Enantioselective Nazarov Cyclizations Catalyzed by an Axial Chiral C6F5-Substituted Boron Lewis Acid

Article abstract of DOI:10.1002/anie.201806011

A chiral variant of B(C₆F₅)₃ with a 3,3′-disubstituted binaphthyl backbone is shown to catalyze Nazarov cyclizations with high levels of enantio- and diastereocontrol. The parent B(C₆F₅)₃ a

Full text of DOI:10.1002/anie.201806011

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Title: Enantioselective Nazarov Cyclizations Catalyzed by an Axial
Chiral, C6F5-Substituted Boron Lewis Acid
Authors: Lars Süsse, Maria Vogler, Marius Mewald, Benedict Kemper,
Elisabeth Irran, and Martin Oestreich
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806011
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10.1002/anie.201806011
Angewandte Chemie International Edition
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Enantioselective Nazarov Cyclizations Catalyzed by an Axial
Chiral, C6F5-Substituted Boron Lewis Acid
Lars Süsse, Maria Vogler, Marius Mewald, Benedict Kemper, Elisabeth Irran, and Martin Oestreich*
Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 85th birthday
F
Abstract: A chiral variant of B(C6F5)3 with a 3,3’-disubstituted
F
F
R
F
F
binaphthyl backbone is shown to catalyze Nazarov cyclizations with
high levels of enantio- and diastereocontrol. Parent B(C6F5)3 also
promotes these ring closures efficiently. This electrocyclization is
another example of the still small family of carbon–carbon bond
formations mediated by B(C6F5)3 as catalyst.
LB
F
B
F
B
F
F
F
F
F
F
F
F
F
F
F
F
F
R
(S)-2·THF (for R = H)
(S)-3·DMS (for R = Ph)
1
The Nazarov cyclization is a highly useful method to access
functionalized cyclopent-2-en-1-ones.[1] A variety of Lewis and
Brønsted acids have been shown to act as efficient catalysts for
this transformation, including the ubiquitous boron Lewis acid
chiral
Lewis acid
as catalyst
O
O
O
O
O
O
R1
R2
R1
R1
+
BF3·OEt2.[2]
Interestingly,
the
now
popular
R2
R2
tris(pentafluorophenyl)borane (B(C6F5)3 (1); Scheme 1, top) and
derivatives thereof have not employed yet despite their similar
Lewis acidity.[3] We are aware of just one example where 1 was
I
cis-II
trans-II
employed as
a
promoter of decarboxylative Nazarov
H
N
H
N
O
O
cyclizations.[4] Moreover, enantioselective variants based on
boron Lewis acids are not known to date. We anticipated that
chiral B(C6F5)3 congeners introduced by us such as (S)-2·THF[5]
and the more sterically hindered (S)-3·DMS[6] with binaphthyl
backbones could serve as catalysts (Scheme 1, top). High levels
of enantiocontrol are still rare for these ring closures when
catalyzed by Lewis acids.[7] For example, only two
enantioselective protocols have been described so far for
converting alkoxy-activated I into cis-II and trans-II (Scheme 1,
bottom).[8–10] Trauner made use of a Sc(III)-pybox complex[8] and
Rawal used a Cr(III)-salen complex;[9] the cyclopentenones II
were obtained with high enantiomeric excess and moderate
diastereoselectivity favoring the cis isomer. We report here
metal-free methods for both the racemic (with 1) and the
enantioselective Nazarov cyclization (with (S)-3·DMS) of
precursors I with good diastereoselectivities.
N
Cr
N
Sc
(OTf)3
N
Mes
O
O
Mes
–
SbF6
tBu
Rawal (2013)
up to 94% ee (cis) / 96% ee (trans)
40% ee / 79% ee for R1 = R2 = Me for R1 = Me and R2 = Aryl/Heteroaryl
with cis:trans = 78:22
with cis:trans = 86:14 to 66:34
tBu
Trauner (2004)
up to 97% ee for R2 = H
Scheme 1. Boron Lewis acids used in the present study (top) and reported
enantioselective Nazarov cyclizations catalyzed by chiral Sc(III) and Cr(III)
Lewis acids (bottom). DMS = dimethyl sulfide; LB = Lewis base; Tf =
trifluoromethanesulfonyl; Mes = mesityl.
