Palladium-catalyzed dynamic kinetic asymmetric transformation of racemic biaryls: Axial-to-central chirality transfer

Article abstract of DOI:10.1021/jacs.5b01285

The first dynamic kinetic asymmetric transformation of racemic biaryl substrates on the basis of axial-to-central chirality transfer has been realized. Chiral Pd-NHC complexes were found to catalyze the dynamic kinetic asymmetric spiroannulation of 4-(2-bromoaryl)-naphthalen-1-ols (or 2′-bromo-[1,1′-biphenyl]-4-ols) with internal alkynes, affording a series of enantioenriched spirocyclic products bearing an all-carbon quaternary stereocenter in good yields (up to 95%) with excellent enantioselectivities (up to 97% ee).

Full text of DOI:10.1021/jacs.5b01285

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Communication
Palladium-Catalyzed Dynamic Kinetic Asymmetric Transformation
of Racemic Biaryls: Axial-to-Central Chirality Transfer
Liu Yang, Huayu Zheng, Lei Luo, Jiang Nan, Jingjing Liu, Yaoyu Wang, and Xinjun Luan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b01285 • Publication Date (Web): 07 Apr 2015
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Palladium-Catalyzed Dynamic Kinetic Asymmetric Transformation of
Racemic Biaryls: Axial-to-Central Chirality Transfer
1
1
†
†
†
Liu Yang, Huayu Zheng, Lei Luo, Jiang Nan, Jingjing Liu, Yaoyu Wang, and Xinjun Luan*
12
13
14
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of
Chemistry & Materials Science, Northwest University, Xi’an 710069, China
15
16
17
Supporting Information Placeholder
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2
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3
3
3
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3
3
40
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4
4
4
catalyzed dearomatization of 2-naphthol derivatives with
alkynes. The synthetic value of these racemic reactions have
ABSTRACT: The first dynamic kinetic asymmetric trans-
formation of racemic biaryl substrates on the basis of axial-
to-central chirality transfer has been realized. Chiral Pd-NHC
complexes were found to catalyze the dynamic kinetic
asymmetric spiroannulation of 4-(2-bromoaryl)-naphthalen-
9
been reflected by the capacity of transferring one biaryl scaf-
fold into another spirocyclic framework bearing an all-
carbon quaternary stereocenter, which offers a potential op-
portunity for enabling the DYKAT of biaryls via axial-to-
central chirality transfer. Along these lines, we speculated
that the phenolic derivative 1, which interconvert rapidly
between (R)-1 and (S)-1, would be an ideal candidate for the
anticipated DYKAT (Scheme 2). Presumably, a chiral catalyst
might be able to discriminate the enantiotopic faces of the
phenolic ring in 1, and further differentiate the formation
rates of 3 and ent-3. However, catalyst-controlled asymmet-
ric dearomatization of phenolic derivatives being restricted
from a single enantioface is very challenging, and to date,
1
-ols (or 2'-bromo-[1,1'-biphenyl]-4-ols) with internal alkynes,
affording a series of enantioenriched spirocyclic products
bearing an all-carbon quaternary stereocenter in good yields
(
up to 95%) with excellent enantioselectivities (up to 97% ee).
Dynamic kinetic asymmetric transformation (DYKAT) rep-
resents one of the most powerful and economical strategies
for the synthesis of enantioenriched compounds in the field
1
10
of asymmetric synthesis. The key feature of DYKAT is the
only a handful of leading examples have been disclosed.
ability of converting both enantiomers of the racemic start-
ing material into a single optically pure product with a theo-
retical yield of 100%. To date, great advances have been
achieved in this area. Remarkably, a number of excellent
catalytic and enzymatic DYKATs with racemic compounds
Herein, we describe the successful execution of our design
for a Pd(0)-catalyzed DYKAT of racemic 1. To the best of our
knowledge, this work represents the first example of DYKAT
of racemic biaryls on the basis of axial-to-central chirality
transfer.
