Enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization

Article abstract of DOI:10.1021/jacs.0c09638

Spirocyclic hexadienones with multiple stereogenic centers are frequently found in natural products but remain challenging targets to synthesize. Herein, we report the enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization reactions, affording spirocyclic hexadienone derivatives with up to three contiguous stereogenic centers in good yields (up to 90%) and excellent enantioselectivity (up to 99% ee). The high efficiency of this reaction is exemplified by the short reaction time (30 min), low catalyst loading (down to 0.2 mol %), and ability to perform the reaction on a gram-scale. The total syntheses of (+)-tatanan B and (+)-tatanan C were also realized using this Ir-catalyzed allylic dearomatization reaction as a key step.

Full text of DOI:10.1021/jacs.0c09638

pubs.acs.org/JACS
Article
Enantioselective Desymmetrization of Bisphenol Derivatives via Ir-
Catalyzed Allylic Dearomatization
Ye Wang, Wen-Yun Zhang, Jia-Hao Xie, Zong-Lun Yu, Jia-Hao Tan, Chao Zheng, Xue-Long Hou,
and Shu-Li You*
Cite This: https://dx.doi.org/10.1021/jacs.0c09638
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Spirocyclic hexadienones with multiple stereogenic
centers are frequently found in natural products but remain
challenging targets to synthesize. Herein, we report the
enantioselective desymmetrization of bisphenol derivatives via Ir-
catalyzed allylic dearomatization reactions, affording spirocyclic
hexadienone derivatives with up to three contiguous stereogenic
centers in good yields (up to 90%) and excellent enantioselectivity
(up to 99% ee). The high efficiency of this reaction is exemplified by the short reaction time (30 min), low catalyst loading (down to
0.2 mol %), and ability to perform the reaction on a gram-scale. The total syntheses of (+)-tatanan B and (+)-tatanan C were also
realized using this Ir-catalyzed allylic dearomatization reaction as a key step.
potent antitumor activity and acetylcholinesterase inhibition.4
INTRODUCTION
Spirocyclic hexadienones bearing multiple stereogenic centers
are key structural motifs found in numerous natural products
■
Spirotriscoumarins A and B show antiviral activity against the
influenza virus A.5 From a retrosynthetic viewpoint, a
(Figure 1). For example, caesalpin J1 and futoenone2 are
desymmetrization reaction of bisphenol derivatives could be
envisaged for the syntheses of these complex natural products.
Catalytic asymmetric dearomatization (CADA) reactions
have great potential for directly converting planar aromatic
starting materials into chiral spiro and fused polycyclic
compounds.6,7 Among the tremendous efforts devoted in this
area, transition-metal-catalyzed asymmetric allylic substitution
reactions have been applied as an efficient strategy in the
construction of spirocyclic hexadienones.8 In 2010, the
Hamada group described a Pd-catalyzed spirocyclization
forming the spiro[4.5]decadienone ring system.8a Shortly
after, our group reported an Ir-catalyzed asymmetric allylic
dearomatization of para-substituted phenols, providing cyclo-
hexadienones containing the spiro cyclopentane, piperidine, or
pyrrolidine ring structure in enantioenriched forms (Scheme
1(a)).8b In their elegant enantioselective synthesis of tatanans
B and C in 2013, Miller, Zakarian, and co-workers
Figure 1. Selected natural products containing spirocyclic hexadie-
none motifs and the synthetic strategy of desymmetrization of
bisphenols via dearomatization.
implemented a Pd-catalyzed allylic dearomatization of a
bisphenol derivative as a key step in forging the central
cyclohexane ring, with the concurrent establishment of three
stereogenic centers (Scheme 1(b)).9 However, under their
optimal conditions, a mixture of tatanans B and C and
biologically active compounds that have been extracted from
herbs used in traditional Chinese medicine. In particular,
spirocyclic hexadienones bearing an adjacent phenol sub-
stituent exist in complicated natural products, including
tatanans B and C, hopeanol, and spirotriscoumarins A and B.
