ARTICLE

DOI: 10.1038/s41467-018-02952-3 OPEN

Enantioselective [3+3] atroposelective annulation

catalyzed by N-heterocyclic carbenes
Changgui Zhao1, Donghui Guo1, Kristin Munkerup 2, Kuo-Wei Huang 2, Fangyi Li1 & Jian Wang 1

Axially chiral molecules are among the most valuable substrates in organic synthesis. They
are typically used as chiral ligands or catalysts in asymmetric reactions. Recent progress for
1234567890():,;

the construction of these chiral molecules is mainly focused on the transition-metal-catalyzed

transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic
carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC
precatalyst, base, Lewis acid and oxidant, a catalytic C–C bond formation occurs, providing
axially chiral α-pyrone−aryls in moderate to good yields and with high enantioselectivities.
Control experiments indicated that alkynyl acyl azoliums, acting as active intermediates, are
employed to atroposelectively assemble chiral biaryls and such a methodology may be
creatively applied to other useful NHC-catalyzed asymmetric transformations.

1 Schoolof Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Bioorganic
Phosphorous Chemistry and Chemical Biology (Ministry of Education), Tsinghua University Beijing, 100084 Beijing, China. 2 Division of Chemical and Life
Sciences & Engineering and KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia.
Correspondence and requests for materials should be addressed to J.W. (email: [email protected])

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3

A
xial chirality, a key stereogenic element, is widely observed (e.g., Maxi-K channel openers, (R)-Streptonigrin; Fig. 1)4. Among
in natural products1–3 and often determines the phar- them, axially chiral biaryls are recognized as one of fundamental
macological properties in biologically active molecules entities of chiral ligands, catalysts, and other useful reagents5.

a Chiral axial molecule

O
MeO
Cl
N COOH
H2N N
OMe
O
F3C * CO2Et H2N Me
* OH
N O
H
(R)-Streptonigrin OMe
Maxi-K channel openers (antitumor agent) OMe

b
Previous work: Reaction type: (Ref. 10)
Esterification
NHC Claisen rearrangement
Cycloaddition
O
cat. NHC
Various
products
w/o [O]

O H Unsaturated acyl
azolium

c
This design: [3+3] atroposelective annulation

R′
O

R R″ R′
R″ R′ O
cat. NHC NHC O
R″ R
[O] O Direct
[3+3]
Alkynyl acyl R O O
O H azolium R
Up to 94% ee

Indirect

NHC [O]
R′′ R′
R′ O O
*
Central to axial

R O O
R′′ R
Fig. 1 Representative molecules and synthetic protocols. a Two representative axially chiral molecules. b NHC-catalyzed transformations via the use of
unsaturated acyl azolium intermediate. c Our synthetic proposal via [3+3] atroposelective annulation. NHCs react with ynals to generate chiral alkynyl acyl
azolium intermediates to further react with cyclic 1,3-diones

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NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3 ARTICLE

Table 1 Optimization of the reaction conditionsa

O
OR

Me + 2a: R = Me
1a O 2 2b: R = Et
Me
O H 2c: R = Bn

15 mol% cat. A 200 mol% nBu4NOAc

150 mol% DQ 20 mol% Mg(OTf)2
Toluene, RT

Me Me

OR
OR OR
O O O O
+ + OR + O

O
Me Me Me
O O O O O O Me
Me Me Me O
3 4 5 Me 6

Entry Deviation from standard conditionsa Yield 3 (%)b er 3 (%)c Yield 4 (%)b Yield 5 (%)b Yield 6 (%)b
1 None 70d 90:10 <5 <5 <5
2 No cat. A 0 − 0 0 0
3 B instead of A <5 − <5 <5 <5
4 C instead of A <5 − <5 <5 60
5 D instead of A 44 −77:23 <5 30 20
6 No Mg(OTf)2 60 90:10 <5 <5 18
7 LiCl instead of Mg(OTf)2 58 90:10 <5 <5 <10
8 In(OTf)3 instead of Mg(OTf)2 63 90:10 <5 <5 <10
9 Sc(OTf)3 instead of Mg(OTf)2 60 90:10 <5 <5 <10
10 Zn(OTf)2 instead of Mg(OTf)2 61 90:10 <5 <5 <10
11 CHCl3 as solvent 40 80:20 <5 15 23
12 THF as solvent 54 85:15 <5 <10 19
13 Dioxane as solvent 20 − <5 <5 50
14 No nBu4NOAc 0 − 0 0 0
15 DIPEA as base 45 80:20 <5 17 20
16 Cs2CO3 as base 40 75:25 <5 20 22
17 KOtBu as base <10 − <5 <5 <5
18 F instead of E <5 − 76 <5 <5
19 G instead of E <5 − 70 <5 <5
20 10 mol% A 69e 91:9 <5 <5 13
21 2b instead of 2a 60f 75:25 <5 <5 18
22 2c instead of 2a 60g 71.5:28.5 <5 <5 <5
aStandard conditions: 1a (0.11 mmol), 2a (0.10 mmol, R = Me), nBu4NOAc (0.2 mmol), oxidant E (0.15 mmol), Mg(OTf)2 (20 mol%), cat. A (15 mol%), toluene (2.0 mL), room temperature, N2, 24 h
bIsolated yield
cDetermined by chiral HPLC
d3aa as major product
e48 h
f3ab as major product
g3ac as major product