3
bearing sp stereocenters have been successfully realized
Scheme 1. Previous Work on DYKAT
2-3
(
Scheme 1A). Meanwhile, some fascinating transformations
featuring the same concept have been implemented by using
A. DYKAT of racemic compounds with central chirality
4-6
racemic allenes or amides (Scheme 1B). Recently, the pur-
suits of more challenging DYKATs with dynamic mixtures of
rapidly racemizing biaryls have gained significant progress.
Several elegant examples were reported for accessing optical-
7
ly enriched biaryls via this strategy (Scheme 1C, left). How-
B. DYKAT of racemic non-biaryls with axial chirality
4
4
ever, DYKAT of an atropisomeric biaryl, with concomitant
creation of a new sp stereocenter by breaking the aromatici-
3
4
49
50
51
52
53
5
5
56
57
58
59
ty of one aryl ring, remains a daunting challenge (Scheme 1C,
right). Notably, asymmetric synthesis of compounds with
central chirality from enantiopure biaryls on the basis of
dearomatizing axial-to-central chirality transfer has been
8
dramatically limited, which is in part due to the need of
high cost chiral biaryls. In contrast, DYKAT, allowing the
direct use of readily available racemic biaryls, would become
a more economical and desirable solution to this novel axial-
to-central stereochemical transformation.
C. DYKAT of racemic biaryls with axial chirality
In this context, we embarked to develop a catalytic DYKAT
of racemic biaryls to access a new type of enantioenriched
3
compounds bearing a sp stereocenter. This DYKAT proposal
was originated from our recent studies on transition-metal-
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Scheme 2. Design of a DYKAT of Configurationally
Page 2 of 5
1a (1a') showed higher reactivity (89% yield), but the enanti-
1
2
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5
6
7
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9
1
1
1
1
1
15
1
1
18
1
2
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2
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5
oselectivity dropped dramatically (29% ee) (entry 16).
Labile Biaryls via Axial-to-Central Chirality Transfer
Table 1. Optimization of the Reaction Conditions
a
b
entry [Pd]
L*
base
solvent
yield (%) ee (%)
t
1
Pd
Pd
Pd
Pd
Pd
2
2
2
2
2
(dba)
(dba)
(dba)
(dba)
(dba)
3
3
3
3
3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
NaO Bu toluene
18
22
8
62
55
73
40
90
64

70
91
35

t
2
3
4
5
6
7
8
9
1
1
1
1
NaO Bu DCE
t
NaO Bu DME
t
NaO Bu THF
45
t
NaO Bu 1,4-dioxane 12
t
[Pd(allyl)Cl]
PdCl
Pd(O CCF )
2
NaO Bu 1,4-dioxane 51
t
2
NaO Bu 1,4-dioxane <5
1
1
t
To test the feasibility of our hypotheses, atropisomeric 1a
NaO Bu 1,4-dioxane 42
2
3
2
t
and alkyne 2a were selected as the model substrates. The
study commenced with a search for chiral Pd catalysts that
can promote the anticipated DYKAT of 1a with 2a in an en-
antioselective manner. Much to our delight, a key break-
through was ultimately achieved by identifying chiral N-
heterocyclic carbenes (NHCs) L1-L5 as the effective ligands.
Pd(OAc)
2
2
2
2
2
NaO Bu 1,4-dioxane 53
t
0
1
2
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
LiO Bu
1,4-dioxane 19
1,4-dioxane <5
t
KO Bu
t
L2 NaO Bu 1,4-dioxane 17
L3
60
75
81

t
NaO Bu 1,4-dioxane 26
t
14 Pd(OAc)2
L4 NaO Bu 1,4-dioxane 37
L5
L1
t
15 Pd(OAc)
2
NaO Bu 1,4-dioxane <5
c
t
1
6
Pd(OAc)
2
NaO Bu 1,4-dioxane 89
29
These readily available C -symmetric NHCs were pioneered
2
a
b
c
Isolated yield. Determined by chiral HPLC. 1a was replaced by 1a'.