These complex natural products display a wide range of
biological activities. Tatanans B and C, isolated from the
rhizomes of Acorus tatarinowii Schott by Yu and co-workers,3
are reported to display antidiabetic activity. Hopeanol displays
Received: September 8, 2020
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 1. Transition-Metal-Catalyzed Allylic
Dearomatization of Phenols
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
time
yield (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L2
L2
L2
5 min
5 min
5 min
45 min
45 min
3 h
24 h
24 h
12 h
12 h
82
74
68
72
63
62
26
<5
33
43
92 (−)
98 (−)
93 (−)
87 (−)
86 (−)
74 (+)
87 (+)
undesired isomers (6:3:2) were obtained. The authors also
reported that when using an Ir-catalyst derived from
[Ir(cod)Cl]2 and P(OPh)3, lower reactivity was observed
(up to 10% yield). Recently, we found that the enantioselective
desymmetrization of bisphenol-derived allylic carbonates could
be achieved via an Ir-catalyzed intramolecular asymmetric
allylic dearomatization reaction (Scheme 1(c)). In most cases,
the desired products bearing multiple stereogenic centers could
be afforded in high yields with excellent stereochemical control
within 30 min. Furthermore, this method was successfully
applied to the total syntheses of tatanans B and C, and the
details of this study are reported herein.
h
N.D.
d
9
10
11
91 (−)
91 (−)
97 (−)
e
f
g
5 min
86 (81 )
a
Reaction conditions: 1a (0.1 mmol), [Ir(cod)Cl]2 (2 mol %), ligand
(4 mol %), Cs2CO3 (1.0 equiv) in THF (1.0 mL) at 50 °C. Catalyst
was prepared via nPrNH2 activation.13 Yield determined by 1H NMR
b
c
using mesitylene as an internal standard. Determined by HPLC
analysis. The sign of the optical rotation is given in parentheses.
[Ir(dbcot)Cl]2 (2 mol %) was used. [Ir(dncot)Cl]2 (2 mol %) was
used. Independently prepared (S,S,Sa)-K1 (4 mol %) was used.
d
e
RESULTS AND DISCUSSION
f
■
g
h
Reaction Development. Using bisphenol-derived allylic
carbonate 1a as the model substrate, various parameters were
first evaluated in the Ir-catalyzed asymmetric allylic sub-
stitution reaction (Table 1).10,11 Treatment of 1a with an Ir-
catalyst derived from [Ir(cod)Cl]2 (2 mol %) and (S,S,Sa)-
Feringa ligand L1 (4 mol %), and Cs2CO3 (1 equiv) as the
base, in THF at 50 °C gave 2a in 82% NMR yield with 92% ee
in 5 min (entry 1). Next, the effect of a variety of chiral
phosphoramidites, the most frequently utilized chiral ligands in
Ir-catalyzed asymmetric allylic substitution reactions, was
evaluated (entries 2−8). It was found that the Alexakis ligand
(S,S,Sa)-L2 performed the best in terms of the enantioselec-
tivity of 2a (98% ee). Furthermore, different Ir-precursors and
prepreparation methods for the chiral Ir-catalysts were
screened, as these modifications have been shown to lead to
marked differences in catalyst stability and often influence the
overall reaction outcomes.12−14 Using [Ir(dbcot)Cl]2 or
[Ir(dncot)Cl]2 as the Ir-precursor led to decreased yields
and enantioselectivity of 2a (33−43% yields, 91% ee, entries 9
and 10).12 Instead of the in situ preparation of the Ir-catalyst
Isolated yield of a 0.2 mmol scale reaction. N.D.: not determined.
all cases, 2a was obtained as a single diastereoisomer. Further
screening of solvents and bases did not lead to better results
(see the SI for details).
After optimal reaction conditions had been established
(entry 11, Table 1), the substrate scope of this reaction was
investigated (Table 2). For the reactions of symmetric 2,6-
disubstituted bisphenol-derived substrates, variation of the
chain linkage (2a−2e) or the alkyl groups at the C2 and C6
positions (2f and 2g) were well accommodated. The
corresponding products were obtained in high yields (70−
88%) with excellent enantioselectivity (93−98% ee). The
absolute configuration of 2c (1S,3R) was unambiguously
determined by X-ray crystallographic analysis of an enantio-
pure sample. However, when an O-linked substrate was
employed, the target product was produced in only 7% yield
(see the SI for details). Notably, when using a 2,6-
unsubstituted phenol derivative, the allylic dearomatization
reaction afforded the desired product 2h in 69% yield and 95%
ee. Specifically, Friedel−Crafts-type allylation at the ortho-
position was not observed, presumably due to the strained
nature of the product. Contrastingly, the incorporation of two
fluorine atoms at the C2 and C6 positions led to a complex
13
n
via PrNH2 activation, the utilization of (S,S,Sa)-L2-derived
cyclometalated Ir-complex (S,S,Sa)-K1 improved the reaction
efficiency (entry 11).14 The NMR yield of 2a was increased to
86% with an isolated yield of 81% and comparable
enantioselectivity on a 0.2 mmol scale reaction. Notably, in
B
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
bis(1-naphthol) derivative, allowing facile access to 2r in 90%
yield with 93% ee. With a lower loading of the Ir-catalyst (0.2
mol %), a gram-scale synthesis of 2a (1.23 g) also gave
comparable results to the 0.2 mmol scale reaction in terms of
yield (76%) and enantiopurity (97% ee) within 1 h (eq 1),
which showed the robustness and practicality of this method.