NHC: Oxidant:
O Me O t
Bu t
Bu
Me
N N Bn N O O E
N
N N Br
BF4 t t
Ar BF4 Bu Bu
N
A: Ar = 2,4,6-(Br)3-C6H2
Br F
B: Ar = Mes Br N
C: Ar = C6F5 D
MnO2 G

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3

O
OMe 15 mol% cat. A OMe
150 mol% DQ O

R +
n
O 200 mol% Bu4NOAc
R R
20 mol% Mg(OTf)2
O H O O
Toluene, RT R
1b–g 2a 3ba–ga

OMe OMe OMe

O O O

Et
O O O O O O
Et
3ba 3ca 3da
61%, 85:15 er 69%, 88:12 er 68%, 90:10 er

OMe OMe OMe

O O O

() Pr ( )
i
4 2
O O O O O O
() iPr ()
4 2
3ea 3fa 3ga
72%, 93:7 er 71%, 94:6 er 70%, 95:5 er

Fig. 2 Scope of cyclic 1,3-diones. Reaction conditions: a mixture of 1b–g (0.11 mmol), 2a (0.10 mmol), nBu4NOAc (0.2 mmol), oxidant E (0.15 mmol), Mg
(OTf)2 (20 mol%), and cat. A (15 mol%) in toluene (2.0 mL) was stirred at room temperature under N2 for 24 h

CN CN
ΔG ≠rot(85 °C) = 119.7 KJ mol–1
t1/2(85 °C) = 7.41 h
OMe MeO
O O
Toluene, 85 °C
i () ()
Pr 2
i
Pr 2
O O O O
() ()
i
Pr 2 i
Pr 2
3gh
Kinetic line: ((In(%t–50)/(%0–50)) vs. time (minutes)
0 200 400 600 800 1000 1200 1400
0.0

–0.5

–1.0

–1.5

y = –0.00155813x + 0.01909193
–2.0
R 2 = 0.99929274

Fig. 3 Determination of the enantiomerization barrier. Reaction conditions: 3 mg of enantio-enriched 3gh were refluxed in 15 mL of toluene at 85 °C.
Samples of 7 µL of this solution were injected on Chiralpak IC (heptane/iPrOH = 80/20, 1 mL min−1, UV detection at 254 nm) to monitor the percentage
decrease of the second eluted enantiomer over time

Over the past few decades, numerous efforts have been devoted to systems26. Later on, the direct asymmetric cross-coupling of two
constructing these axially chiral biaryls, but successful examples aryls has proven to be a feasible method27–33. However, the poor
are relatively scarce in contrast to their great potential in various enantiocontrol and low coupling efficiency greatly limit their
applications6–25. In 1984, Meyers and coworkers reported the first applications. More recently, an elegant route to synthesize axially
example of central-to-axial chirality conversion in biarylic chiral biaryls was demonstrated via an aromatic ring

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NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3 ARTICLE

4 R1
R1 3
O 2
15 mol% cat. A R2 OMe
R2 OMe 150 mol% DQ O
()
i
Pr 2 + 200 mol% nBu4NOAc
O
i
() 20 mol% Mg(OTf)2 i ()
Pr 2 Pr 2
Toluene, RT O O
O H i
()
Pr 2

1g 2d–t 3gd–gt

OMe Ph
4 4
Ph
3
OMe OMe OMe
O O O

() () i
()
i i Pr
Pr 2 Pr 2 2
O O O O O O
() () i
()
i i Pr 2
Pr 2 Pr 2

3gd 3ge 3gf

57%, 90:10 er 76%, 93:7 er 74%, 95:5 er

CN X X 6
4 5
OMe
O
OMe OMe
O O
i ()
() () Pr 2
i i O O
Pr 2 Pr 2 ()
O O O O i
Pr 2
i () i
()
Pr 2 Pr 2
X = Ph, 68%, 96:4 er (3gj)
3gg X = CN, 70%, 95.5:4.5 er (3gh) X = Et, 66%, 95:5 er (3gk)
60%, 92.5:7.5 er X = Ph, 71%, 93:7 er (3gi) X = CN, 72%, 96.5:3.5 er (3gl)