We began with B(C6F5)3 (1) as catalyst and were pleased to
see that 5.0 mol% of 1 promoted our model cyclization 4a to 5a
in high yield and with good cis:trans ratio (Table 1, entry 1). This
result is one of the few examples of a carbon–carbon bond
formation catalyzed by B(C6F5)3 (1).[11] For comparison,
triphenylborane did not mediate this reaction (entry 2). We
directly continued with chiral B(C6F5)3 congeners (S)-2·THF and
(S)-3·DMS; their Lewis acidities had been estimated
approximately 80% of 1 by the Gutmann–Beckett method (see
the Supporting Information for details and the molecular
structure of (S)-3·Et3PO).[5,12] Chiral (S)-2·THF indeed catalyzed
the desired ring closure but far less cleanly than 1 (entry 3); 25%
isolated yield of 5a were obtained at full conversion of 4a after
two hours but the enantioselectivity of 31% ee was promising. In
contrast, a smooth reaction was found with (S)-3·DMS under an
otherwise identical setup (entry 4). After six hours, the isolated
yield of 5a was 92%, and the enantioselectivity was 90% ee and
the cis:trans ratio 88:12. Also, the absolute configuration was
opposite to that found with (S)-2·THF (entry 4 versus entry 3).
These results were obtained in 1,2-F2C6H4; a screening of
related solvents led to lower enantiomeric excesses (entries
5‒8), and Lewis-basic THF was detrimental to conversion (entry
9). Returning to 1,2-F2C6H4 as the optimal solvent, less (1.0
mol%) and more (5.0 mol%) catalyst loading was tested (entries
[*]
L. Süsse, M. Vogler, Dr. M. Mewald, Dr. E. Irran,[++] Prof. Dr. M.
Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
Dr. M. Mewald, Dr. B. Kemper, Prof. Dr. M. Oestreich
Organisch-Chemisches Institut,
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
++
[
]
X-ray crystal-structure analyses.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201806011
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COMMUNICATION
10 and 11). Compared to the routinely used 2.4 mol% of (S)-
3·DMS (entry 4), the yields remained high in both cases but the
enantioselectivity dwindled at the reduced catalyst loading.
of 5 was secured by X-ray diffraction; the molecular structures of
5d and 5l are reported in the Supporting Information.
An Et instead of a Me group as R1 had a dramatic effect on
stereocontrol (4m→5m); both enantiomeric excess (90% versus
79%) and diastereomeric ratio (88:12 versus 63:37) were
markedly diminished. The precursor with R1 = R2 = Me cyclized
with no diastereocontrol (4n→5n); similar observations had
been made before.[9] Acyclic substrate 4o required three days
for full conversion and the isolated yield was just 53% but the
enantiomeric excess of 5o was very good (86% ee; cf. 80% ee
in Ref. [9]).
Table 1. Development of Nazarov cyclizations catalyzed by C6F5-substituted
boron Lewis acids.
O
O
boron
O
O
O
Lewis acid
O
Me
Ph
+
Me
Me
solvent
RT
Ph
Ph
(S)-3·DMS
(2.4 mol%)
O
O
O
4a
cis-5a
trans-5a
O
O
O
R1
R2
+
d.r.[a]
Yield
[%][b]
ee[c]
R1
R1
Entry
Borane (mol%)
Solvent
Time
1,2-F2C6H4
RT
[%][d]
R2
R2
4b–o
cis-5b–o
trans-5b–o
1
1 (5.0)
CH2Cl2
CH2Cl2
6 h
14 h
2 h
6 h
4 h
4 h
4 h
4 h
4 d
6 h
2 h
87:13
—
93
n.r.
25
92
85
95
89
95
25[g]
93
92
—
O
O
O
2
Ph3B (5.0)
(S)-2·THF (2.4)
—
O
O
O
Me
Me
Me
3
1,2-F2C6H4
1,2-F2C6H4
ClC6H5
n.d.[e]
88:12
90:10
88:12
96:4
–31[f]
90
4
(S)-3·DMS (2.4)
(S)-3·DMS (2.4)
(S)-3·DMS (2.4)
(S)-3·DMS (2.4)
(S)-3·DMS (2.4)
(S)-3·DMS (2.4)
(S)-3·DMS (1.0)
(S)-3·DMS (5.0)
5
82
Me
OMe
Cl
5b: 90% after 6 h
93% ee (cis)
cis:trans = 91:9
5c: 85% after 6 h
64% ee (cis)
5d (X-ray): 86% after 6 h
89% ee (cis)
6
C6H6
82
cis:trans = 92:8
cis:trans = 89:11
7
toluene
62
O
O
O
O
O
O
8
CH2Cl2
85:15
78:22
91:9
87
Me
Me
Me
9
THF
81
Br
10
11
1,2-F2C6H4
1,2-F2C6H4
83
Br
Br
5e: 97% after 6 h
93% ee (cis)
91:9
89
5f: 84% after 6 h
90% ee (cis)
cis:trans = 90:10
5g: 85% after 6 h
96% ee (cis)
cis:trans = 85:15
[a] cis:trans ratio determined by 1H NMR spectroscopy prior to purification. [b]
Combined isolated yield of both diastereomers after purification by flash
chromatography on silica gel. [c] Enantiomeric excess of cis isomer. [d]
Determined by HPLC analysis on a chiral stationary phase. [e] Determination
of the the diastereomeric ratio failed because of low purity. [f] Opposite
absolute configuration. [g] 36% conversion. n.r. = no reaction. n.d. = not
determined.