Table 2. Substrate Scope
Synthetic Applications. A series of synthetic trans-
formations of spirocyclic hexadienone 2a were carried out
(Scheme 2). The O-methylation of 2a afforded ether 3 in 89%
a
Scheme 2. Transformations of 2a
a
Reaction conditions: (a) NaH (1.2 equiv), MeI (10 equiv), THF, 0
°C to rt, 30 min; (b) Pd/C, H2, ethyl acetate, rt, 10 min; (c) Ac2O
(1.5 equiv), pyridine (2 equiv), DCM, 0 °C to rt; (d) 9-BBN, THF,
rt, 10 min; (e) H2O2, NaOH, rt, 15 min.
a
Reaction conditions: 1 (0.2 mmol), (S,S,Sa)-K1 (4 mol %), Cs2CO3
b
(1.0 equiv) in THF (2.0 mL) at 50 °C. Combined yield and ratio of
two diastereoisomers.
yield. The terminal olefin group of 2a was readily reduced
under Pd/C and H2 conditions, leading to 4 in 50% yield.
Furthermore, the O-acylation of 2a brought about 5, which
was subsequently transformed into primary alcohol 6 in 77%
yield via hydroboration/oxidation of the terminal olefin
moiety. Notably, no erosion of the enantiopurity of the
compounds was observed.
The synthetic utility of this Ir-catalyzed allylic dearomatiza-
tion of phenols was further showcased by the total synthesis of
tatanans B and C (Scheme 3). Following the work of Miller,
Zakarian, and their co-workers,9 both enantiomers of function-
alized bisphenol-derived allylic carbonate 7 were synthesized.
Notably, a significant match/mismatch phenomenon was
identified between the enantiomers of 7 and the chiral Ir-
catalyst. Only (+)-7 was found to be reactive with (S,S,Sa)-K1,
leading to a pair of atropisomers (5:1) of dearomatized
product 8 in 79% combined yield, while (−)-7 remained
mainly intact under the same reaction conditions. After
subsequent O-methyl protection and hydrogenation of the
terminal olefin, an inseparable mixture of atropisomers
(+)-tatanan C and (+)-tatanan B (5:1) was obtained in a
total yield of 55% [three steps from (+)-7]. Notably, the
formation of other undesired isomers during the dearomatiza-
mixture, which could be caused by the reduced nucleophilicity
of the phenol ring (see the SI for details). When different alkyl
groups (iPr and Me) were introduced to the C2 and C6
positions at the same time, a pair of diastereoisomers of 2i
(1.5,1) was obtained in a combined yield of 70%, with both
major and minor isomers in excellent enantiopurity (94−96%
ee). To our delight, the reactions of more sterically demanding
substrates, containing C3 or C5 substituents at the phenol ring,
all proceeded smoothly with excellent atroposelectivity
i
(>95:5). Different alkyl (Me, Et, and Pr) or methoxyl groups
were well tolerated in these cases. All the desired products
(2j−2q) were obtained in good yields (69−87%) with high
enantioselectivity (92−99% ee). Notably, according to the X-
ray crystallographic analysis of 2q, the newly formed terminal
olefin and the C5 substituent on the original phenol ring were
located on the opposite side of the central six-membered ring,
avoiding steric congestion in the C−C bond-forming transition
state. Further efforts toward the synthesis of five- or seven-
membered spirocyclic hexadienones were not successful (see
the SI for details). Finally, the reaction could be expanded to a
C
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 3. Syntheses of (+)-Tatanan B and (+)-Tatanan C
CONCLUSIONS
■
In conclusion, we have applied our desymmetrization strategy
to the Ir-catalyzed intramolecular allylic dearomatization
reaction of phenols. Spirocyclic dienone derivatives with up
to three stereogenic centers were synthesized with high
efficiency (up to 90% yield and 99% ee within 30 min).