Cl F

6 6
6
OMe OMe
O O
OMe
O

i () i ()
Pr 2 Pr 2
i () O O O O
Pr 2 () i
()
O O i
Pr 2 Pr 2
i ()
Pr 2
3gm 3gn 3go
70%, 95:5 er 71%, 95:5 er 67%, 94:6 er

4
7 5 1 5 1
X OMe Ph OMe OMe
O
O O

i ()
Pr 2 i
() ()
O O Pr 2 i
Pr 2
i () O O O O
Pr 2
i () ()
Pr 2 i
Pr 2
X = Ph, 72%, 96:4 er (3gp)
X = CN, 60%, 93:7 er (3gq) 3gs 3gt
X = Et, 71%, 97:3 er (3gr) 60%, 96:4 er 61%, 92:8 er

Fig. 4 Scope of ynals. Reaction conditions: a mixture of 1g (0.11 mmol), 2d−t (0.10 mmol), nBu4NOAc (0.2 mmol), oxidant E (0.15 mmol), Mg(OTf)2 (20
mol%), and cat. A (15 mol%) in toluene (2.0 mL) was stirred at room temperature under N2 for 24 h

formation34,35. Despite these advances, this field is still in its Herein, we report a highly enantioselective NHC-catalyzed [3+3]
infancy and efficient synthetic routes still need to be identified. atroposelective annulation of ynals with cyclic 1,3-diones44, thus
Chiral N-heterocyclic carbenes (NHCs) as versatile catalysts paving a route toward axially chiral biaryls. It is noteworthy that
have been well studied in last few decades36–43, but most of the the NHC-bounded alkynyl acyl azoliums as active intermediates
reports are only focused on the assembly of central chirality. are generated from ynals in contrast to unsaturated acyl azoliums

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3

R1
R1
NEt2 OMe
OMe O
O Toluene
+
RT
Me R2
2 NEt2
R R2
O O
R2 Me
8 9 10

Ph F

OMe OMe
O O OMe
O

i 2
NEt2 Pr
NEt2 i
Pr 2
Me i NEt2
Pr 2 Me
i 2 Me
Pr
10a 10b 10c
52%, 93:7 er 52%, 95:5 er 64%, 93:7 er
NC

OMe NC OMe Ph OMe

O O O

i 2 i
4 Pr NEt2 Pr 2
NEt2 NEt2
i 2 Me i
4 Me Pr Pr 2 Me
10d 10e 10f
78%, 96:4 er 80%, 90.5:9.5 er 48%, 95:5 er

Fig. 5 Scope of Diels–Alder reaction. Reaction conditions: a mixture of 8 (0.1 mmol), 9 (1.0 mmol), in toluene (2.0 mL) was stirred at room temperature for
72 h