by Grubbs and have proven to be excellent promoters for Ru-
1
2-13
catalyzed asymmetric ring-closing metathesis,
while their
use in Pd-catalyzed asymmetric transformations remains
Table 2. Evaluation of the Additive Effects
1
4
underdeveloped. As shown in Table 1, the initial finding
showed that the desired reaction proceeded in the presence
t
of Pd (dba) (10 mol%), L1 (20 mol%), and NaO Bu (1.5 equiv)
2
3
in toluene at 80 C, affording the spirocyclic product 3aa in
18% yield with 62% ee (entry 1).
Encouraged by this primary observation, we attempted to
improve the reaction performance by screening a variety of
solvents, which revealed a significant impact on not only the
catalytic activity of the Pd catalyst but also the stereocontrol
of the spiroannulation of 1a with 2a (entries 2-5). In coordi-
nating solvents THF and 1,4-dioxane, the reaction led to
higher chemical yield (45%) and better enantioselectivity
a
b
entry
1
additive
solvent
yield (%)
ee (%)
TBACl
TBABr
TBAI
TBAOAc
NaI
KI
TBAI
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
25
48
73
10
71
78
74
72
91
3
2
3
4
5
6
7
8
84
85
0
86
87
93
96
93
(
90% ee) for 3aa, respectively. Taking 1,4-dioxane as the reac-
tion solvent, several Pd sources were investigated (entries 6-
NaI
THF
THF
9), and Pd(OAc) turned out to be the optimal catalyst pre-
2
9
KI
cursor in terms of reactivity and enantioselectivity (53% yield,
91% ee). The reaction was then examined by using other ba-
a
b
Isolated yield. Determined by chiral HPLC.
t
t
We posited that the modest chemical conversion for 1a af-
ter the above optimization might be the result of alkyne 2a’s
binding towards the Pd center of intermediate A (or B) was
inhibited by the ligated bromide. So TBA-halide salts were
first studied as the additive for the model reaction (Table 2,
entries 1-3), and TBAI was indeed able to improve the reac-
tion conversion, albeit with slight drop of enantioselectivity.
Combining with the control run by using TBAOAc (entry 4),
the experimental data indicated that the halides could influ-
ence the reaction greatly. Moreover, NaI and KI were ob-
served to show similar effects as TBAI (entries 5-6). Eventual-
ly, it was very lucky to find that the reaction performance
could be dramatically enhanced by switching the solvent to
THF (entries 7-9). TBAI, NaI and KI affected the reaction
very differently. For example, the run with NaI allowed pro-
ducing 3aa in 72% yield with 96% ee, while the parallel reac-
tion with KI could give 3aa in 91% yield with 93% ee. Despite
the outstanding enantioselectivity with NaI as the additive,
ses such as LiO Bu and KO Bu (entries 10-11), but none of
t
them could give comparable result as the run with NaO Bu.
Subsequently, a series of NHC ligands, which incorporate a
methyl, ethyl, cyclohexyl or phenyl group on the ortho-
position of the aryl side chains, were assayed for the DYKAT
of 1a (entries 12-15). The experimental results indicated that
the alkyl-substituted NHCs (L2-L4) were generally effective,
with the bulkier ligand showing the better catalytic outcome.
However, L5 that bears an ortho-phenyl substituent was to-
tally inactive towards the desired spiroannulation. Addition-
ally, achiral NHC ligands such as SIPr and SIMes were also
tested, but they could not enable the formation of 3aa at all.
