Modular Synthesis of Enantioenriched 1,1,2-Triarylethanes by an Enantioselective Arylboration and Cross-Coupling Sequence

Article abstract of DOI:10.1021/acscatal.7b00300

An enantioselective Cu/Pd-catalyzed borylative coupling of styrenes with aryl/alkenyl iodides was realized using a chiral sulfoxide-phosphine (SOP) ligand. Enantioenriched 1,1-diarylethyl and β-aryl-homoallylic boronates are readily prepared. A streamlined procedure merging arylboration and subsequent Pd-catalyzed Suzuki-Miyaura cross-coupling enables the modular assembly of enantioenriched 1,1,2-triarylethanes, including two medicinally important chiral small-molecule targets.

Full text of DOI:10.1021/acscatal.7b00300

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Article
Modular Synthesis of Enantioenriched 1,1,2-Triarylethanes by
an Enantioselective Arylboration and Cross-Coupling Sequence
Bin Chen, Peng Cao, Xuemei Yin, Yang Liao, Liyin Jiang, Jialin Ye, Min Wang, and Jian Liao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00300 • Publication Date (Web): 17 Feb 2017
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ACS Catalysis
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Modular Synthesis of Enantioenriched 1,1,2-Triarylethanes by an
Enantioselective Arylboration and Cross-Coupling Sequence
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†
‡
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‡
*
,†,‡
Bin Chen, Peng Cao, Xuemei Yin, Yang Liao, Liyin Jiang, Jialin Ye, Min Wang and Jian Liao
†
College of Chemical Engineering, Sichuan University, Chengdu 610065 , China
‡
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
ABSTRACT: An enantioselective Cu/Pdꢀcatalyzed borylative coupling of styrenes with aryl/alkenyl iodides was realized using a
chiral sulfoxideꢀphosphine (SOP) ligand. Enantioenriched 1,1ꢀdiarylethyl and βꢀarylꢀhomoallylic boronates are readily prepared. A
streamlined procedure merging arylboration and subsequent Pdꢀcatalyzed SuzukiꢀMiyaura crossꢀcoupling enables the modular asꢀ
sembly of enantioenriched 1,1,2ꢀtriarylethanes, including two medicinally important chiral smallꢀmolecule targets.
KEYWORDS: asymmetric catalysis, 1,1,2-triarylethanes, arylboration, cross-coupling, modular synthesis
disclosed elegant tactics for the Cu/Pdꢀcatalyzed arylboration
■
INTRODUCTION
of styrenes toward the preparation of racemic 2ꢀborylꢀ1,1ꢀ
diarylethanes, which demonstrate substantial utility for the
syntheses of gemꢀdiaryl and polyaryl compounds. We enviꢀ
Chiral 1,1,2ꢀtriarylethanes, in which three aryl groups are
installed on one ethane skeleton, are fundamental structural
motifs present in numerous bioactive compounds and drugs,
including an orally active antiꢀinflammatory phosphodiesterꢀ
ase IV inhibitor CDP840 (A), a glucagon receptor antagonist
for treating typeꢀII diabetes (B), lasofoxifene (C) for treating
14
sioned that an enantioselective arylboration could provide a
concise method for the synthesis of otherwise difficult to acꢀ
15
1
cess homochiral gemꢀdiarylethyl boronic esters. More imꢀ
portantly, this method, if coupled with the robust Bꢀalkyl Suꢀ
zukiꢀMiyaura crossꢀcoupling, would reveal opportunities for
the modular construction of chiral 1,1,2ꢀtriarylethanes.
2
3
4
osteoporosis, and bedaquiline (D) for treating tuberculosis
(
Figure 1). All these opticallyꢀpure chiral compounds contain
(Scheme 1)
a gemꢀdiarylmethine stereocenter, a common skeleton in many
pharmaceuticals and natural products. Although asymmetric
methods for the construction of gemꢀdiarylmethine stereocenꢀ
ters are well established, few are applicable to the synthesis of
chiral 1,1,2ꢀtriaryethanes. To date, catalytic asymmetric hyꢀ
drogenation of 1,1,2ꢀtriaryethenes and stereospecific crossꢀ
coupling of enantioenriched 1ꢀborylꢀ1,2ꢀdiarylethanes are
5
Scheme 1. This Strategy for Construction of Enantioen-
riched 1,1,2-Triarylethanes
6
7
8
9
among the most wellꢀestablished approaches. In order to obꢀ
tain more structurally diverse enantioenriched 1,1,2ꢀ
triaryethanes, new and straightforward methods for rapidly
assembling these motifs are highly desired.
