In-BiphPHOX
catalyst. A number of hydrogenation conditions were
investigated, as shown in Table 1. We commenced our study
by using 1a as the model substrate with 1.0 mol % Ir/P,N-
ligand in o-xylene under 20 bar hydrogen for 24 h. Initial
examination of the P,N-ligated iridium catalyst showed that
(aS)-Ir/In-BiphPHOX was the best with regard to both
conversion and enantioselectivity (>99% conv, 98% ee; entry
3). Other types of axially flexible ligands, iPr-BiphPHOX and
tBu-BiphPHOX, also gave moderate to good enantioselectivity
(85% ee and 93% ee, respectively) (entries 1 and 2). Catalysis
with the ligand tBu-PHOX gave the desired product with poor
conversion and as the opposite enantiomer (entry 4).
Additionally, there was no reaction when mono-tBu-RuPHOX
was used as the ligand (entry 5). The ligand (aS)-tBu-
BinaphPHOX, bearing the same axial chirality as (aS)-Ir/In-
BiphPHOX, gave the desired product with excellent
enantioselectivity but poor conversion (entry 6). The effect
of the solvent on the reaction was also examined with catalyst
(aS)-Ir/In-BiphPHOX. Solvents commonly used for the Ir-
catalyzed asymmetric hydrogenation of olefins (e.g., CH2Cl2
and toluene) allowed the reaction to proceed smoothly,
providing the desired product with the same enantioselectivity
Under the optimal reaction conditions, a variety of 3-
substituted 2H-chromenes were hydrogenated to the corre-
sponding chiral 3-substituted chromanes (Scheme 2). It was
found that 2H-chromenes bearing both electron-deficient and
electron-rich mono- and disubstituted fused benzene rings
could all be hydrogenated in high yields and enantioselectivities
(2a−g). Substrates with different halogen groups on the
benzene ring (6-, 7-, or 8-substituted groups) could all be
reduced smoothly, providing the desired adducts in high yields
and ee’s (2b−f). Additionally, when electron-deficient or
electron-rich aryl substituents were introduced as the R2
group, the desired transformations proceeded in high yields
and enantioselectivities (2j−l). Substrates bearing substituents
on both of the benzene rings provided the corresponding
products in excellent yields and ee’s (2h, 2i). Substrates bearing
a disubstituted phenyl group or β-naphthyl group as R2 gave
the desired products with 98% ee (2m, 2n). The best
enantioselectivity was obtained when furyl was used as the R2
group (99.7% ee, 2o). The substrate bearing a methyl group as
B
DOI: 10.1021/acs.orglett.7b02341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of 2H-Chromenes
Scheme 3. Substrate Scope of Benzo[e][1,2]oxathiine 2,2-
Dioxides
a
a
Reaction conditions: 0.24 mmol scale of substrate, S/C = 100, 60 bar
H2, 2 mL of CH2Cl2, 48 h, 40 °C. Isolated yields are shown.
Enantioselectivities were determined by HPLC using a chiral column.
b
For the reaction conditions, see Scheme 2.
in enantioselective excess (4d, 4e). The absolute configuration
of product 4e was determined to be S by X-ray crystallographic
analysis.15
a
Reaction conditions: 0.24 mmol scale of substrate, S/C = 100, 10 bar
H2, 2 mL of CH2Cl2, 24 h, rt. Isolated yields are shown.
Enantioselectivities were determined by HPLC using a chiral column.
b
We next investigated the synthesis of the bioactive
compound (S)-equol using our Ir/In-BiphPHOX catalytic
system. Excellent catalytic results (98% ee) were obtained
when the substrate to catalyst ratio (S/C) was 1000. (S)-Equol
could be obtained in 82% yield with 95% ee via the removal of
the Me groups according to a literature procedure.6b Our
catalyst system provides an efficient and enantioselective
synthesis of (S)-equol via asymmetric hydrogenation (Scheme
4).
H2 (50 bar).
R2 also gave the corresponding product 2p in excellent yield
with good ee, albeit under a high hydrogen pressure. The
absolute configuration of product 2e was unambiguously
determined to be S by X-ray crystallographic analysis (Figure
2).15
Scheme 4. Larger-Scale Synthesis of (S)-Equol by
Asymmetric Hydrogenation
Figure 2. X-ray structure of 2e.