cis:trans = 90:10
O
O
O
O
O
O
Me
Me
Me
CF3
5h: 96% after 6 h
79% ee (cis)
Ph
5i: 83% after 1 d
86% ee (cis)
5j: 96% after 1 d
85% ee (cis)
cis:trans = 91:9
We then examined the scope of this enantioselective
Nazarov cyclization with the optimized procedure (Scheme 2).
For the preparation of the racemic mixtures, the same set of
precursors was cyclized with B(C6F5)3 (1) as catalyst (see the
Supporting Information for yields and cis:trans ratios). Electronic
and steric variation of the aryl group (R2) in 4 had little effect on
enantioinduction and diastereoselectivity except for strongly
electron-donating OMe (4c→5c) and electron-withdrawing CF3
groups (4h→5h) where the enantioselection eroded to 64 and
79% ee, respectively. The series regioisomeric aryl bromides
4e–g afforded consistently high enantiomeric excesses and
diastereomeric ratios with the highest ee for the ortho isomer.
The diastereoselectivity collapsed with a 1,1’-biphenyl-4-yl group
(4i→5i) but was restored with a β-naphthyl group (4j→5j).
Heteroaryl groups such as fur-2-yl (4k→5k) and thien-2-yl
(4l→5l) were also compatible but the enantiomeric excess was
significantly lower in the latter case. In general, these results,
particularly the cis:trans ratios, compare favorably with those
obtained by Rawal and co-workers.[9] The absolute configuration
cis:trans = 86:14
cis:trans = 77:23
O
O
O
O
Me
O
Me
S
5k: 92% after 9 h
92% ee (cis)
cis:trans = 90:10
5l (X-ray): 90% after 6 h
79% ee (cis)
cis:trans = 94:6
O
O
O
O
O
EtO
Et
Me
Me
Me
5m: 75% after 6 h
79% ee (cis)
cis:trans = 63:37
5n: 86% after 9 h
83% ee (cis)
cis:trans = 57:43
5o: 53% after 3 d
86% ee (cis)
cis:trans = n.d.
Scheme 2. Scope of the enantioselective Nazarov cyclization catalyzed by
(S)-3·DMS (cis:trans ratios determined by 1H NMR spectroscopy prior to
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10.1002/anie.201806011
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purification; combined yields determined after purification by flash
chromatography on silica gel; enantiomeric excesses determined by HPLC
analysis on chiral stationary phases). n.d. = not determined.
[1]
[2]
For reviews of the Nazarov cyclization, see: a) M. G. Vinogradov, O. V.
Turova, S. G. Zlotin, Org. Biomol. Chem. 2017, 15, 8245–8269; b) D. R.
Wenz, J. Read de Alaniz, Eur. J. Org. Chem. 2015, 23–37; c) W. T.
Spencer III, T. Vaidya, A. J. Frontier, Eur. J. Org. Chem. 2013, 3621–
3633; d) T. Vaidya, R. Eisenberg, A. J. Frontier, ChemCatChem 2011,
3, 1531–1548.
Indole-derived 6 had recently been a challenging precursor
in an investigation by Zhu, Zhou, and co-workers using
cooperative catalysis (6→7 with 59% ee (cis) and 97% ee
(trans) and cis:trans = 60:40).[13] Our protocol converted 6
predominantly into the cis isomer of 7 in high yield but the
enantiomeric excess was low (Scheme 3, top); the relative
configuration of 7 was established as cis by X-ray diffraction (the
molecular structure is reported in the Supporting Information).