■RESULTS AND DISCUSSION
We recently demonstrated that chiral sulfoxideꢀphosphine
ligands (SOP) are highly effective for the Cu and Pd coꢀ
catalyzed enantioselective allylboration of styrenes under mild
11e
conditions. We have also showed that under these condiꢀ
tions, the borylative coupling of oꢀmethyl styrene (1a) and
phenyl iodide (2a) was feasible, generating the chiral gemꢀ
diarylethyl boronic ester (3aa) in 54% yield with 90% ee. Furꢀ
ther systematic optimization led to conditions that furnish (S)ꢀ
3aa in excellent NMR yield (97%) with high ee (96%) (see
Table S1ꢀS7 in SI for details, see below for absolute stereoꢀ
chemical assignment). Control experiments demonstrated that,
in the absence of Pd(dppf)Cl , only the hydroboration product
2
Figure 1. Selected chiral 1,1,2-triarylethanes
(4) was generated (Table 1, entries 2 and 3). Moreover, the
Recent advances in transition metalꢀcatalyzed carboboration
chemistry have provided a new platform for the discovery and
loading of Pd catalyst exhibited a high correlation with the
yield of 3aa (Table 1, entries 4 and 5). These results indicated
1
0
I
II
synthesis of organoboron compounds. The carboboration of
that 3aa was generated via a Cu ꢀPd transmetallation process,
3
olefins readily furnishes multifunctional and chiral C(sp )ꢀ
instead of the direct crossꢀcoupling of a benzylcopper interꢀ
11
12
13
16
boronates. In 2014, Semba and Nakao, as well as Brown,
mediate with the aryl iodide. Palladium complexes ligated by
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XꢀPhos, PPh or racꢀBINAP generated 3aa in much lower
yield and enantioselectivity (Table 1, entries 6ꢀ8). The assessꢀ
3la, 3ma and 3na in good yields. Presumably, these modified
3
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conditions enhanced the rate of the Pdꢀmediated cycle to
match that of the Cuꢀmediated cycle, which is faster with more
ment of copper catalysts revealed that commercially available
(S,S)ꢀMeꢀDuphos and (R)ꢀBINAP are much less effective than
(R)ꢀSOP (Table 1, entries 9ꢀ10 vs. entry 1). Following our best
observed reaction conditions, neither PhBr nor PhCl afforded
the targeted product (Table 1, entries 10ꢀ12). When PhOTf
was employed as the electrophile, 3aa was observed in low
yield even at higher reaction temperature. (Table 1, entries 13ꢀ
6t,17
electronꢀdeficient substrates.
Furthermore, vinyl hetꢀ
eroaryls, such as 3ꢀvinyl indole and 2ꢀvinyl thiophene, also
worked well to afford gemꢀ(hetero)diarylethylboronates (3sa
and 3ta) in good yields and ee’s. In addition, this reaction
provided an attractive platform for the lateꢀstage modification
of some important bioactive compounds such as αꢀamino esꢀ
ters (3ua, 90% yield, dr = 97.5/2.5) and steroids (3va, 93%
yield, dr = 97/3). To note, the model reaction can be scaled up
to 5 mmol, with 1.53 g of 3aa (93% ee) being obtained with
the use of 2 mol % of catalyst loading (both Cu catalyst and
Pd catalyst). Recently, Brown demonstrated that chiral NHCꢀ
carbene ligands are effective for the asymmetric arylboration
1
4) Lastly, PhBr became an viable substrate at elevated temꢀ
°
perature (100 C, Table 1, entry 15), giving 3aa in reasonable
0
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yield and enantiomeric excess.