This observation illustrated that devising mono-ortho-alkyl-
substituted aryl side chains in L1-L4 were crucial for the title
transformation. Up to this point, the superior conditions for
1a could provide product 3aa in 53% yield with 91% ee (entry
9). Notably, the related attempt with the iodo-counterpart of
5
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studies of additional starting material combinations illustrat-
yield with 84% ee, implying that the two enantiomers of 1m
15
1
2
3
4
5
6
7
8
9
1
1
12
13
ed that yields were often poor to modest. Therefore, KI was
chosen as the additive for further studies, although its role
was unclear at the current stage.
could interconvert rapidly under the reaction conditions.
Noteworthy, heterocyclic 1n was also effective for this pro-
cess. More importantly, the phenol derivatives were found to
be suitable for this transformation. Symmetrical 1o was first
investigated, and the achiral 3oa was collected in 35% yield.
Next, unsymmetrical phenolic 1p and 1q were then tested,
and enantioenriched 3pa and 3qa were obtained in good
yields. Finally, we have to mention that substrate 1r, which
was actually attempted towards its asymmetric transfor-
Table 3. Survey the Scope of Biaryls
9c
mation previously, could be converted into the desired
product 3ra in 86% yield, but no stereocontrol was realized.
This outcome indicated that configurationally labile biaryls
were required for enabling this novel DYKAT method. In
addition, no encouraging results were achieved for substrates
14
15
16
1s and 1t under the current reaction conditions.
We next turned our attention to study on the spiroannula-
tion of various alkynes with 1a (Table 4). Regarding the
symmetrical alkynes containing aromatic rings, a broad
range of substituents were tolerated on the para- (2b-e),
meta- (2f), or ortho-position (2g), and products 3ab-ag were
obtained in 68-92% yield with 83-93% ee. To our delight, the
alkyne 2h bearing heterocyclic groups such as 2-thienyl
could undergo the annulation with 1a efficiently, leading to
3ah in 93% yield with 97% ee. The absolute configuration of
3ah was assigned to be (S) by X-ray. Moreover, dialkylacety-
lenes (2i-j) were also adaptable in this process. Specifically,
the runs with unsymmetrical 2k-m proceeded smoothly to
give products 3ak-am in 75-92% yield with 88-96% ee (for
major regioisomers), and the alkene and silyl functionalities
remained untouched. With respect to the regioselectivities
17
18
19
20
2
2
23
24
25
26
27
28
29
30
3
3
(
1.3:1 to 2:1), the alkynes 2k-m were preferentially installed in
a manner that alkyl group is close to the spirocyclic carbon
9a,c
center, which is opposite to the related examples.
Table 4. Survey the Scope of Alkynes
3
34
35
36
37
38
3
40
41
a
b
c
1
.0 mmol reaction scale. C = 0.2 M. L4 was used in place of L1.
To explore the generality of this DYKAT method, the reac-
tion scope was first examined by employing an important
number of 4-(2-bromoaryl)naphthalen-1-ols (1a-n) to react
with 2a, and the results are summarized in Table 3. Overall, a
variety of enantioenriched spiro[indene-1,1'-naphthalen]-4'-
ones were successfully prepared in 55-93% yield with 84-97%
ee. Satisfactorily, the 1-naphthol coupling partner could be
diversely substituted on the 4- or 5-position of the phenyl
ring, including electron-neutral or electron-donating groups
such as methyl (1b,g) and methoxy (1k) groups, and electron-
withdrawing groups such as trifluoromethyl (1c,j), cyano (1d),
chloro (1e), ester (1f) and fluoro (1h-i) groups. For substrates
42
4
4
45
46
47
48
49
50
51
52
1c, 1d, 1f and 1g, higher concentration (0.2 M) was used to
provide appreciable yields for their corresponding products.
For substrates 1e and 1j, L4 was proven to be the better lig-
and. Remarkably, a sterically congested substrate 1l was tol-
erable, affording spirocyclic 3la in 90% yield with 95% ee via
two challenging CC bond forming steps. Moreover, sub-
strate 1m that contains two ortho-halide groups (Cl and Br)
was able to undergo the title DYKAT to produce 3ma in 93%
53
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To demonstrate the potential utility of this method, two
transformations of product 3aa were performed (Scheme 3).