Notably, this method could be scaled up to a gram-scale in the
presence of only 0.2 mol % of the Ir-catalyst. By using this
reaction as a key step, the total syntheses of (+)-tatanan B and
(+)-tatanan C were accomplished with superior atroposelec-
tivity relative to that reported in the literature.9
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09638.
tion step described in previous work9 was avoided under our
conditions.
It is noteworthy that dearomatized product 2c can be
transformed into ring-opened compound trans-10 when
reacting under the standard allylic dearomatization conditions
for an extended period of time (45 min, Scheme 4a). We
Experimental procedures and analysis data for all new
compounds (PDF)
X-ray structure of 2c (CIF)
X-ray structure of 2q (CIF)
AUTHOR INFORMATION
Corresponding Author
Scheme 4. Ring-Opening/Rearomatization of 2c and
Synthetic Attempts toward (−)-Tatanan A
■
Shu-Li You − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China; orcid.org/0000-0003-4586-8359;
Email: slyou@sioc.ac.cn
Authors
Ye Wang − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
China
Wen-Yun Zhang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Jia-Hao Xie − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Zong-Lun Yu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Jia-Hao Tan − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Chao Zheng − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
speculated that the formation of trans-10 could be attributed to
a base-promoted ring-opening/rearomatization sequence. In
order to verify this hypothesis, 2c was treated with 1 equiv of
tBuOK. Indeed, compound 10 was obtained smoothly in a high
yield (84% for trans-10, trans-10/cis-10 = 9:1). Considering
the structural similarity between 10 and tatanan A,5 we further
tested the synthesis toward (−)-tatanan A from 8. Unfortu-
nately, the proposed transformation did not occur in the
t
n
presence of BuOK or BuLi at room temperature or 50 °C
(Scheme 4b).
D
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Reactions. Chimia 2018, 72, 610. (k) Zheng, C.; You, S.-L. Catalytic
Asymmetric Dearomatization (CADA) Reaction-Enabled Total
Synthesis of Indole-based Natural Products. Nat. Prod. Rep. 2019,
36, 1589. (l) Huck, C. J.; Sarlah, D. Shaping Molecular Landscapes:
Recent Advances, Opportunities, and Challenges in Dearomatization.
Chem. 2020, 6, 1589. For a book: (m) You, S.-L., Ed. Asymmetric
Dearomatization Reactions; Wiley-VCH: Weinheim, 2016.
Xue-Long Hou − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China; orcid.org/0000-0003-4396-3184
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09638
(7) For selected recent examples of catalytic asymmetric
dearomatization reaction of phenols and naphthols: (a) Liu, X.;
Wang, P.; Bai, L.; Li, D.; Wang, L.; Yang, D.; Wang, R. Construction
of Vicinal All-Carbon Quaternary Stereocenters Enabled by a
Catalytic Asymmetric Dearomatization Reaction of β-Naphthols
with 3-Bromooxindoles. ACS Catal. 2018, 8, 10888. (b) Wang, P.;
Wang, J.; Wang, L.; Li, D.; Wang, K.; Liu, Y.; Zhu, H.; Liu, X.; Yang,
D.; Wang, R. Asymmetric Dearomative Halogenation of β-Naphthols:
the Axial Chirality Transfer Reaction. Adv. Synth. Catal. 2018, 360,
401. (c) Wang, L.; Yang, D.; Li, D.; Zhu, H.; Wang, P.; Liu, X.; Bai,
L.; Wang, R. Diversiform Reactivity of Naphthols in Asymmetric
Dearomatization or O-Alkylation Reactions with Aziridines. Adv.
Synth. Catal. 2018, 360, 4491. (d) Han, L.; Wang, H.; Luan, X.
Pd(II)-Catalyzed [3 + 2] Spiroannulation of α-Aryl-β-naphthols with
Alkynes via a C−H Activation/Dearomatization Approach. Org.
Chem. Front. 2018, 5, 2453. (e) Wang, J.-J.; Yang, H.; Gou, B.-B.;
Zhou, L.; Chen, J. Enantioselective Organocatalytic Sulfenylation of
β-Naphthols. J. Org. Chem. 2018, 83, 4730. (f) Xia, Z.-L.; Zheng, C.;
Xu, R.-Q.; You, S.-L. Chiral Phosphoric Acid Catalyzed Aminative
Dearomatization of α-Naphthols/Michael Addition Sequence. Nat.