(Fig. 1) made from ynals via an internal redox reaction, which Substrate scope. With the most efficient catalytic conditions in
have been intensively investigated in organic reactions, such as hand, we next examined the substrate scope (Fig. 2). The R
esterification, Claisen rearrangement, cycloaddition, etc45–55. Our substituent of cyclic 1,3-dione 1 was investigated firstly. Sub-
mechanistic studies have completely ruled out the route, invol- strates equipped with cyclic substituents (e.g., four- and six-
ving the formation of unsaturated acyl azolium followed by a membered rings) on cyclic 1,3-dione scaffold gave the corre-
central-to-axial chiral conversion. sponding products 3ba and 3ca in good yields but only with
moderate er. In addition, reactions for cyclic 1,3-dione substrates
bearing alkyl chains in different length proceeded smoothly under
Results standard reaction conditions (3da−fa). While substrate cyclic 1,3-
Reaction optimization. We began our study with the model dione (2g) bearing a long alkyl chain was used, a good yield and
reaction of 5,5-dimethylcyclohexane-1,3-dione (1a) and 3-(2- high er value were achieved (Fig. 2, 3ga, 70% yield and 95:5 er).
methoxynaphthalen-1-yl)propiolaldehyde (2a). Key results are To address the stability of the products, we conducted several
briefly summarized in Table 1. Using nBu4NOAc as the base, Mg experiments and the related results verified that the rotation
(OTf)2 as the additive56,57, E as the oxidant, and toluene as the barrier of the chiral axis was high enough to prevent the
solvent, a number of chiral NHC catalysts A−D58–62 were initially racemization of product 3gh during the reaction or its
screened. No desired product was detected in the presence of purification: with ΔG≠rot = 119.7 KJ mol−1 at 85 °C, the half-life
widely used NHC catalysts B and C. Pleasingly, chiral triazolium of rotation is 7.41 h at 85 °C (Fig. 3; for details, see Supplementary
NHC precatalyst with N-2,4,6-(Br)3C6H2 substituent (Table 1, D) Discussion).
provided axially chiral 3aa with a moderate er, but albeit in a low Further investigation on the scope of ynals was conducted
yield (Table 1, entry 5). Along with the formation of 3aa, (Fig. 4). The steric and electronic effects on the aromatic ring of
byproducts of 4aa, 5aa, and 6aa, which resulted from different ynals were evaluated by the variation of substituent patterns.
unexpected intermediates and reaction pathways, were produced When examined substrates bear electron-withdrawing or
simultaneously. Given the significance of reaction conditions to electron-donating groups at 3-, 4-, 6-, 7-, or 8-substituted
the success of a focused catalytic transformation, we carried out a positions on naphthalene rings, moderate to good yields and
comprehensive optimization of reaction parameters. As outlined high er values were regularly obtained (3gd−gr). When a
in Table 1, addition of 1a and 2a to a mixture of catalyst A (15 substituted phenyl ring replaced the naphthalene ring in ynals,
mol%), oxidant E (1.5 equiv.), and nBu4NOAc (2.0 equiv.) with high er could still be achieved (3gs and 3gt). The absolute
Mg(OTf)2 (20 mol%), provided 3aa in 70% yield and 91:9 er configuration of 3au was determined to be (S) by X-ray
(Table 1, entry 1). crystallography, and other products were assigned by analogy.

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NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3 ARTICLE

Breslow intermediate I then undergoes oxidation to generate the

Product firstly proposed intermediate, alkynyl acyl azolium II, which
3
O subsequently reacts with cyclic 1,3-dione 1 to form intermediate
OMe
H 2 III. III undergoes Michael addition to the alkynyl azolium moeity
Ar OMe
N N Mg+
O
NHC to form the allenolate intermediate and after subsequent proton
Ar
N N N transfer from the 1,3-dione to the allene, intermediate IV is
O
O O
R
R
N OMe
reached. Next O–C bond is formed to create V and the NHC can
be released and finally generated product 3. As the generation of
O
V OH I [O]
NHC-bounded unsaturated acyl azolium intermediates from
ynals has been reported by Zeitler45, Lupton46,47, Bode48–51,
Path A Ar
Scheidt52, and others53–55, an alternative pathway may involve
Ar
OMe
O Ar = 2,4,6-(Br)3C6H2
N N the direct annulation of NHC-bounded unsaturated acyl azolium
N N
O
N
OMe intermediate VI with cyclic 1,3-dione 1 leading to byproduct 4.
Mg+ O
O
N
O O
R
II
However, as highlighted in Fig. 7 (Eq. (1)), the oxidative dehy-
R
IV drogenation of 4aa to 3aa does not proceed in the presence of
H+
Transfer
1
O oxidant alone or under standard reaction conditions. As such, 3aa
Ar
O
cannot be generated from the α,β-unsaturated acyl azolium
N N
R
R
intermediate.
N OMe Base
O
O +
O During the process of optimization, byproduct 5 was found
Mg Ar
N N clearly and confirmed by NMR spectra, presumably generated

Path B
O

R
R
N OMe through the Knoevenagel condensation of 3 with 1.0 equivalent of
O O
Allenolate O Mg+ [O] 1. To examine this hypothesis, a controlled experiment was
Product O
R
carried out (Fig. 7, Eq. (3)). Surprisingly, the er value of 7 is not
3 III R consistent with the er value of 3gs (59:41 er vs. 96:4 er) and this
observation indicates that an alternative pathway may be
operating (Fig. 6, Path C). Building upon intermediate IV, we
1
Ar suggest that the Knoevenagel condensation process generates
N N
[O] O
OMe intermediate VI which subsequently leads to 5 via annulation.
N