The results indicated that the enone functionality could be
manipulated properly under mild reaction conditions.
(4) For examples, see: (a) Imada, Y.; Ueno, K.; Kutsuwa, K.; Mu-
1
2
3
4
5
6
7
8
9
1
1
1
13
14
15
16
17
18
19
20
2
2
23
2
25
26
27
28
29
30
31
3
3
34
35
36
3
38
39
40
4
42
4
4
45
46
47
48
49
50
51
5
53
rahashi, S. Chem. Lett. 2002, 140. (b) Trost, B. M.; Fandrick, D. R.;
Dinh, D. J. Am. Chem. Soc. 2005, 127, 14186. (c) Deska, J.; del Pozo
Ochoa, C.; Bäckvall, J. E. Chem. Eur. J. 2010, 16, 4447. (d) Wan, B.; Ma,
S. Angew. Chem. Int. Ed. 2013, 52, 441.
Scheme 3. Synthetic Transformations of 3aa
(5) For examples, see: (a) Zhang, Z.; Bender, C. F.; Widenhoefer, R.
A. J. Am. Chem. Soc. 2007, 129, 14148. (b) Osborne, J. D.; Randell-Sly,
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2
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1
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0630.
(
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Am. Chem. Soc. 2013, 135, 2963.
In conclusion, we have developed an unprecedented Pd-
catalyzed enantioselective annulation of phenolic derivatives
with alkynes, thus leading to a new class of spirocyclic mole-
cules bearing an all-carbon quaternary stereogenic center
with excellent enantioselectivities (up to 97% ee). This pro-
cess, to the best of our knowledge, is the first successful ex-
ample of transferring one class of racemic atropisomeric
biaryls into another type of optically enriched compounds
with central chirality relying on the DYKAT strategy.
(
7) For examples, see: (a) Bringmann, G.; Breuning, M.; Henschel,
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Soc. 2013, 135, 15730. (e) Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J.
Am. Chem. Soc. 2013, 135, 16829.
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Bertrand, M. P. Nechab, M. Chem. Soc. Rev. 2013, 42, 8434. For ex-
amples, see: (b) De Jong, F.; Siegel, M. G.; Cram, D. J. J. Chem. Soc.,
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ASSOCIATED CONTENT
Supporting Information
(
9) (a) Nan, J.; Zuo, Z.; Luo, L.; Bai, Lu, Zheng, H.; Yuan, Y.; Liu, J.;
Experimental procedures, spectral data, and crystallographic
data in cif format. This material is available free of charge via
the Internet at http://pubs.acs.org.
Luan, X.; Wang, Y. J. Am. Chem. Soc. 2013, 135, 17306. (b) Gu, S.; Luo,
L.; Liu, J.; Bai, L.; Zheng, H.; Wang, Y.; Luan, X. Org. Lett. 2014, 16,
6132. (c) Zheng, H.; Bai, L.; Liu, J.; Nan, J.; Zuo, Z.; Yang, L.; Wang, Y.;
Luan, X. Chem. Commun. 2015, 51, 3061. (d) Zuo, Z.; Yang, X.; Liu, J.;
Nan, J.; Bai, L.; Wang, Y.; Luan X. J. Org. Chem. 2015, 80, 3349.
AUTHOR INFORMATION
(
10) For reviews, see: (a) Roche, S. P.; Porco Jr, J. A. Angew. Chem.
Corresponding Author
Int. Ed. 2011, 50, 4068. (b) Zhuo, C.; Zhang, W.; You, S. Angew. Chem.
Int. Ed. 2012, 51, 12662. For examples, see: (c) Nemoto, T.; Ishige, Y.;
Yoshida, M.; Kohno, Y.; Kanematsu, M.; Hamada, Y. Org. Lett. 2010,
xluan@nwu.edu.cn
1
2
2, 5020. (d) Uyanik, M.; Yasui, T.; Ishihara, H. Angew. Chem. Int. Ed.