Commun. 2019, 10, 3150. (g) Tang, S.-B.; Tu, H.-F.; Zhang, X.; You,
S.-L. Rhodium-Catalyzed Asymmetric Allylic Dearomatization of β-
Naphthols: Enantioselective Control of Prochiral Nucleophiles. Org.
Lett. 2019, 21, 6130. (h) Xu, R.-Q.; Yang, P.; Zheng, C.; You, S.-L.
Pd-Catalyzed Asymmetric Intramolecular Arylative Dearomatization
of para-Aminophenols. Chin. J. Chem. 2020, 38, 683−689.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key R&D Program of China
(2016YFA0202900), NSFC (21532010, 21772219,
21821002), Science and Technology Commission of Shanghai
Municipality (18QA1404900), Chinese Academy of Sciences
(XDB20000000, QYZDY-SSW-SLH012), and the Youth
Innovation Promotion Association (2017302) of CAS for
generous financial support. S.-L.Y. thanks the support from the
Tencent Foundation through the XPLORER PRIZE. Dr.
James A. Rossi-Ashton (University of York) is acknowledged
for helpful discussions.
REFERENCES
■
(1) (a) Shimokawa, T.; Kinjo, J.-E.; Yamahara, J.; Yamasaki, M.;
Nohara, T. Two novel aromatic compounds from Caesalpinia sappan.
Chem. Pharm. Bull. 1985, 33, 3545. (b) Miyahara, K.; Kawasaki, T.;
Kinjo, J.-E.; Shimokawa, T.; Yamahara, J.; Yamasaki, M.; Harano, K.;
Nohara, T. The X-ray analysis of caesalpin J from sappan lignum.
Chem. Pharm. Bull. 1986, 34, 4166.
(8) (a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu,
M.; Hamada, Y. Novel Method for Synthesizing Spiro[4.5]-
cyclohexadienones through a Pd-Catalyzed Intramolecular ipso-
Friedel−Crafts Allylic Alkylation of Phenols. Org. Lett. 2010, 12,
5020. (b) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.;
You, S.-L. Iridium-catalyzed intramolecular asymmetric allylic
dearomatization of phenols. Angew. Chem., Int. Ed. 2011, 50, 4455.
(9) Xiao, Q.; Jackson, J. J.; Basak, A.; Bowler, J. M.; Miller, B. G.;
Zakarian, A. Enantioselective synthesis of tatanans A−C and
reinvestigation of their glucokinase-activating properties. Nat. Chem.
2013, 5, 410.
(2) Ogiso, A.; Kurabayashi, M.; Mishima, H.; Woods, M. C. The
structure of futoenone, a novel spiro-cyclohexadienone derivative.
Tetrahedron Lett. 1968, 9, 2003.
(3) Ni, G.; Shen, Z.-F.; Lu, Y.; Wang, Y.-H.; Tang, Y.-B.; Chen, R.-
Y.; Hao, Z.-Y.; Yu, D.-Q. Glucokinase-activating sesquinlignans from
the rhizomes of acorus tatarinowii schott. J. Org. Chem. 2011, 76,
2056.
(4) Ge, H. M.; Xu, C.; Wang, X. T.; Huang, B.; Tan, R. X.
Hopeanol: a potent cytotoxin with a novel skeleton from Hopea
exalata. Eur. J. Org. Chem. 2006, 2006, 5551.
(5) Tang, Z.-H.; Liu, Y.-B.; Ma, S.-G.; Li, L.; Li, Y.; Jiang, J.-D.; Qu,
J.; Yu, S.-S. Antiviral spirotriscoumarins A and B: two pairs of
oligomeric coumarin enantiomers with a spirodienone-sesquiterpene
skeleton from Toddalia asiatica. Org. Lett. 2016, 18, 5146.
(10) For reviews on Ir-catalyzed asymmetric allylic substitution
reactions: (a) Takeuchi, R.; Kezuka, S. Iridium-catalyzed formation of
carbon-carbon and carbon-heteroatom bonds. Synthesis 2006, 2006,
3349. (b) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.;
̈
(6) For selected reviews on dearomatization reactions: (a) Roche, S.