Central-to-axial
* O
O OMe Moreover, there is an interesting observation found during the
chirality transfer R
O O NHC
optimization of reaction conditions with Lewis acids (Table 1,
? R
Byproduct 4 VI entry 6). When Mg(OTf)2 is omitted from the reaction condition,
the yield of byproduct 6 increases to 18%, which can be explained
by the fact that 1 can now do a direct ‘O’ attack to the alkynyl on
intermediate II, because the Mg2+ ion is not there to coordinate 1
O
R R and II. Therefore, Mg2+ plays a critical role as it reduces the
ketoenolate’s ‘O’ attack (transition state VIII, Path D) and
R
O N
R N NHC
Path C
O
N
Ar
O O OMe promotes the ‘C’ attack (intermediate III, Path A, Fig. 6).
O O
Preliminary computational studies were conducted on steps III
1 R
OMe
R
O O to V in Path A assuming an acetate ligand on the magnesium ion
R R
VII
Byproduct 5 to provide insights into the observed enantioselectivity. It was
found that the energies of all transition states from III to the
allenalate are higher than those of the rest of processes and we
thus hypothesize that the enentioselectivity is determined in this
intramolecular C–C bond forming reaction. Interestingly, in
Path D

Ar
OMe
NHC
N N
contrast to other studies on the α,β-unsaturated acyl azolium
OMe
O
O
N
O
analogs, this step creats two components of axial chirality, namely
O
O
'O' attack the allenolate and the 2-methoxynaphthalen-1-yl moiety, in
R
O 1
R O
R
addition to one chiral center of the 1,3-dione. The twisted alkynyl
Byproduct 6 VIII R acyl azolium plane allows the ketoenolate group to stay away
from the indane ring (Fig. 8), whose role is to discriminate the
Fig. 6 Postulated mechanistic pathways. Path A shows the formation of
strain energy during the formation of the allenolate center rather
product 3. Path B suggests the formation of byproduct 4. Path C is a
than the intuitive effect to block the approach of the nucleophile.
probable way to generate byproduct 5. Path D indicates a plausible route to
explain the formation of byproduct 6
Discussion
To demonstrate the utility of above synthesized products, we In summary, we have successfully developed an NHC-catalyzed
successfully converted 8 into commonly used axially biaryls 10. atroposelective annulation of cyclic 1,3-diones with ynals, pro-
As shown in Fig. 5, Diels–Alder reaction of 8 and 9 afforded the viding chiral α-pyrone-aryls in moderate to good yields with high
corresponding axially chiral naphthyl–phenyl products 10 in enantioselectivities. This protocol features good functional group
acceptable yields and no racemization was observed. tolerance, and allows the rapid assembly of axially chiral mole-
cules from simple and readily available starting materials under
mild conditions. Our computational investigation suggests that
Mechanistic studies. The origins of chemo- and stereo-selectivity the enantioselectivity is determined during the Michael addition
of this reaction are rationalized by the postulated mechanism of the ketoenolate to the alkynyl azolium moiety. Further inves-
illustrated in Fig. 6 (Path A). The addition of NHC catalyst to tigations on axially chiral compounds as hits in medicinal
ynal 2 yields an NHC-bounded Breslow intermediate I63,64. chemistry or as chiral ligands or catalysts in asymmetric

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3

1a + 2a

Standard
conditions OMe OMe
O DQ (1.5 eq) O
H (1)
No DQ Or
standard
Me conditions Me
O O O O
Me Me
4aa 3aa
74%, 67:33 er (No reaction)

1a + 2u
C11
Br
O1
Standard C3 C2 O2
C13
conditions OMe C4 C14
O O3
C5
C1 C12
C15 C22 (2)
C10 C20
C6 C16
O4
C19 C17
C9
Me C7
O O C8 C18
C21
Me
Br1

(S)-3au X-ray single crystal structure

68%, 91:9 er (3au)
1st
crystallization 50%, 99:1 er

1g + 2s i i
Pr
Pr
2 2

Standard Ph OMe Ph
conditions O
O O
+ (3)
OMe
i
( )
Pr 2 ( )
O O i
Pr 2
( ) O O
i 2
Pr ( )
i 2
Pr
3gs 7
60%, 96:4 er 20%, 59:41 er

Standard conditions
No reaction

Fig. 7 Control experiments. (1) 4aa failed to undergo oxidation to form 3aa in the presence of DQ. (2) The absolute configuration of 3au was determined to
be (S) by X-ray crystallography. (3) Under standard conditions, the reaction of 1g with 2s yielded 3gs and 7. However, we found that 7 was not directly
generated from 3gs under currrent conditions

TS1 (0) H C O N Br Mg TS1′′ (+1.2)

Fig. 8 Comparison of transition states. Relative free energy (kcal mol−1) of TS1 and TS1' are displayed in the brackets

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NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02952-3 ARTICLE

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