Also, the unactivated substrate 8 did undergo the ring closure
but led to regioisomeric 9 and 10 with poor enantiomeric
excesses (Scheme 3, bottom). These systems had furnished the
best results with Rawal’s method [e.g., 9 (trans): 78%, 86% ee,
trans:cis > 95:5).[9]
For selected examples with BF3·OEt2 as catalyst, see: a) K. E. Harding,
K. S. Clement, J. Org. Chem. 1984, 49, 3870–3871; b) K. E. Harding, K.
S. Clement, C.-Y. Tseng, J. Org. Chem. 1990, 55, 4403–4410; c) P.
Chiu, S. Li, Org. Lett. 2004, 6, 613–616; d) R. D. Mazzola, Jr., T. D.
White, H. R. Vollmer-Snarr, F. G. West, Org. Lett. 2005, 7, 2799–2801;
e) P. Larini, A. Guarna, E. G. Occhiato, Org. Lett. 2006, 8, 781–784.
a) M. A. Beckett, D. S. Brassington, S. J. Coles, M. B. Hursthouse,
Inorg. Chem. Commun. 2000, 3, 530–533; for an overview of the Lewis
acidity of several electron-deficient boranes, see: b) I. B. Sivaev, V. I.
Bregadze, Coord. Chem. Rev. 2014, 270-271, 75–88.
[3]
[4]
K. Komatsuki, Y. Sadamitsu, K. Sekine, K. Saito, T. Yamada, Angew.
Chem. Int. Ed. 2017, 56, 11594–11598; Angew. Chem. 2017, 129,
11752–11756.
[5]
[6]
M. Mewald, R. Fröhlich, M. Oestreich, Chem. Eur. J. 2011, 17, 9406–
9414.
a) L. Süsse, J. Hermeke, M. Oestreich, J. Am. Chem. Soc. 2016, 138,
6940–6943; b) J. Hermeke, M. Mewald, E. Irran, M. Oestreich,
Organometallics 2014, 33, 5097–5100.
[7]
For Lewis acid-catalyzed enantioselective Nazarov cyclizations, see: a)
V. K. Aggarwal, A. J. Belfield, Org. Lett. 2003, 5, 5075–5078; b) I. Walz,
A. Togni, Chem. Commun. 2008, 4315–4317; c) K. Yaji, M. Shindo,
Synlett 2009, 2524–2528; d) M. Kawatsura, K. Kajita, S. Hayase, T.
Itoh, Synlett 2010, 1243–1246; e) P. Cao, C. Deng, Y.-Y. Zhou, X.-L.
Sun, J.-C. Zheng, Z. Xie, Y. Tang, Angew. Chem. Int. Ed. 2010, 49,
4463–4466; Angew. Chem. 2010, 122, 4565–4568; f) N. Shimada, C.
Stewart, W. F. Bow, A. Jolit, K. Wong, Z. Zhou, M. A. Tius, Angew.
Chem. Int. Ed. 2012, 51, 5727–5729; Angew. Chem. 2012, 124, 5825–
5827; g) Z. Xu, H. Ren, L. Wang, Y. Tang, Org. Chem. Front. 2015, 2,
811–814; h) S. Raja, M. Nakajima, M. Rueping, Angew. Chem. Int. Ed.
2015, 54, 2762–2765; Angew. Chem. 2015, 127, 2801–2804; i) K.
Kitamura, N. Shimada, C. Stewart, A. C. Atesin, T. A. Ateşin, M. A. Tius,
Angew. Chem. Int. Ed. 2015, 54, 6288–6291; Angew. Chem. 2015, 127,
6386–6389.
Scheme 3. Limitations the enantioselective Nazarov cyclization catalyzed by
(S)-3·DMS (cis:trans and regioisomeric ratios determined by 1H NMR
spectroscopy prior to purification; combined yields determined after purification
by flash chromatography on silica gel; enantiomeric excesses determined by
HPLC analysis on chiral stationary phases.
[8]
[9]
a) G. Liang, S. N. Grandl, D. Trauner, Org. Lett. 2003, 5, 4931–4934; b)
G. Liang, D. Trauner, J. Am. Chem. Soc. 2004, 126, 9544–9545.
a) G. E. Hutson, Y. E. Türkmen, V. H. Rawal, J. Am. Chem. Soc. 2013,
135, 4988–4991; for a Cr(III)-salen complex embedded in a metal-
To summarize, we have disclosed here an efficient
enantioselective Nazarov cyclization catalyzed by an axial chiral
variant of B(C6F5)3. As in previous but unrelated work,[6a] the
steric hindrance exerted by the 3,3’-disubstituted binaphthyl
backbone of the boron Lewis acid (S)-3·DMS is crucial for
achieving high enantioinduction. Enantiomeric excesses are
high (up to 96% ee) and cis:trans ratios often synthetically useful.