P.; Porco, J. A., Jr. Dearomatization Strategies in the Synthesis of
Complex Natural Products. Angew. Chem., Int. Ed. 2011, 50, 4068.
(b) Zhuo, C.-X.; Zhang, W.; You, S.-L. Catalytic asymmetric
dearomatization reactions. Angew. Chem., Int. Ed. 2012, 51, 12662.
(c) Ding, Q.; Ye, Y.; Fan, R. Recent advances in phenol
dearomatization and its application in complex syntheses. Synthesis
2012, 45, 1. (d) Wu, W.-T.; Zhang, L.; You, S.-L. Catalytic
asymmetric dearomatization (CADA) reactions of phenol and aniline
derivatives. Chem. Soc. Rev. 2016, 45, 1570. (e) Sun, W.; Li, G.; Hong,
L.; Wang, R. Asymmetric dearomatization of phenols. Org. Biomol.
Chem. 2016, 14, 2164. (f) Zheng, C.; You, S.-L. Catalytic asymmetric
dearomatization by transition-metal catalysis: a method for trans-
formations of aromatic compounds. Chem. 2016, 1, 830. (g) Chen, J.-
B.; Jia, Y.-X. Recent Progress in Transition-Metal-Catalyzed
Enantioselective Indole Functionalizations. Org. Biomol. Chem.
2017, 15, 3550. (h) Bariwal, J.; Voskressensky, L. G.; Van der
Eycken, E. V. Recent Advances in Spirocyclization of Indole
Derivatives. Chem. Soc. Rev. 2018, 47, 3831. (i) Wertjes, W. C.;
Southgate, E. H.; Sarlah, D. Recent Advances in Chemical
Dearomatization of Nonactivated Arenes. Chem. Soc. Rev. 2018, 47,
7996. (j) An, J.; Bandini, M. Gold-catalyzed Dearomatization
Weihofen, R. Iridium-catalysed asymmetricallylic substitutions. Chem.
Commun. 2007, 675. (c) Hartwig, J. F.; Stanley, L. M. Mechanistically
driven development of iridium catalysts for asymmetric allylic
substitution. Acc. Chem. Res. 2010, 43, 1461. (d) Hartwig, J. F.;
Pouy, M. J. Iridium-catalyzed allylic substitution. Top. Organomet.
Chem. 2011, 34, 169. (e) Liu, W.-B.; Xia, J.-B.; You, S.-L. Iridium-
catalyzed asymmetric allylic substitutions. Top. Organomet. Chem.
2011, 38, 155. (f) Tosatti, P.; Nelson, A.; Marsden, S. P. Recent
advances and applications of iridium-catalysed asymmetric allylic
substitution. Org. Biomol. Chem. 2012, 10, 3147. (g) Helmchen, G. Ir-
catalyzed asymmetric allylic substitution reactions-fundamentals and
applications in natural products synthesis. In Molecular Catalysts;
Gade, L. H.; Hofmann, P., Eds.; Wiley-VCH: Weinheim, 2014; pp
235−254. (h) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Iridium-
catalyzed diastereo-, enantio-, and regioselective allylic alkylation with
prochiral enolates. ACS Catal. 2016, 6, 6207. (i) Qu, J.; Helmchen, G.
Applications of Iridium-catalyzed asymmetric allylic substitution
reactions in target-oriented synthesis. Acc. Chem. Res. 2017, 50,
2539. (j) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.;
You, S.-L. Iridium-catalyzed asymmetric allylic substitution reactions.
̈
Chem. Rev. 2019, 119, 1855−1969. (k) Rossler, S. L.; Petrone, D. A.;
E
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Carreira, E. M. Iridium-catalyzed asymmetric synthesis of functionally
rich molecules enabled by (phosphoramidite,olefin) ligands. Acc.
Chem. Res. 2019, 52, 2657−2672.
disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene
and Ir catalysis. Nat. Catal. 2020, 3, 48. (w) Tu, H.-F.; Yang, P.; Lin,
Z.-H.; Zheng, C.; You, S.-L. Time-dependent Enantiodivergent
Synthesis via Sequential Kinetic Resolution. Nat. Chem. 2020, 12,
838.
(11) For selected recent examples on Ir-catalyzed asymmetric allylic
substitution reactions: (a) Jiang, S.-Z.; Zeng, X.-Y.; Liang, X.; Lei, T.;
Wei, K.; Yang, Y.-R. Iridium-catalyzed enantioselective indole
cyclization: application to the total synthesis and absolute stereo-
chemical assignment of (−)-aspidophylline A. Angew. Chem., Int. Ed.