010, 49, 2175. (e) Wu, Q.; Liu, W.; Zhuo, C.; Rong, Z.; Ye, K.; You, S.
Author Contributions
†
L.Y., H.Z. and L.L. contributed equally to this work.
Angew. Chem. Int. Ed. 2011, 50, 4455. (f) Rousseaux, S.; García-
Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S. J. Am. Chem.
Soc. 2011, 133, 9282. (g) Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2012,
134, 20017. (h) Zhuo, C.; You, S. Angew. Chem. Int. Ed. 2013, 52, 10056.
(i) Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.; Yamasaki, M.; Shiro,
M.; Fujioka, H.; Maruzama, A.; Kita, Y. J. Am. Chem. Soc. 2013, 135,
4558. (j) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268. (k)
Wang, S.; Yin, Q.; Zhuo, C.; You, S. Angew. Chem. Int. Ed. 2015, 54,
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NSFC (21222201, 21271147, 51202192) and the
“1000 Youth Talents Plan” for financial support. We thank
6
47. (l) Nan, J.; Liu, J.; Zheng, H.; Zuo, Z.; Hou, L.; Hu, H.; Wang, Y.;
Prof. Biao Wu for X-ray crystallographic assistance.
Luan, X. Angew. Chem. Int. Ed. 2015, 54, 2356. (m) Yang, D.; Wang, L.;
Han, F.; Li, D.; Zhao, D.; Wang, R. Angew. Chem. Int. Ed. 2015, 54,
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HPLC timescale (for the HPLC spectrum, see SI). Moreover, the two
enantiomers of 1a could interconvert rapidly at higher than the room
temperature, see: (a) Lafon, O.; Lesot, P.; Fan, C.; Kagan, H. B. Chem.
Eur. J. 2007, 13, 3772; (b) Bott, G.; Field, L. D.; Sternhell, S. J. Am.
Chem. Soc. 1980, 102, 5618.
(12) For examples, see: (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H.
Org. Lett. 2001, 3, 3225. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J.
Am. Chem. Soc. 2006, 128, 1840.
(13) For examples of using this type of NHCs in Ni- or Cu-
catalyzed asymmetric transformations, see: (a) Chaulagain, M. R.;
Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568.
(b) Lee, K.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455.
(14) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b) Jen-
sen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63. (c) Xu, L.; Shi, Y. J.
Org. Chem. 2008, 73, 749.
2
Soc. Rev. 2001, 30, 321. (d) Rachwalski, M.; Vermue, N.; Rutjes, F. P. J.
T. Chem. Soc. Rev. 2013, 42, 9268.
(
2) For examples, see: (a) Trost, B. M.; Toste F. D. J. Am. Chem.
Soc. 1999, 121, 3543. (b) Trost, B. M.; McEachern, E. J.; J. Am. Chem.
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Natl. Acad. Sci. USA 2004, 101, 5761. (d) Parsons, A. T.; Johnson, J. S. J.
Am. Chem. Soc. 2009, 131, 3122. (e) Yamaguchi, A.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 10842. (f) Wang, Y.; Kuz-
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2
011, 133, 12972. (g) Dornan, P. K.; Kou, K. G. M.; Houk, K. N.; Dong,
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5
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V. M. J. Am. Chem. Soc. 2014, 136, 291. (h) de Nanteuil, F.; Serrano, E.;
Perrotta, D.; Waser, J. J. Am. Chem. Soc. 2014, 136, 6239.
(
3) For examples, see: (a) Mikami, K.; Yoshida, A. Angew Chem. Int.
Ed. Engl. 1997, 36, 858. (b) Zhao, Y.; Tam, Y.; Wang, Y.; Li, Z.; Sun, J.
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(15) Unconsumed 1m was always recovered as a racemic mixture
when the reaction between 1m and 2a was conducted at 30-80 C.
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