Table 1. Enantioselective Arylboration: Effect of Changing
a
Reaction Parameters
14
of βꢀsubstituted styrenes. Under our conditions, however, the
βꢀsubstituted styrenes (e.g. 1x and 1y) were inert even at highꢀ
er reaction temperatures, probably due to the failure of the
addition of (SOP)CuBpin to these olefins. The arylboration of
norbornadiene was surveyed and exoꢀ3wa was afforded in
good yield, high diastereoselectivity, and moderate enantioseꢀ
lectivity. The stereochemical outcomes of these reactions are
consistent with that of our previously reported enantioselective
11e
18
b
c
allylboration
and borylstannation processes, suggesting
Entry
Change from optimized conditions
None
3aa/4 (%) ee (%)
that the Cu/Pd transmetallation process occurrs in a stereoreꢀ
tentive manner, probably through the intermediates I and II.
(Scheme 2)
1
2
3
4
5
6
97/trace
0/50
96
ꢀ
no Pd(dppf)Cl2
°
a
no Pd(dppf)Cl , 100 C
0/45
ꢀ
2
Table 2. Scope of styrenes
2.5 mol% of Pd(dppf)Cl2
1 mol% of Pd(dppf)Cl2
92/5
96
91
85
60/30
24/62
Pd/XPhos precatalyst instead of
Pd(dppf)Cl2
7
(PPh ) PdCl instead of
Pd(dppf)Cl2
17/60
65/26
17/65
80
3 2
2
8
racꢀBINAP/PdCl instead of
87
2
Pd(dppf)Cl2
9
(S,S)ꢀMeꢀDuphos instead of (R)ꢀ
ꢀ78
SOP
10
(R)ꢀBINAP instead of (R)ꢀSOP
PhCl instead of PhI
68/26
0/50
ꢀ50
ꢀ
1
1
1
1
2
3
PhBr instead of PhI
0/50
ꢀ
PhOTf instead of PhI
25/20
40/15
66/30
95
91
82
°
14
PhOTf instead of PhI, 60 C
°
1
5
PhBr instead of PhI, 100 C
a
Reaction was performed with 1a (0.2 mmol), 2a (0.3 mmol),
B (pin) (0.3 mmol), CuCl (10 mol %), (R)ꢀSOP (12 mol %),
2
2
Pd(dppf)Cl (5 mol %), KOH (0.4 mmol), 2ꢀMeTHF ( 2 mL ) at
2
°
b
1
c
0
C for 36 h. Determined by H NMR spectroscopy. Deterꢀ
mined by chiral HPLC.
With improved reaction conditions in hand, the substrate
scope of this Cu/Pd coꢀcatalyzed enantioselective arylboration
was surveyed. As shown in Table 2, a broad range of styrenes
with diverse functional groups (alkyl, aryl, ethers, and haloꢀ
gens) could be effectively converted into the corresponding
chiral gemꢀdiarylethylboronic esters 3 in good to excellent
isolated yields (70ꢀ95%) and high enantioselectivities (90ꢀ98%
ee). Notably, for electronꢀdeficient styrenes, higher loading of
the Pdꢀcatalyst (10 mol %) and higher reaction temperatures
a
Conditions: 1 (0.2 mmol), 2a (0.3 mmol), B (pin) (0.3 mmol),
2
2
CuCl (10 mol %), (R)ꢀSOP (12 mol %), Pd(dppf)Cl (5 mol %),
2
°
b
KOH (0.4 mmol), 2ꢀMeTHF (2 mL) at 0 C for 36 h. Isolated
°
°
yield and the data in parentheses was the isolated yield of 3aa in 5
(25 C instead of 0 C) were needed to afford 3ba, 3ea, 3fa,
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c
mmol scale reaction. Determined by chiral HPLC and the data in
of the resulting products. Initial evaluations of the Pdꢀcatalysts
found that neither Pd(dppf)Cl nor RuPhos/Pd(OAc) gave
1
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parentheses was ee value of 3aa in 5 mmol scale reaction.
Pd(dppf)Cl (10 mol %), 2ꢀMeTHF (3 mL) at 25 C. Pd(dppf)Cl
10 mol %), 2ꢀMeTHF (3 mL) at 0 C.
2
2
d
°
e
2
2
good results, although these catalysts were appropriate for
°
20
(
previously reported crossꢀcouplings of primary alkylborons.