2016, 55, 4044. (b) Liu, J.; Cao, C.-G.; Sun, H.-B.; Zhang, X.; Niu, D.
Catalytic asymmetric umpolung allylation of imines. J. Am. Chem. Soc.
2016, 138, 13103. (c) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A.
Y.; Tran, K.; Stoltz, B. M. Enantioselective γ-alkylation of α,β-
unsaturated malonates and ketoesters by a sequential Ir-catalyzed
asymmetric allylic alkylation/Cope rearrangement. J. Am. Chem. Soc.
2016, 138, 5234. (d) Zhan, M.; Li, R.-Z.; Mou, Z.-D.; Cao, C.-G.; Liu,
J.; Chen, Y.-W.; Niu, D. Silver-assisted, iridium-catalyzed allylation of
bis[(pinacolato)boryl]methane allows the synthesis of enantioen-
riched homoallylic organoboronic esters. ACS Catal. 2016, 6, 3381.
(e) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Enantioselective
iridium-catalyzed allylic alkylation reactions of masked acyl cyanide
equivalents. Org. Lett. 2017, 19, 1527. (f) Chen, J.; Zhao, X.; Dan, W.
Diasteroselective and enantioselective Ir-catalyzed allylic substitutions
of 1-substituted 1-fluoro-1-(arenesulfonyl)methylene derivatives. J.
Org. Chem. 2017, 82, 10693. (g) Jiang, X.; Beiger, J. J.; Hartwig, J. F.
Stereodivergent allylic substitutions with aryl acetic acid esters by
synergistic iridium and Lewis base catalysis. J. Am. Chem. Soc. 2017,
139, 87. (h) Shen, D.; Chen, Q.; Yan, P.; Zeng, X.; Zhong, G.
Enantioselective dearomatization of naphthol derivatives with allylic
alcohols by cooperative iridium and Brønsted acid catalysis. Angew.
Chem., Int. Ed. 2017, 56, 3242. (i) Shockley, S. E.; Hethcox, J. C.;
Stoltz, B. M. Enantioselective synthesis of acyclic α-quaternary
carboxylic acid derivatives through iridium-catalyzed allylic alkylation.
Angew. Chem., Int. Ed. 2017, 56, 11545. (j) Wang, Y.; Zheng, C.; You,
S.-L. Iridium-catalyzed asymmetric allylic dearomatization by a
desymmetrization strategy. Angew. Chem., Int. Ed. 2017, 56, 15093.
(k) Butcher, T. W.; Hartwig, J. F. Enantioselective synthesis of tertiary
allylic fluorides by iridium-catalyzed allylic fluoroalkylation. Angew.
Chem., Int. Ed. 2018, 57, 13125. (l) Hethcox, J. C.; Shockley, S. E.;
Stoltz, B. M. Enantioselective synthesis of vicinal All-carbon
quaternary centers via iridium-catalyzed allylic alkylation. Angew.
Chem., Int. Ed. 2018, 57, 8664. (m) Jiang, X.; Boehm, P.; Hartwig, J.
F. Stereodivergent allylation of azaaryl acetamides and acetates by
synergistic iridium and copper catalysis. J. Am. Chem. Soc. 2018, 140,
1239. (n) Wei, L.; Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J.
Stereodivergent synthesis of α,α-disubstituted α-amino acids via
synergistic Cu/Ir catalysis. J. Am. Chem. Soc. 2018, 140, 1508.
(o) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. Ir/Cu dual catalysis:
enantio- and diastereodivergent access to α,α-disubstituted α-amino
acids bearing vicinal stereocenters. J. Am. Chem. Soc. 2018, 140, 2080.