Other types of benzo-fused oxygen-containing six-mem-
bered-ring substrates were also tested with our catalyst system.
4-Phenyl-2H-chromene (3a) was hydrogenated with poor
enantioselectivity (4a).16 Pleasingly, benzo[e][1,2]oxathiine
2,2-dioxides 3b−e could be hydrogenated with good results.
The corresponding products are important skeletons present in
bioactive compounds,17 and asymmetric syntheses of such
molecules have not been widely reported (Scheme 3).18 For
example, Hayashi reported an asymmetric addition of
arylboronic acids to α,β-unsaturated sulfonyl compounds in
the presence of a rhodium catalyst coordinated with a chiral
diene ligand.18c With our catalytic system, these types of
compounds could also be prepared with full conversion when
the reaction was conducted under a hydrogen pressure of 60
bar at 40 °C. Although the desired product was obtained with
only 27% ee when R3 was methyl (4b), the enantioselectivity
increased greatly to 94% ee when R3 was changed to a phenyl
group. Substrates with a methoxy group at the 7-position or a
methyl group at the para position of the phenyl ring could also
be reduced to the desired products, albeit with a slight decrease
In conclusion, we have developed a highly efficient iridium-
catalyzed asymmetric hydrogenation of substituted 2H-
chromenes and 4-substituted benzo[e][1,2]oxathiine 2,2-
dioxides in excellent yields and enantioselectivities. A direct
and efficient route for the construction of chiral (S)-equol was
successfully achieved.
C
DOI: 10.1021/acs.orglett.7b02341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(c) Church, T. L.; Andersson, P. G. Coord. Chem. Rev. 2008, 252,
513−531. (d) Gridnev, I. D.; Imamoto, T. Chem. Commun. 2009,
7447−7464. (e) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011,
111, 1713−1760. (f) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G.
Chem. Rev. 2012, 112, 2557−2590. (g) Carroll, M. P.; Guiry, P. J.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02341.
■
S
Chem. Soc. Rev. 2014, 43, 819−833. (h) Verendel, J. J.; Pam
̀
ies, O.;
Dieguez, M.; Andersson, P. G. Chem. Rev. 2014, 114, 2130−2169.
́
Details of experimental procedures, characterization data,
and copies of 1H and 13C NMR spectra and HPLC charts
for new compounds (PDF)
X-ray data for 2e (CIF)
X-ray data for 4e (CIF)
(i) Zhang, Z.; Butt, N. A.; Zhang, W. Chem. Rev. 2016, 116, 14769−
14827. (j) Zhao, D.; Candish, L.; Paul, D.; Glorius, F. ACS Catal.
2016, 6, 5978−5988. (k) Zhu, S.-F.; Zhou, Q.-L. Acc. Chem. Res. 2017,
50, 988−1001.
(10) (a) Schnider, P.; Koch, G.; Pret
́
o
̂
t, R.; Wang, G.; Bohnen, F. M.;
Kruger, C.; Pfaltz, A. Chem. - Eur. J. 1997, 3, 887−892. (b) Lightfoot,
̈
A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897−2899.
AUTHOR INFORMATION
Corresponding Authors
■
(11) Selected recent papers on the development of P,N ligands:
(a) McIntyre, S.; Hormann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Adv.
̈
Synth. Catal. 2005, 347, 282−288. (b) Kaiser, S.; Smidt, S. P.; Pfaltz, A.
Angew. Chem., Int. Ed. 2006, 45, 5194−5197. (c) Zhu, S.-F.; Xie, J.-B.;
Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886−
12891. (d) Lu, W.; Chen, Y.; Hou, X. Angew. Chem., Int. Ed. 2008, 47,
10133−10136. (e) Tolstoy, P.; Engman, M.; Paptchikhine, A.;
Bergquist, J.; Church, T. L.; Leung, A. W.-M.; Andersson, P. G. J.
Am. Chem. Soc. 2009, 131, 8855−8860. (f) Han, Z.; Wang, Z.; Zhang,
X.; Ding, K. Angew. Chem., Int. Ed. 2009, 48, 5345−5349. (g) Zhu, Y.;
Fan, Y.; Burgess, K. J. Am. Chem. Soc. 2010, 132, 6249−6253.