Our work complements the existing metal-catalyzed
procedures[8,9] and important contributions by Rueping and co-
workers using chiral Brønsted acids.[10] This electrocyclization
also expands the application of B(C6F5)3 and its chiral congeners
to carbon–carbon bond-forming reactions.[11]
organic framework as
a heterogeneous catalyst for the Nazarov
cyclization, see: b) Q. Xia, Y. Liu, Z. Li, W. Gong, Y. Cui, Chem.
Commun. 2016, 52, 13167–13170.
[10] For Brønsted acid-catalyzed enantioselective Nazarov cyclizations of
this substrate type, see: a) M. Rueping, W. Ieawsuwan, A. P.
Antonchick, B. J. Nachtsheim, Angew. Chem. Int. Ed. 2007, 46, 2097–
2100; Angew. Chem. 2007, 119, 2143–2146; b) M. Rueping, W.
Ieawsuwan, Adv. Synth. Catal. 2009, 351, 78–84; c) G. Pousse, A.
Devineau, V. Dalla, L. Humphreys, M.-C. Lasne, J. Rouden, J. Blanchet,
Tetrahedron 2009, 65, 10617–10622; d) S. Raja, W. Ieawsuwan, V.
Korotkov, M. Rueping, Chem. Asian J. 2012, 7, 2361–2366.
[11] For an up-to-date review on B(C6F5)3-catalyzed carbon–carbon bond
formation reactions, see: a) B. Rao, R. Kinjo, Chem. Asian J. 2018, 13,
1279–1292; for representative examples, see: b) K. Ishihara, N. Hanaki,
M. Funahashi, M. Miyata, H. Yamamoto, Bull. Chem. Soc. Jpn. 1995,
68, 1721–1730; c) C. Chen, M. Harhausen, R. Liedtke, K. Bussmann, A.
Fukazawa, S. Yamaguchi, J. L. Petersen, C. G. Daniliuc, R. Fröhlich, G.
Kehr, G. Erker, Angew. Chem. Int. Ed. 2013, 52, 5992–5996; Angew.
Chem. 2013, 125, 6108–6112; d) J.-H. Zhou, B. Jiang, F.-F. Meng, Y.-
H. Xu, T.-P. Loh, Org. Lett. 2015, 17, 4432–4435; e) S. Tamke, Z.-W.
Qu, N. A. Sitte, U. Flörke, S. Grimme, J. Paradies, Angew. Chem. Int.
Ed. 2016, 55, 4336–4339; Angew. Chem. 2016, 128, 4408–4411; f) Y.
Soltani, L. C. Wilkins, R. L. Melen, Angew. Chem. Int. Ed. 2017, 56,
11995–11999; Angew. Chem. 2017, 129, 12157–12161.
Acknowledgements
L.S. and M.V. were supported through an Einstein Visiting
Fellowship of the Einstein Foundation Berlin to Prof. Dr. Douglas
W. Stephan (2016–2019). M.O. thanks the Einstein Foundation
Berlin for an endowed professorship. We are grateful to Sofiya
Marinova for the verification of our early findings.
Keywords: asymmetric catalysis • boron • C–C bond formation •
[12] G. J. P. Britovsek, J. Ugolotti, A. J. P. White, Organometallics 2005, 24,
1685–1691.
electrocyclic reactions • Lewis acids
[13] G.-P. Wang, M.-Q. Chen, S.-F. Zhu, Q.-L. Zhou, Chem. Sci. 2017, 8,
7197–7202.
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Suggestion for the Entry for the Table of Contents
COMMUNICATION
L. Süsse, M. Vogler, M. Mewald, B.
Kemper, E. Irran, M. Oestreich*
Page No. – Page No.
Enantioselective Nazarov
Cyclizations Catalyzed by an Axial
Chiral, C6F5-Substituted Boron Lewis
Acid
Boron with torque! An axial chiral variant of tris(pentafluorophenyl)borane,
B(C6F5)3, promotes Lewis acid-catalyzed Nazarov cyclizations of activated
precursors with high enantiomeric excesses (see scheme). The diastereoselectivity
is also good, usually favoring the cis isomer in synthetically useful ratios. B(C6F5)3
catalyzes the ring closure of the same set of substrates in racemic fashion.
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