Interestingly, racꢀBINAP/Pd(OAc) is quite effective for the
2
Scheme 2. Proposed model of this stereospecific Cu to Pd
transmetallation
coupling of 3aa (93% ee) and bromobenzene, giving the exꢀ
pected 1,1,2ꢀtriarylethane 5a in excellent yield (95%) without
any detectable erosion of ee (93% ee, see Table S9 in SI for
details). Encouraged by this result, we envisioned merging the
crossꢀcoupling and Cu/Pdꢀcatalyzed arylboration procedures
without the isolation of 3. This can be realized by directly
adding the second aryl electrophile (3.0 equiv), racꢀ
0
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We next examined the arylboration of parent styrene (1z)
with substituted phenyl iodides. As shown in Table 3, both
electronꢀrich and poor aryl iodides could afford the desired
products in excellent yields (80ꢀ93%) with high ee’s (94ꢀ97%)
BINAP/Pd(OAc) and aqueous KOH to the arylboration reacꢀ
2
21
tion mixture. Following this sequence, 5a was afforded in
good overall yield (80%) with high enantioselectivity (94%
ee). An additional filtration of the arylboration reaction mixꢀ
ture through Celite can insure reproducibility and effectively
increase the reaction yield (95% NMR and 90% isolated).
With this streamlined procedure, diverse enantioenriched
1,1,2ꢀtriarylethane molecules can be modularly assembled
(Table 4). For instance, a wide range of substituted phenyl
bromides were quite reactive in the second crossꢀcoupling and
were thus incorporated into the corresponding triarylethanes
(5bꢀ5g) in good to excellent yields (82ꢀ91%) with excellent
enantioselectivties (94ꢀ97% ee). An array of triarylethanes
(5hꢀ5m) derived from substituted phenyl iodides are also readꢀ
ily accessed under our standard conditions in good yields with
similar ee values to our arylborylated intermediates (3zbꢀ3zh).
The power of this modular strategy is further demonstrated by
the asymmetric synthesis of (R)ꢀ5nꢀ5p and their enantiomers
under standard conditions, with both high yields (80ꢀ87%) and
ee’s (92ꢀ95%).
(3zbꢀ3zh). It should be noted that the reaction is highly selecꢀ
tive for the iodide leaving group, F, Cl and Br substituents
survive this transformation without any competitive coupling
products. Sterically hindered aryl iodides also reacted smoothꢀ
ly with styrene to provide 3zi and 3zj in good yields and enanꢀ
tioselectivities. The absolute configuration of (R)ꢀ3zj was conꢀ
firmed by conversion to a known compound and comparison
19
of the resulting optical rotation with literature values. Notaꢀ
bly, 1ꢀ, 2ꢀ and 3ꢀiodopyridines all worked well when the ratio
of styrene to pyridine electrophiles was tuned slightly (3zkꢀ
3
zm). Alkenyl halides are also competent electrophiles allowꢀ
ing for the productions of enantioenriched βꢀarylꢀhomoallylic
boronates (3znꢀ3zt) in good yields (45ꢀ83%) with good to
excellent enantioselectivities (80ꢀ96% ee).
a
Table 3. Scope of aryl iodides
a
Table 4. Scope of chiral 1, 1, 2-triarylethyane
a
Conditions: 1z (0.2 mmol), 2 (0.3 mmol), B (pin) (0.3 mmol),
2
2
CuCl (10 mol %), (R)ꢀSOP (12 mol %), Pd(dppf)Cl (5 mol %),
2
°
b
KOH (0.4 mmol), 2ꢀMeTHF (2 mL) at 0 C for 36h. Isolated
yield. Determined by chiral HPLC. Pd(dppf)Cl (10 mol %), 2ꢀ
MeTHF (3 mL) at 25 C. 1z (0.3 mmol), 2 (0.2 mmol), at 25 C.
c
d
2
°
e
°
f
°
1
z (0.3 mmol), 2 (0.2 mmol), at 0 C
After establishing satisfactory conditions for the asymmetric
arylboration protocol with Cu/Pd catalysis, following work
3
2
focused on the C(sp )ꢀC(sp ) SuzukiꢀMiyaura crossꢀcoupling
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a
Conditions: 1 (0.3 mmol), 2 (0.2 mmol), CuCl (10 mol %), (R)ꢀ
Supporting Information.
1
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9
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SOP (12 mol %), Pd(dppf)Cl (5 mol %), KOH (0.4 mmol), 2ꢀ
MeTHF (2 mL) at 0 C for 36h. The resulted mixture was filtrated
through a pad of Celite and concentrated in vacuo, then the crude
enantioenriched 1,1ꢀdiaryethylboronate was reacted with arylꢀ
boromide 4 (0.6 mmol) in the presence of racꢀBINAPꢀPd(OAc)2
Experimental details, analytic data (NMR, HPLC, ESIꢀHRMS)
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
2
°
■AUTHOR INFORMATION
(
1
15 mol %), KOH (3 mmol), THF (3 mL) and H O (0.3 mL) at
00 C for 12h. Isolated yield. Determined by chiral HPLC.
2
°
b
c
Corresponding Author
*
Eꢀmail: jliao@cib.ac.cn
To illustrate the efficiency and convenience of the estabꢀ
Notes
lished streamlined methodology, two medicallyꢀrelevant chiral
7
,9b,12,22
The authors declare no competing financial interest.
molecules, CDP840 (A)
and the glucagon receptor anꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
2,9a
tagonist B, were synthesized (Scheme 3). Firstly, the enanꢀ
tioselective borylative coupling of 1r and 2a, followed by
crossꢀcoupling with 6 catalyzed by Pd(dppf)Cl2, afforded
■ACKNOWLEDGMENT
23
We thank the NSFC (Nos. 21472184, 21272226, 21572218, and
2
1402186) and WesternꢀLight Foundation of CAS for financial
CDP840 (1.02 g with 90% optical purity). The formal syntheꢀ
sis of B stems from the asymmetric transformation of 7 with
support. J. J. Chruma (Sichuan University) provided valuable
manuscript revisions.
2
a and 8. Using our streamlined procedure, the key intermediꢀ
ate 9 was obtained in good yield (82%) with high enantioseꢀ
lectivity (93% ee). Hydrolysis of 9 to 10 (90% yield) and the
following condensation with the appropriate amine to afford
11 (92% yield, 93% ee) accomplished the formal synthesis of
B.
■
REFERENCES
(1) Alexander, R. P.; Warrellow, G. J.; Head, J. C.; Boyd, E. C.; Porꢀ
ter, J. R. US5608070.
(
2) Stelmach, J. E.; Keith, R.; Parmee, E. R.; Tata, J. R.
US2006009694.
Scheme 3. Synthesis of CDP840 and glucagon receptor
antagonist B.
(3) Shiina, I.; Sano, Y.; Nakata, K. US20090012314.
(4) (a) Andries, K. J. L. M.; Koul, A. US20060142279. (b) Saga, Y.;
Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 7905ꢀ7907.
(
2
(
1
5) For a recent review, see: Ameen, D.; Snape, T. J. MedChemComm
013, 4, 893ꢀ907.
6) Selected reviews: (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003,
03, 2829ꢀ2844. (b) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm,
C. Chem. Soc. Rev. 2006, 35, 454ꢀ470. (c) Tian, P.; Dong, H.ꢀQ.; Lin,
G.ꢀQ. ACS Catal. 2012, 2, 95ꢀ119. (d) Cherney, A. H.; Kadunce, N.
T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587ꢀ9652. For selected
examples, see: (e) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. An-
gew. Chem. Int. Ed. 2007, 46, 6488ꢀ6491. (f) Fessard, T. C.; Andrews,
S. P.; Motoyoshi, H.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46,
9
331ꢀ9334. (g) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden,
C. M. J. Am. Chem. Soc. 2009, 131, 5024ꢀ5025. (h) Taylor, B. L. H.;
Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133,
389ꢀ391. (i) Do, H.ꢀQ.; Chandrashekar, E. R. R.; Fu, G. C. J. Am.
Chem. Soc. 2013, 135, 16288ꢀ16291. (j) Bess, E. N.; Sigman, M. S.
Org. Lett. 2013, 15, 646ꢀ649. (k) Harris, M. R.; Hanna, L. E.; Greene,
M. A.; Moore, C. E.; Jarvo, E. R. J. Am. Chem. Soc. 2013, 135, 3303ꢀ
3
306. (l) Chu, W.ꢀD.; Zhang, L.ꢀF.; Bao, X.; Zhao, X.ꢀH.; Zeng, C.;
Du, J.ꢀY.; Zhang, G.ꢀB.; Wang, F.ꢀX.; Ma, X.ꢀY.; Fan, C.ꢀA. Angew.
Chem. Int. Ed. 2013, 52, 9229ꢀ9233. (m) Matthew, S. C.; Glasspoole,
B. W.; Eisenberger, P.; Crudden, C. M. J. Am. Chem. Soc. 2014, 136,
5
2
2
828ꢀ5831. (n) Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc.
014, 136, 6534ꢀ6537. (o) Huang, Y.; Hayashi, T. J. Am. Chem. Soc.
015, 137, 7556ꢀ7559. (p) Cahard, E.; Male, H. P. J.; Tissot, Ma.;
Gaunt, M. J. J. Am. Chem. Soc. 2015, 137, 7986ꢀ7989. (q) Lou, Y.;
Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem. Int. Ed.
2015, 54, 12134ꢀ12138. (r) Guduguntla, S.; Hornillos, V.; Tessier, R.;
FananasꢀMastral, M.; Feringa, B. L. Org. Lett. 2016, 18, 252ꢀ255. (s)
Wu, C.; Yue, G.; Nielsen, C. D.ꢀT.; Xu, K.; Hirao, H.; Zhou, J. J. Am.
Chem. Soc. 2016, 138, 742ꢀ745. (t) Friis, S. D.; Pirnot, M. T.;
Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 8372ꢀ8375. (u) Zhou,
Q.; Cobb, K. M.; Tan, T.; Watson, M. P. J. Am. Chem. Soc. 2016,
138, 12057ꢀ12060.
(7) (a) Houpis, I. N.; Molina, A.; Dorziotis, I.; Reamer, R. A.; Volante,
R. P.; Reider, P. J. Tetrahedron Lett. 1997, 38, 7131ꢀ7134. (b) Lynch,
J. E.; Choi, W.ꢀB.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.;
Ball, R. G. J. Org. Chem. 1997, 62, 9223ꢀ9228. (c) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Tetrahedron Lett. 2007, 48, 4007ꢀ4010.
■CONCLUSION
We herein report a streamlined procedure for the modular
synthesis of enantioenriched 1,1,2ꢀtriarylethanes by an enantiꢀ
oselective arylboration and Bꢀalkyl SuzukiꢀMiyaura coupling
sequence. The synthetic strategy employs readily available
chemical feedstocks (styrenes and aryl halides) and relatively
inexpensive metal catalysts (copper and palladium), avoids the
isolation of intermediates, and allows for easy scaleꢀup. The
generality and modularity of this reaction promises its use in
the syntheses of the medically relevant, structurally diverse
1,1,2ꢀtriarylethanes.
■ASSOCIATED CONTENT
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(
8) Tolstoy, P.; Engman, M.; Paptchikhine, A.; Bergquist, J.; Church,
T. L.; Leung, A. W.; Andersson, P. G. J. Am. Chem. Soc. 2009, 131,
855ꢀ8860.
9) (a) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774ꢀ
3777. (b) Crudden, C. M.; Ziebenhaus, C.; Rygus, J. P.; Ghozati, K.;
(18) Jia, T.; Cao, P.; Wang, D.; Lou, Y.; Liao, J. Chem. Eur. J. 2015,
21, 4918ꢀ4922.
(19) 3zj’ was prepared from 3zj and the absolute configuration was
determined by comparison with literature 6r.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
(
1
Unsworth, P. J.; Nambo, M.; Voth, S.; Hutchinson, M.; Laberge, V. S.;
Maekawa, Y.; Imao, D. Nat. commun. 2016, 7, 11065.
(10) Selected examples for Pdꢀcatalyzed carboboration: (a) Yang, F.ꢀ
Y.; Wu, M.ꢀY.; Cheng, C.ꢀH. J. Am. Chem. Soc. 2000, 122, 7122ꢀ
7
123. (b) Suginome, M.; Yamamoto, A.; Murakami, M. Angew.
(20) Selected reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457ꢀ2483 (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007,
40, 275ꢀ286. (c) Molander, G. A.; Canturk, B. Angew. Chem. Int. Ed.
2009, 48, 9240ꢀ9261. Selected examples: (d) Miyaura, N.; Ishiyama,
T.; Sasaki, H.; Ishikawa, M.; Sato, M.; Suzuki, A. J. Am. Chem. Soc.
1989, 111, 314ꢀ321. (e) Andrus, M. B.; Song, C. Org. Lett. 2001, 3,
3761ꢀ3764. (f) Molander, G. A.; Yun, C.ꢀS. Tetrahedron 2002, 58,
1465ꢀ1470. (g) Molander, G. A.; Yun, C.ꢀS.; Ribagorda, M.; Biolatto,
B. J. Org. Chem. 2003, 68, 5534ꢀ5539. (h) Molander, G. A.; Vargas,
F. Org. Lett. 2007, 9, 203ꢀ206. (i) Molander, G. A.; Ham, J.; Seapy, D.
G. Tetrahedron 2007, 63, 768ꢀ775. (j) Molander, G. A.; Sandrock, D.
L. Org. Lett. 2007, 9, 1597ꢀ1600. (k) Molander, G. A.; JeanꢀGerard, L.
J. Org. Chem. 2007, 72, 8422ꢀ8426. (l) Dreher, S. D.; Lim, S.ꢀE.;
Sandrock, D. L.; Molander, G. A. J. Org. Chem. 2009, 74, 3626ꢀ3631.
Chem. Int. Ed. 2005, 44, 2380ꢀ2382. (c) Daini, M.; Yamamoto, A.;
Suginome, M. J. Am. Chem. Soc. 2008, 130, 2918ꢀ2919. Selected
examples for Niꢀcatalyzed carboboration: (d) Yamamoto, A.;
Suginome, M. J. Am. Chem. Soc. 2005, 127, 15706ꢀ15707. (e)
Suginome, M.; Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc.
2006, 128, 14438ꢀ14439. Selected examples for Cuꢀcatalyzed carbobꢀ
oration, see: (f) Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
010, 132, 5990ꢀ5992. (g) Zhang, L.; Cheng, J.; Carry, B.; Hou, Z. J.
Am. Chem. Soc. 2012, 134, 14314ꢀ14317. (h) Alfaro, R.; Parra, A.;
Aleman, J.; Ruano, J. L. G.; Tortosa, M. J. Am. Chem. Soc. 2012, 134,
1
5165ꢀ15168. (i) Yoshida, H.; Kageyuki, I.; Takaki, K. Org. Lett.
013, 15, 952ꢀ955. (j) Liu, P.; Fukui, Y.; Tian, P.; He, Z.ꢀT.; Sun, C.ꢀ
2
Y.; Wu, N.ꢀY.; Lin, G.ꢀQ. J. Am. Chem. Soc. 2013, 135, 11700ꢀ11703.
k) Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2013, 135,
635ꢀ2640. (l) Meng, F.; Jang, H.; Jung, B.; Hoveyda, A. H. Angew.
(
m) Yang, C.ꢀT.; Zhang, Z.ꢀQ.; Tajuddin, H.; Wu, C.ꢀC.; Liang, J.;
(
2
Liu, J.ꢀH.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L.
Angew. Chem. Int. Ed. 2012, 51, 528ꢀ532. (n) Mlynarski, S. N.;
Schuster, C. H.; Morken, J. P. Nature 2014, 505, 386ꢀ390.
(21) In this case, the ratio of styrenes and aryl iodides was optimized
and tuned to 1.5/1. (for details, see supporting information)
Chem. Int. Ed. 2013, 52, 5046ꢀ5051. (m) Semba, K.; Bessho, N.;
Fujihara, T.; Terao, J.; Tsuji, Y. Angew. Chem. Int. Ed. 2014, 53,
9
2014, 513, 367ꢀ374. (o) Zhou, Y.; You, W.; Smith, K. B.; Brown, M.
K. Angew. Chem. Int. Ed. 2014, 53, 3475ꢀ3479. (p) Su, W.; Gong, T.ꢀ
J.; Lu, X.; Xu, M.ꢀY.; Yu, C.ꢀG.; Xu, Z.ꢀY.; Yu, H.ꢀZ.; Xiao, B.; Fu,
Y. Angew. Chem. Int. Ed. 2015, 54, 12957ꢀ12961. (q) Itoh, T.;
Shimizu, Y.; Kanai, M. J. Am. Chem. Soc. 2016, 138, 7528ꢀ7531. (r)
Semba, K.; Ohtagaki, Y.; Nakao, Y. Org. Lett. 2016, 18, 3956ꢀ3959.
007ꢀ9011. (n) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature
(
22) Aggarwal, V. K.; Bae, I.; Lee, H. Y.; Richardson, J.; Williams, D.
T. Angew. Chem. Int. Ed. 2003, 42, 3274ꢀ3278.
23) In this transformation, SuzukiꢀMiyaura cross coupling with the
use of racꢀBINAP/Pd(OAc) as catalyst gave poor results.
(
2
(
9
s) Zhao, W.; Montgomery, J. J. Am. Chem. Soc. 2016, 138, 9763ꢀ
766. (t) Rae, J.; Yeung, K.; McDouall, J. J. W.; Procter, D. J. Angew.
Chem. Int. Ed. 2016, 55, 1102ꢀ1107. (u) Yeung, K.; Ruscoe, R. E.;
Rae, J.; Pulis, A. P.; Procter, D. J. Angew. Chem. Int. Ed. 2016, 55,
1
1912ꢀ11916. (v) Smith, J. J.; Best, D.; Lam, H. W. Chem. Commun.
016, 52, 3770ꢀ3772. (w) Li, X.; Meng, F.; Torker, S.; Shi, Y.; Hovꢀ
2
eyda, A. H.; Angew. Chem. Int. Ed. 2016, 55, 9997ꢀ10002. (x) Meng,
F.; Li, X.; Torker, S.; Shi, Y.; Shen, X.; Hoveyda, A. H. Nature 2016,
5
37, 387ꢀ393. (y) Jiang, L.; Cao, P.; Wang, M.; Chen, B.; Wang, B.;
Liao, J. Angew. Chem. Int. Ed. 2016, 55, 13854ꢀ13858.
11) For enantioselective carboboration of olefins, see: (a) Meng, F.;
Haeffner, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 11304ꢀ
1307. (b) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura,
(
1
M. Angew. Chem. Int. Ed. 2008, 47, 7424ꢀ7427. (c) Zhong, C.; Kunii,
S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132,
11440ꢀ11442. (d) Nelson, H. M.; Williams, B. D.; Miro, J.; Toste, F.
D. J. Am. Chem. Soc. 2015, 137, 3213ꢀ3216. (e) Jia, T.; Cao, P.;
Wang, B.; Lou, Y.; Yin, X.; Wang, M.; Liao, J. J. Am. Chem. Soc.
2
(
(
Eur. J. 2014, 20, 12032ꢀ12036. (b) Logan, K. M.; Smith, K. B.;
Brown, M. K. Angew. Chem. Int. Ed. 2015, 54, 5228ꢀ5231.
(14) While this manusript was organized, an example of enantioselecꢀ
tive arylboration of olefins was reported by Brown, see: Logan, K. M.;
Brown, M. K. Angew. Chem. Int. Ed. 2017, 56, 851ꢀ855.
015, 137, 13760ꢀ13763.
12) Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 7567ꢀ7570.
13) (a) Smith, K. B.; Logan, K. M.; You, W.; Brown, M. K. Chem.
(
2
(
15) Zhang, L.; Zou, Z.; Wang, X.; Huang, Z. J. Am. Chem. Soc.
014, 136, 15501ꢀ15504.
16) (a) Shrestha, B.; Thapa, S.; Gurung, S. K.; Pike, R. A. S.; Giri, R.
J. Org. Chem. 2016, 81, 787ꢀ802. (b) Basnet, P.; Thapa, S.; Dickie, D.
A.; Giri, R. Chem. Commun. 2016, 52, 11072ꢀ11075.
(
deficient styrenes unavoidably provided a large amount of hydroboraꢀ
tion adduct (30ꢀ50% yield).
o
17) With the use of 5 mol% loading of Pd(dppf)Cl
2
at 0 C, electronꢀ
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