(p) He, Z.-T.; Hartwig, J. F. Enantioselective α-functionalizations of
ketones via allylic substitution of silyl enol ethers. Nat. Chem. 2019,
11, 177−183. (q) Wang, Y.; Zhang, W.-Y.; You, S.-L. Ketones and
aldehydes as O-nucleophiles in iridium-catalyzed intramolecular
asymmetric allylic substitution reaction. J. Am. Chem. Soc. 2019,
141, 2228. (r) Sarkar, R.; Mukherjee, S. Enantioselective direct
vinylogous allylic alkylation of 4-methylquinolones under iridium
catalysis. Org. Lett. 2019, 21, 5315. (s) Pearson, C. M.; Fyfe, J. W. B.;
Snaddon, T. N. A Regio- and Stereodivergent Synthesis of
Homoallylic Amines by a One-Pot Cooperative-Catalysis-Based
Allylic Alkylation/Hofmann Rearrangement Strategy. Angew. Chem.,
Int. Ed. 2019, 58, 10521. (t) Brito, G. A.; Jung, W.-O.; Yoo, M.;
Krische, M. J. Enantioselective Iridium-Catalyzed Allylation of
Acetylenic Ketones via 2-Propanol-Mediated Reductive Coupling of
Allyl Acetate: C14-C23 of Pladienolide D. Angew. Chem., Int. Ed.
2019, 58, 18803. (u) Liu, X.-J.; Jin, S.; Zhang, W.-Y.; Liu, Q.-Q.;
Zheng, C.; You, S.-L. Sequence-Dependent Stereodivergent Allylic
Alkylation/Fluorination of Acyclic Ketones. Angew. Chem., Int. Ed.
2020, 59, 2039. (v) Singha, S.; Serrano, E.; Mondal, S.; Daniliuc, C.
G.; Glorius, F. Diastereodivergent synthesis of enantioenriched α,β-
(12) dbcot: (a) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.;
Helmchen, G. Iridium-catalyzed asymmetric allylic substitution-very
high regioselectivity and air stability with a catalyst derived from
dibenzo[a,e]cyclooctatetraene and a phosphoramidite. Angew. Chem.,
̈
Int. Ed. 2008, 47, 7652. (b) Gartner, M.; Mader, S.; Seehafer, K.;
Helmchen, G. Enantio- and regioselective iridium-catalyzed allylic
hydroxylation. J. Am. Chem. Soc. 2011, 133, 2072. (c) Raskatov, J. A.;
̈
Jakel, M.; Straub, B. F.; Rominger, F.; Helmchen, G. Iridium-catalyzed
allylic substitutions with cyclometalated phosphoramidite complexes
bearing a dibenzocyclooctatetraene ligand: preparation of (π-allyl)Ir
complexes and computational and NMR spectroscopic studies. Chem.
- Eur. J. 2012, 18, 14314. dncot: (d) Ye, K.-Y.; Zhao, Z.-A.; Lai, Z.-
W.; Dai, L.-X.; You, S.-L. Highly regioselective allylic substitution
reactions catalyzed by an air-stable (π-allyl)iridium complex derived
from dinaphthocyclooctatetraene and a phosphoramidite ligand.
Synthesis 2013, 45, 2109.
n
(13) For a catalyst prepared via PrNH2 activation, see: Shu, C.;
Leitner, A.; Hartwig, J. F. Enantioselective allylation of aromatic
amines after in situ generation of an activated cyclometalated iridium
catalyst. Angew. Chem., Int. Ed. 2004, 43, 4797.
(14) For using cyclometalated Ir-complex as a catalyst, see:
(a) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. The allyl
intermediate in regioselective and enantioselective iridium-catalyzed
asymmetric allylic substitution reactions. J. Am. Chem. Soc. 2009, 131,
̈
7228. (b) Spiess, S.; Raskatov, J. A.; Gnamm, C.; Brodner, K.;
Helmchen, G. Ir-catalyzed asymmetric allylic substitutions with
(phosphoramidite)Ir complexes-resting states, synthesis, and charac-
terization of catalytically active (π-allyl)Ir complexes. Chem. - Eur. J.
̈
2009, 15, 11087. (c) Raskatov, J. A.; Spiess, S.; Gnamm, C.; Brodner,
K.; Rominger, F.; Helmchen, G. Ir-catalysed asymmetric allylic
substitutions with cyclometalated (phosphoramidite)Ir complexes-
resting States, catalytically active (π-allyl)Ir complexes and computa-
tional exploration. Chem. - Eur. J. 2010, 16, 6601. (d) Raskatov, J. A.;
̈
Jakel, M.; Straub, B. F.; Rominger, F.; Helmchen, G. Iridium-catalyzed
allylic substitutions with cyclometalated phosphoramidite complexes
bearing a dibenzocyclooctatetraene ligand: preparation of (π-allyl)Ir
complexes and computational and NMR spectroscopic studies. Chem.
- Eur. J. 2012, 18, 14314.
F
https://dx.doi.org/10.1021/jacs.0c09638
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX