A nordehydroabietyl amide-containing chiral diene for rhodium-catalysed asymmetric arylation to nitroolefins

Article abstract of DOI:10.1039/c6ob02202b

A highly enantioselective rhodium catalysed asymmetric arylation (RCAA) of nitroolefins with arylboronic acids is presented using a newly developed, C₁-symmetric, non-covalent interacted, phellandrene derived, nordehydroabietyl amide-containing chiral diene under mild conditions. Stereoelectronic effects were studied, suggesting an activation of the bound substrate through the secondary amide as a hydrogen-bond donor.

Full text of DOI:10.1039/c6ob02202b

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Journal Name
ARTICLE
Nordehydroabietyl amide-containing chiral diene for rhodium-
catalysed asymmetric arylation to nitroolefins
Received 00th January 20xx,
Accepted 00th January 20xx
Ruikun Li,a Zhongqing Wena and Na Wu*a,b
A highly enantioselective rhodium catalysed asymmetric arylation (RCAA) of nitroolefins with arylboronic acids is
presented using a newly developed, C1-symmetric, non-covalent interacted, phellandrene derived, nordehydroabietyl
amide-containing chiral diene under mild conditions. Stereoelectronic effects were studied, suggesting an activation of the
bound substrate through the secondary amide as a hydrogen-bond donor.
DOI: 10.1039/x0xx00000x
www.rsc.org/
rapidly with Rh/olefin than with analogous Rh/BINAP complexes.
Therefore, C2-symmetric bicyclo[3.3.0] dienes by Lin were
established under harsh heating.9a This was followed by Wu’s
bicyclo[2.2.1]heptadiene,9b yet with the cost of its limited
lifetime.9c,d Miscellaneous electron-deficient ligands were also
developed, e.g., sulfinylphosphines,10a olefin sulfoxides,10b
phosphoramidites,10c deoxycholic acid-derived phosphites.10d These
hybrid ligands still possess some limitations, e.g., the sulfinyl
moieties were mostly limited to tert-butyl substitution.
Inspired by Carreira’s carvone derived diene11 and Hayashi’s
phellandrene derived diene,12 we thought a strategy is required: (1)
to interact the catalyst with bound substrate close enough to
facilitate reactions in an intramolecular fashion; (2) to introduce an
extra chiral template and assist the stereospecific discrimination by
stereoelectronic effects. From this point of view, the dienyl amide13
with an additional hydrogen-bonding site represents an unmet
The rhodium-catalysed asymmetric arylation (RCAA) of
organoboronic acids to electron-deficient olefins, pioneered by
Miyaura and Hayashi,1 is one of the most efficient methods for
enantioselective C-C bond formation. In particular, excellent results
were achieved using unsaturated carbonyl compounds.2 Among the
Michael acceptors,3 nitroalkenes have been described as “synthetic
chameleons”4 because the optically versatile nitroalkanes obtained
by RCAA can be transformed into a wide variety of optically active
compounds such as α-substituted ketones5 and biologically 2-
arylethylamines,6 which are useful chiral building blocks in protein
kinase B (PKB) inhibitor,6a Telcagepant,6b and montanine-type
Amaryllidaceae alkaloids bearing the cherylline synthon (Figure 1).6c
Despite the great synthetic importance of optically active nitro
compounds, RCAA to nitroolefins encountered the challenge by
virtue of the difficulty in controlling the stereoselectivity and easily
homocoupling of nitroalkanes under conventional basic conditions.7
In 2000, Hayashi and co-workers discovered the first asymmetric
addition to cyclic nitroalkenes using a Rh/BINAP catalyst,5 followed
by their impressive study on kinetic experiments on the 1,4-
addition of phenylboronic acid to enones.8
need
for
further
pursuit.
Dehydroabietylamine
and
nordehydroabietylamine possess excellent structural backbones
and well-defined contiguous stereocenters,14 yet reports on their
derivatives in asymmetric catalysis are scarce, mainly by virtue of
poor asymmetric control due to distal manipulation of the bulky
chiral template.15a Here, we make use of the unique hindrance of
nordehydroabietyl amide to discriminate the prochiral face of
nitroalkenes and developed a C1-symmetric, hydrogen bonding
interacted, phellandrene-derived, nordehydroabietyl amide-
containing chiral diene that accomplishes RCAA of nitroolefins
smoothly.
3a and 3f are readily synthesized by amidation of α-phellandrene
Diels-Alder derived dienyl carboxylic acid with optically pure
Figure 1. Biologically active 2,2-bisarylethylamines.
dehydroabietylamine,
and
with
nordehydroabietylamine,15
respectively. The latter could be obtained by Schmidt reaction of
dehydroabietic acyl azide derived from dehydroabietic acid.15b,c
Whereas (R)-phellandrene is commercial available, the (S)-
counterpart could be produced from Wilkinson’s hydrogenation of
(R)-carvone16a and Shapiro’s olefination16 sequentially on its
hydrazone.
Conventional basic conditions13 were first employed for RCAA to
representative 1a (Table 1). The addition of inorganic bases (entries
1-3) led to rapid decomposition of nitrostyrene with its homocoupl-
These studies indicate the catalyst turnover occurs much more
a. School of Chemistry and Pharmaceutical Science, Guangxi Normal University,
Gulin, Guangxi, 541004, China. E-mail: wuna07@gxnu.edu.cn.
b. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen, China, 518055.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of conditions.[a]
Gratifyingly, solvents show a crucial effect in increasing both
View Article Online
DOI: 10.1039/C6OB02202B
the reaction rate and conversion. We thought a stronger protic
solvent may benefit the reaction. However, the effect of the
acids CF3CH2OH and HOAc (entries 12 and 13), used as solvents,
is mainly to neutralize triethyl amine and, as a consequence,
the reaction does not work. Finally, EtOH was proven to be the
best solvent in good conversion (yield 90%), promising 91% ee
value ((S)-product as the major enantiomer) and shortened
time (entry 11); Therefore, with Et3N in EtOH as the best
condition, a variety of chiral dienes were prepared and
assessed to explore further the stereoelectronic effects of (R)-
3a analogues. Dienes lacking hydrogen bonding were tested
first, among which, Hayashi’s 3d12b with a 2-naphthyl ester
noticeably afforded an excellent yield (entry 16). However,
enantioselectivity dropped to 71%. Lam’s 3e13a tertiary amide
was obviously inferior by affording the racemic product (entry
17). By contrast, hydrogen-bond donors 3b and 3c13d, lacking
chiral centers on the cyclohexane and the benzyl group,
respectively, provided 4a in moderate ees, with the yields
somewhat diminished (entries 14 and 15). This demonstrates
that the performance of dienes bearing secondary amides are
better than those otherwise, indicating amides’ hydrogen
bonds are capable of interacting with nitrostyrene during the
process of stereochemical induction. To bind closer to the
substrate, we wanted to reduce the steric hinderance of the
amide by linking the diene to dehydroabietyl amide fragment,
where the constrained quaternary carbon was no longer
adjacent to N-H bond. (R)-3f did offer an outstanding yield,
nonetheless accompanied by losing some degree of
enantioselectivity (entry 18). This steric effect is intriguing. It
illustrates that sterically encumbering nordehydroabietyl
amide is essential to sustain the high efficiency of
enantioselection. What is more, we intended to find out if the
additional chiral template was a matched combination9d,13a
with the (R)-diene, so we synthesized the diastereomeric
ligand by connecting nordehydroabietyl amide scaffold with
(S)-phellandrene derived diene and applied it into RCAA
correspondingly. As a matter of fact, (S)-3g offered a
preference of the (R)-product with a slightly inferior yield
(86%), yet with similar ee value as that of (R)-3a (entry 19). It
shows a weak matched-mismatched effect, implying the
asymmetric induction is mainly determined by the absolute
configuration of the diene fragment. On the other hand,
hydrogen bonds from secondary amides presumably promote
non-covalent interactions with nitrostyrene, thus enhancing
both enantioselectivities and bridging the gap of matched and
mismatched effects on the outcome of the reaction.17 Another
factor is likely to be attributed to the steric effect of the
appreciably bulky nordehydroabietyl amide,18 distinguishing
prochiral faces (Re/Si) through arylrhodation of the bound
substrate, has outcompeted the mismatched effect of two
chiral templates.13d
entry diene
base
solvent
THF
yield[b]
0
ee[c]
N.D.d
(R)-3a
NaOH
1
(R)-3a
NaOHe
KFe
EtOH
EtOH
23
40
89
74
2
(R)-3a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(S)-3g
Pyridine
DABCO
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
EtOH
EtOH
EtOH
N.R.f
N.R.f
25
N.D.d
N.D.d
92
N.D.d
N.D.d
N.D.d
N.D.