*E-mail: gqyang@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Guoqiang Yang: 0000-0002-8356-6653
Wanbin Zhang: 0000-0002-4788-4195
Notes
The authors declare no competing financial interest.
̀ ́
(h) Mazuela, J.; Norrby, P.-O.; Andersson, P. G.; Pamies, O.; Dieguez,
M. J. Am. Chem. Soc. 2011, 133, 13634−13645. (i) Wang, X.; Han, Z.;
Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 936−940.
(j) Patureau, F. W.; Worch, C.; Siegler, M. A.; Spek, A. L.; Bolm, C.;
Reek, J. N. H. Adv. Synth. Catal. 2012, 354, 59−64. (k) Qu, B.;
Samankumara, L. P.; Ma, S.; Fandrick, K. R.; Desrosiers, J.-N.;
Rodriguez, S.; Li, Z.; Haddad, N.; Han, Z. S.; McKellop, K.; Pennino,
S.; Grinberg, N.; Gonnella, N. C.; Song, J. J.; Senanayake, C. H. Angew.
Chem., Int. Ed. 2014, 53, 14428−14432. (l) Li, S.; Xiao, T.; Li, D.;
Zhang, X. Org. Lett. 2015, 17, 3782−3785. (m) Peters, B. K.; Liu, J.;
Margarita, C.; Rabten, W.; Kerdphon, S.; Orebom, A.; Morsch, T.;
Andersson, P. G. J. Am. Chem. Soc. 2016, 138, 11930−11935.
(12) Asymmetric hydrogenation of 4H-chromenes: Valla, C.; Baeza,
A.; Menges, F.; Pfaltz, A. Synlett 2008, 2008, 3167−3171.
ACKNOWLEDGMENTS
■
This work was partly supported by the NNSFC (21232004 and
21620102003), STCSM (15JC1402200), and SHMEC
(201701070002E00030). We thank the Instrumental Analysis
Center of SJTU.
REFERENCES
■
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893−930.
(2) (a) Sawadjoon, S.; Kittakoop, P.; Kirtikara, K.; Vichai, V.;
Tanticharoen, M.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 5470−
5475. (b) Deng, J.-Z.; Starck, S. R.; Li, S.; Hecht, S. M. J. Nat. Prod.
2005, 68, 1625−1628. (c) Maloney, D. J.; Deng, J.-Z.; Starck, S. R.;
Gao, Z.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 4140−4141.
(13) Yang, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Yu, Y.-B.; Li, S.;
Zhou, Q.-L. Tetrahedron 2012, 68, 5172−5178.
(14) (a) Tian, F.; Yao, D.; Liu, Y.; Xie, F.; Zhang, W. Adv. Synth.
Catal. 2010, 352, 1841−1845. (b) Liu, Y.; Yao, D.; Li, K.; Tian, F.; Xie,
F.; Zhang, W. Tetrahedron 2011, 67, 8445−8450. (c) Liu, Y.; Zhang,
W. Angew. Chem., Int. Ed. 2013, 52, 2203−2206. (d) Liu, Y.; Gridnev,
I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014, 53, 1901−1905. (e) Xia,
J.; Yang, G.; Zhuge, R.; Liu, Y.; Zhang, W. Chem. - Eur. J. 2016, 22,
18354−18357. (f) Meng, K.; Xia, J.; Wang, Y.; Zhang, X.; Yang, G.;
Zhang, W. Org. Chem. Front. 2017, 4, 1601−1605.
(3) Adlercreutz, H.; Mousavi, Y.; Clark, J.; Hockerstedt, K.;
̈
Hamalainen, E.; Wahala, K.; Makela, T.; Hase, T. J. Steroid Biochem.
̈
̈
̈
̈
̈
̈
̈
̈
Mol. Biol. 1992, 41, 331−337.
(4) (a) Gharpure, S. J.; Sathiyanarayanan, A. M.; Jonnalagadda, P.
Tetrahedron Lett. 2008, 49, 2974−2978. (b) Tilley, A. J.; Zanatta, S. D.;
Qin, C. X.; Kim, I.-K.; Seok, Y.-M.; Stewart, A.; Woodman, O. L.;
Williams, S. J. Bioorg. Med. Chem. 2012, 20, 2353−2361. (c) Xiao, Z.-
P.; Peng, Z.-Y.; Dong, J.-J.; He, J.; Ouyang, H.; Feng, Y.-T.; Lu, C.-L.;
Lin, W.-Q.; Wang, J.-X.; Xiang, Y.-P.; Zhu, H.-L. Eur. J. Med. Chem.
2013, 63, 685−695.
(15) The crystallographic data for 2e (CCDC 1562372) and 4e
(CCDC 1562373) can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
(5) (a) Uyanik, M.; Hayashi, H.; Ishihara, K. Science 2014, 345, 291−
294. (b) Zhu, Y.; Zhang, W.-Z.; Zhang, L.; Luo, S. Chem. - Eur. J. 2017,
23, 1253−1257. (c) Ashley, E. R.; Sherer, E. C.; Pio, B.; Orr, R. K.;
Ruck, R. T. ACS Catal. 2017, 7, 1446−1451.
(16) The absolute configuration is consistent with a previous report:
Wang, Z.; Sun, J. Org. Lett. 2017, 19, 2334−2337.
́
(17) Selected reviews: (a) Backvall, J.-E.; Chinchilla, R.; Najera, C.;
̈
Yus, M. Chem. Rev. 1998, 98, 2291−2312. (b) Meadows, D. C.;
Gervay-Hague, J. Med. Res. Rev. 2006, 26, 793−814. Selected
examples: (c) Tozer, M. J.; Harper, E. A.; Kalindjian, S. B.; Pether, M.
J.; Shankley, N. P.; Watt, G. F. Bioorg. Med. Chem. Lett. 1999, 9, 1825−
1830. (d) Tamamura, H.; Koh, Y.; Ueda, S.; Sasaki, Y.; Yamasaki, T.;
Aoki, M.; Maeda, K.; Watai, Y.; Arikuni, H.; Otaka, A.; Mitsuya, H.;
Fujii, N. J. Med. Chem. 2003, 46, 1764−1768. (e) Hanessian, S.; Sailes,
H.; Therrien, E. Tetrahedron 2003, 59, 7047−7056.
(6) (a) Versteeg, M.; Bezuidenhoudt, B. C. B.; Ferreira, D.; Swart, K.
J. J. Chem. Soc., Chem. Commun. 1995, 1317−1318. (b) Heemstra, J.
M.; Kerrigan, S. A.; Doerge, D. R.; Helferich, W. G.; Boulanger, W. A.
Org. Lett. 2006, 8, 5441−5443. (c) Takashima, Y.; Kaneko, Y.;
Kobayashi, Y. Tetrahedron 2010, 66, 197−207. (d) Orr, R. K.;
Campeau, L.-C.; Chobanian, H. R.; McCabe Dunn, J. M.; Pio, B.;
Plummer, C. W.; Nolting, A.; Ruck, R. T. Synthesis 2017, 49, 657−666.
(7) Lee, J.-W.; List, B. J. Am. Chem. Soc. 2012, 134, 18245−18248.
(8) (a) Qin, T.; Metz, P. Org. Lett. 2017, 19, 2981−2984. A similar
reaction via hydrogenation was reported in a patent: (b) Okuma, T.;
Arai, N.; Inoue, T.; Ooka, K.; Azuma, K. JP 2015 044770 A, 2015.
(9) Selected reviews about metal-catalyzed asymmetric hydro-
genation: (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029−
3070. (b) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272−3296.
(18) (a) Ghandi, M.; Nazeri, M. T.; Kubicki, M. Tetrahedron 2013,
69, 4979−4989. (b) Wolckenhauer, S. A.; Devlin, A. S.; Du Bois, J.
Org. Lett. 2007, 9, 4363−4366. (c) Nishimura, T.; Takiguchi, Y.;
Hayashi, T. J. Am. Chem. Soc. 2012, 134, 9086−9089. (d) Moghaddam,
F. M.; Khodabakhshi, M. R.; Kiamehr, M.; Ghahremannejad, Z.
Tetrahedron Lett. 2013, 54, 2685−2689.
D
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