91
N.D.d
N.D.d
76
56
71
tolueneg 19
THFg
CH2Cl2
trace
15
19
g
EtOAcg
EtOH
TFEh
HOAc
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
90
N.R.f
N.R.f
53
84
97
88
97
1
80
-92
86
a) The reaction was carried out with nitro-p-Me-styrene 1a (0.36 mmol), PhB(OH)2 (0.9
mmol), [RhCl(C2H4)2]2 (1.5 mol %), diene 3* (3.3 mol %), and corresponding base (0.18
b)
c)
e)
mmol) in solvent (4 mL) at room temperature under N2 for 4 h; Isolated yield;
Enantiomeric excesses were determined by chiral HPLC analysis; d) Not determined;
f)
g)
h)
Corresponding inorganic base (1.5 M) in 0.12 mL H2O; No reaction; 8 h; TFE =
trifluoroethanol.
ing adduct being observed (entry 1), yet with a slight impact on
the satisfying enantioselectivity. This indicates a milder base is
needed to release rhodium nitronate slowly. However, rigid or
bulky amines still have a detrimental effect on the conversion
(entries 4-7). Another concern is that hydrolysis of a rhodium
nitronate in donating solvents could reduce polymerization.
Next we conducted control experiments involving non-polar,
polar aprotic, and polar protic solvents (entries 7-13).
On the basis of these results, the condition in entry 11 of
Table 1 was selected to explore the scope of nitroalkenes with
various arylboronic acids (Table 2). A range of arylboronic acids
Table 2. Asymmetric conjugate addition to linear
nitroalkenes.[a]
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB02202B
entry
R
Ar2
4
yield[b]
ee[c]
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4 4f
4-BnOC6H4 4g
4-tBuC6H4
1-Npd
2-Npd
biphenyl-4
Ph
4b
4c
4d
4e
95
78
58
83
99
98
64
93
91
93
97
52
64
94
93
95
93
46
77
90
98
84
81
85
96
97
condition (a) PhB(OH)2 (2.5 equiv.), Et3N (0.5 equiv.), EtOH, 70 oC, 5 h; (b) Ph4BNa (1
equiv.), 1,4-dioxane, 80 oC, 4 h.
Scheme 1. 1,4-Asymmetric addition to chalcones.
Based on the aforementioned process, a model was postulated
that explains the stereochemical outcome of the addition reaction
(Figure 3). The coordination mode mainly depends on the size of
nordehydroabietyl amide. The interaction of nitroolefins to diene-
Rh-Ar occurs in a Si-face manner to minimize unfavorable steric
repulsion between nitroalkenes and the amide moiety. In addition,
EtOH is believed to act as a hydrogen bond linker that helps the
secondary amide as a hydrogen bond donor closer to the nitro
group, thus greatly accelerating the addition.
4h
4i
4j
4k
4l
4m
4n
10
11
12e 4-Me2NC6H4
Ph
Ph
13e
3,4-
diMeOC6H4
4-FC6H4
4-ClC6H4
n-Bu
14
15
16
17
Ph
Ph
Ph
4-BrC6H4
4o
4p
4q
4r
83
96
64
91
73
86
61
82
Ph
a)
The reaction was carried out on a 0.36 mmol scale nitroolefin with 2.5 equiv of
arylboronic acid, [RhCl(C2H4)2]2 (1.5 mol %), (R)-3a (3.3 mol %), and 0.5 equiv of Et3N in
b)
ethanol at room temperature for 4 h under nitrogen atmosphere; Yield of isolated
c)
d)
product; Enantiomeric excesses were determined by chiral HPLC analysis; Np =
naphthyl; e) heating at 50 oC for 8 h.
Figure 3. A model for stereochemical induction.
that gave arylation products with moderate to high yields and ee
values are electron-rich ones, including 2-Me (entry 1), 4-OMe
(entry 5) and 4-BnO (entry 6) analogues. The electron-withdrawing
substituents on the arylboronic acids were also tolerated (entries 2-
4, and 17), and the performance of bulky ones (entries 7-10) is also
effective in conversion and stereochemical induction. For
nitrostyrene scope, the ones bearing strong electron-donating
groups (entries 12 and 13) are a bit sluggish and need heating (52%
and 64%, respectively). An aliphatic nitroalkene (entry 16) also
proved to be reactive under the current protocol, yielding a
moderate 64% yield and 61% ee. The absolute configuration of
representative 4e was confirmed by X-ray crystallography (Figure 2).
Although rhodium-catalysed conjugate addition has been
developing rapidly, only a few examples of asymmetric 1,6-
additions to dienones have been reported by a chiral bisphosphine-
rhodium catalyst.19 This may be ascribed to the considerable
difficulty in controlling regioselectivity of the addition to extended
conjugate systems. The phenylboronic acid displayed no
nucleophilic activity, then the use of aryl zinc19a and aryltitanate
reagents19b in the presence of chlorotrimethylsilane followed by
acidic hydrolysis does not offer a practical access to chiral 1,6-
regioselective addition to α,β,γ,δ-unsaturated carbonyl compounds.
During our efforts to realize 1,6-addition to cyclic dienones, we
found the ligands without hydrogen bonding interaction, or lacking
nordehydroabietyl amide moiety albeit with hydrogen bonding, led
to low conversions and inferior ee values (Table 3, entries 3, 4, 6-9).
In contrast, (R)-3a, or an alternative (R)-3h, gave exclusively 1,6-
addition product 8a in high yields with satisfying enantioselectivities
upon the addition of sodium tetraphenyl boron to cyclic dienones at
milder heating 50 ℃ (Table 3, entries 5 and 10).19 In our proposed
Rh/diene-dienone interacted model, the free hydroxyl group from
(R)-3h presumably binds to carbonyl of dienone via hydrogen-bond
interaction, as also existed in nordehydroabietyl amide moiety in
(R)-3a, thus approaches the substrate close enough to facilitate
Figure 2. X-ray crystal structure of 4e
(displacement ellipsoids are drawn at the 45% probability level).
RCAA’s conversion at
a less bulky δ-position. The control
To illustrate the practicability of current protocol, (R)-3a was
applied to RCAA of an electron-rich chalcone and a phenoxy
alternative. Compared with conventional inorganic basic conditions,
experiment is of evidence, supporting hydrogen-bond interaction
crucial in determining prominent facial discrimination.
asymmetric 1,4-adducts were also obtained in gratifying yields with Table 3. Regioselective 1,6-asymmetric addition.20
good ees (Scheme 1).
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Teichert and B. L. Feringa, Angew. Chem. Int. EVidew.,A2rt0ic1le0O,n4lin9e
,
2486; (f) C. Monti, C. Gennari and U. Piarulli, Chem. Eur. J.,
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2007, 13, 1547; (g) S. Helbig, S. Sauer, N. Cramer, S. Laschat,
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R. Mariz, X. J. Luan, M. Gatti, A. Linden and R. Dorta, J. Am.
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3
4
6
(a) G. Calderari and D. Seebach, Helv. Chim. Acta., 1985, 68
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,
5
6
T. Hayashi, T. Senda and M. Ogasawara, J. Am. Chem. Soc.,
2000, 122, 10716.
For PKB inhibitor chiral resolution, see (a) G. Saxty, S. J.
Woodhead, V. Berdini, T. G. Davies, M. L. Verdonk, P. G.
Wyatt, R. G. Boyle, D. Barford, R. Downham, M. D. Garrett
and R. A. Carr, J. Med. Chem., 2007, 50, 2293; For chemical
entry
L* (R)-
3a
T
yield (%)a
94
ee (%)
35
-
1
2
80
b
3a
80
-
transformation
of
chiral
nitroalkanes
into
2,2-
3
3d
3f
80
26
28
93
69
28
4
15
9
bisarylethylamines, see (b) C. S. Burgey, D. V. Paone, A. W.
Shaw, J. Z. Deng, D. N. Nguyen, C. M. Potteiger, S. L. Graham,
J. P. Vacca and T. M. Williams, Org. Lett., 2008, 10, 3235; (c)
X. Bao, Y.-X. Cao, W.-D. Chu, H. Qu, J.-Y. Du, X.-H. Zhao, X.-Y.
Ma, C.-T. Wang and C.-A. Fan, Angew. Chem. Int. Ed., 2013,
52, 14167.
For direct Michael addition of nitroalkanes to nitroalkenes,
read (a) X.-Q. Dong, H.-L. Teng and C.-J. Wang, Org. Lett.,
2009, 11, 1265; (b) D. Enders, R. Hahn and I. Atodiresei, Adv.
Synth. Catal., 2013, 355, 1126.
4
80
5
3a
50c
50c
50c
50c
50c
50c
91
81
41
56
83
93
6
3b
3c
7
7
8
3d
3e
9
69
87
8
9
(a) A. Kina, H. Iwamura and T. Hayashi, J. Am. Chem. Soc.,
2006, 128, 3904; (b) A. Kina, Y. Yasuhara, T. Nishimura, H.
Iwamura and Tamio Hayashi, Chem. Asian J., 2006, 1, 707.
10
3h
a) isolated yield after 3 h at 80 oC, unless otherwise specified; brsm = based on starting
For RCAA to nitroolefins employing dienes, see (a) Z.-Q.
Wang, C.-G. Feng, S.-S. Zhang, M.-H. Xu and G.-Q. Lin, Angew.
Chem. Int. Ed., 2010, 49, 5780; (b) K. -C. Huang, B. Gopula, T.
-S. Kuo, C. -W. Chiang, P. -Y. Wu, J. P. Henschke and H. -L. Wu,
Org. Lett., 2013, 15, 5730; (c) G. Berthon-Gelloz and T.
Hayashi, J. Org. Chem., 2006, 71, 8957. For diene catalysis
reviews, see ref. 2d and (d) J. B. Johnson and T. Rovis, Angew.
Chem. Int. Ed., 2008, 47, 840.
b)
matierial’s yield; upon addition of TMSCl (1 equiv.), incomplete conversion after 7 h
stirring; c) 16 h.
Conclusions
In summary, we have developed a low-loading rhodium-
nordehydroabietyl amide-containing chiral diene catalysed
conjugate arylation to nitroalkenes in high yield and ee. The
work exemplifies the capacity of nordehydroabietyl amide
moiety containing a unique hindrance and non-covalent
interaction with electron-deficient olefins, which was evident
and further illustrated in 1,6-site-selective rhodium-chiral
diene catalysed asymmetric arylation of dienone.
10 For RCAA to nitroolefins using various hybrid ligands, see (a)
F. Lang, G. Chen, L. Li, J. Xing, F. Han, L. Cun and Jian Liao,
Chem. Eur. J., 2011, 17, 5242; (b) F. Xue, D. Wang, X. Li and B.
Wan, J. Org. Chem., 2012, 77, 3071; (c) S. Hajra, R. Ghosh, S.
Chakrabarti, A. Ghosh, S. Dutta, T. K. Dey, R. Malhotra, S.
Asijaa, S. Roy, S. Dutta and S. Basu, Adv. Synth. Catal., 2012,
354, 2433; (d) V. R. Jumde and A. Iuliano, Adv. Synth. Catal.,
2013, 355, 3475.
11 (a) C. Fischer, C. Defieber, T. Suzuki and E. M. Carreira, J. Am.
Chem. Soc., 2004, 126, 1628; (b) C. Defieber, J.-F. Paquin, S.
Serna and E. M. Carreira, Org. Lett., 2004, 6, 3873.
Acknowledgements
12 (a) K. Okamoto, T. Hayashi and V. H. Rawal, Org. Lett., 2008,
10, 4387; (b) K. Okamoto, T. Hayashi and Viresh H. Rawal,
Chem. Commun., 2009, 32, 4815.
13 For RCAA to alkenylheteroarenes employing diene amides,
see (a) G. Pattison, G. Piraux and H. -W. Lam, J. Am. Chem.
Soc., 2010, 132, 14373; (b) A. Saxena and H.- W. Lam, Chem.
This work was supported by NSFC (21462004), State Key Laboratory
for the Chemistry and Molecular Engineering of Medicinal
Resources (CMEMR2014-A04), 2015GXNSFBA 139032 and GXNU. Z.
Wen thanks GX student training program.
Sci., 2011, 2, 2326; (c) A. A. Friedman, J. Panteleev, J. Tsoung,
V. Huynh and M. Lautens, Angew. Chem. Int. Ed., 2013, 52,
Notes and references
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Yasukawa, A. Suzuki, H. Miyamura, K. Nishino and S.
Kobayashi, J. Am. Chem. Soc., 2015, 137, 6616; (f) T.
Yasukawa, H. Miyamura and S. Kobayashi, Chem. Sci., 2015,
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6, 6224; (g) H. Miyamura, A. Suzuki, T. Yasukawa and S.
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4 | J. Name., 2012, 00, 1-3
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14 G. Zhang, Y. Zhang, X. Jiang, W. Yan and R. Wang, Org. Lett.,
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View Article Online
DOI: 10.1039/C6OB02202B
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1
17 for the kinetic control experiment, please see supporting
information.
18 Attempt to ethylation with (R)-3a and (R)-3b failed, either by
NaH-n-Bu4NI, or n-BuLi, or LiHMDS, possibly due to the steric
hindrance of ligands.
19 (a) T. Hayashi, S. Yamamoto and N. Tokunaga, Angew. Chem.
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addition to acyclic dienoates, see (c) G. Herrán, C. Murcia,
and A. G. Csákỹ, Org. Lett., 2005, , 5629; (d) G. Herrán and A.
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20 For full optimization, see supporting information.
6, 305; For Rh catalysed racemic 1,6-
7
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