Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation

Article abstract of DOI:10.1038/nchem.2710

Axially chiral biaryls, as exemplified by 1,1′-bi-2-naphthol (BINOL), are key components of catalysts, natural products and medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls by a cation-directed O-alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O-alkylation with e.r. up to 98:2. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives without compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating atropisomeric enolates, leading to highly atropselective O-alkylation. This dynamic kinetic resolution process offers a general approach to the synthesis of enantioenriched atropisomeric materials.

Full text of DOI:10.1038/nchem.2710

ARTICLES
PUBLISHED ONLINE: 23 JANUARY 2017 | DOI: 10.1038/NCHEM.2710
Catalytic enantioselective synthesis of atropisomeric
biaryls by a cation-directed O-alkylation
John D. Jolliffe, Roly J. Armstrong and Martin D. Smith
*
Axially chiral biaryls, as exemplified by 1,1′-bi-2-naphthol (BINOL), are key components of catalysts, natural products and
medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross
coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of
an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric
biaryls by a cation-directed O-alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived
ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O-alkylation with e.r.
up to 98:2. Oxidation with DDQ gives access to C2-symmetric and non-symmetric BINOL derivatives without
compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating
atropisomeric enolates, leading to highly atropselective O-alkylation. This dynamic kinetic resolution process offers a
general approach to the synthesis of enantioenriched atropisomeric materials.
tropisomerism is a phenomenon whereby restricted rotation on acidic workup to yield a conjugated alkene. Treatment of this
about a single bond leads to the formation of stereoisomers. material with m-chloroperoxybenzoic acid furnished an epoxide
A
Atropisomerism is a key feature of many natural products, that underwent rearrangement to the desired ketone 1 on treatment
drug molecules and catalysts, and is of increasing importance in all with stoichiometric BF3·OEt2 (ref. 34). Ketone 1 is racemic and
of those fields1–4. Consequently, new methods for the enantioselective point chiral, but does not demonstrate restricted rotation about
synthesis of atropisomeric compounds and especially biaryl derivatives the Cα-aryl bond. With this intermediate in hand, we examined the
are extremely valuable. The utility and importance of this class of ammonium salt catalysed O-alkylation reaction. We were pleased to
stereoisomer is exemplified by 1,1′-bi-2-naphthol (BINOL), which rep- observe that treatment of 1 with benzyl bromide in the presence of
resents a privileged architecture in synthetic chemistry. Conventionally, aqueous KOH and tetra-N-butylammonium bromide afforded
atropisomeric biaryls are synthesized in enantioenriched form through racemic enol ether 2 in 96% yield with no trace of C-alkylation.
metal-mediated cross coupling5, de novo construction of an aromatic Analytical HPLC, using a chiral stationary phase, indicated that 2
ring6, point-to-axial chirality transfer7 or an atropselective transform- was atropisomeric, with no interconversion between enantiomers
ation of an existing biaryl (Fig. 1a)8–11. There are also a growing observed at room temperature on the HPLC timescale. Consequently,
number of metal-free atropselective biaryl syntheses that span these we turned our attention to the possibility of an enantioselective
strategic approaches12–22. We reasoned that a versatile method for the process and were pleased to observe that upon treatment of 1 with a
synthesis of BINOL derivatives could be achieved by using a chiral biphasic mixture of benzyl bromide, N-benzylquinidinium bromide 3,
counterion to achieve atropselective enolate O-alkylation23. Chiral and aqueous potassium hydroxide in toluene we obtained 2 in a
counterions have been used extensively for the synthesis of amino moderate, but promising, 60:40 e.r. (Table 1).
acid derivatives though the C-alkylation of enolates derived from
Changing the base to aqueous cesium hydroxide afforded an
glycine Schiff base derivatives (Fig. 1b)24,25. We proposed that we increase in enantioselectivity (to 73:27 e.r.). We subsequently
could reverse the polarity of this transformation26 and access O-alky- explored >30 catalysts for this transformation in combination with
lation as an alternative mode of reactivity. This could be achieved by a range of solvents and bases; for a full account of the optimization
the use of a ketone as the enolate precursor rather than an ester27–30
,
process employed see Supplementary Information page 6. We par-
and suppression of C-alkylation through steric hindrance. We reasoned ticularly focused on how the nature of the N-pendant group on the
that this principle could be applied to the atropselective alkylation of 1- quinidine-derived catalyst could influence enantioselectivity.
aryl-2-tetralones by a dynamic kinetic resolution process31, leading to Changing from N-benzyl (in 3) to N-3,5-bis(trifluoromethyl)
an organocatalytic synthesis of enantioenriched BINOLs (Fig. 1c). benzyl (in 4) led to an incremental increase in atropselectivity (to
This has the potential to be an especially valuable process, as it 80:20 e.r.), and applying 2-naphthyl derivative 5 increased selectiv-
would enable access to non-C2-symmetrical biaryl diols. These com- ity further (to 83:17 e.r.). A further increase in selectivity (to 88:12 e.r.)
pounds are particularly challenging to assemble, and general catalytic was observed when N-2,3,4-trifluorobenzyl containing catalyst 6
enantioselective methods for their synthesis are not currently avail- was used. Assessment of the architecturally distinct phase-transfer
able32, despite their value as ligands and catalysts33.
catalyst 7, introduced by Maruoka35, led to a significant drop in
enantioselectivity (53:47 e.r.) and so this class of catalyst was not
investigated further. We subsequently examined a series of base
Results
A suitable 1-aryl-2-tetralone substrate to probe the potential for and solvent combinations, which established that an increase in
atropselective O-alkylation was prepared on a multi-gram scale in enantioselectivity (to 92:8 e.r.) could be attained by switching the
three preparative steps. This involved a cerium(III) mediated solvent to benzene and the base to solid potassium phosphate36.
addition of the Grignard reagent derived from 1-bromo-2-methox- To establish whether the free OH group in 6 was playing a role in
ynaphthalene to α-tetralone, with subsequent elimination of water the performance of this catalyst, we generated 8 in which this
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. e-mail: martin.smith@chem.ox.ac.uk
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2710
ARTICLES
a
b
Selective biaryl
bond formation
Point-to-axial
chirality transfer
R2
R3
R1
R4
R2
R3
R1
R4
H
X
Y
+
R4N Br–
Ph R1
N
Ph
(i)
(ii)
t
t
Ph
N
CO2 Bu
Ph
CO2 Bu
Base, R1-Br
R1
R4
R2
R3
c
R2
R1
R1
R2
R1
R2
+
R4N Br–
R2
R3
O
OR3
R1
R3
OBn
OR3
(iv)
(iii)
Z
Base, BnI
then [ox]
R3
Atropselective
arene formation
Desymmetrization
of an existing biaryl
22 examples, up to 98:2 e.r.
R4 R4
Figure 1 | Strategies for the enantioselective synthesis of biaryls. a, Previous approaches to the enantioselective synthesis of biaryls include: (i) metal-
mediated cross coupling, where enantioselectivity arises in the formation of the biaryl C–C bond; (ii) point-to-axial chirality transfer, where an existing
stereocentre in the molecule influences atropselectivity; (iii) atropselective transformation of an existing biaryl by desymmetization, kinetic resolution or
dynamic kinetic resolution; and (iv) [2 + 2 + 2] cycloaddition, where a chiral catalyst controls the union of two fragments to generate a new aromatic ring.
b, Previous ammonium-salt-catalysed amino-acid synthesis by enantioselective C-alkylation of a glycine Schiff base derivative. c, A new approach to the
enantioselective synthesis of atropisomeric biaryls by a counterion-directed O-alkylation.
Table 1 | Optimization of atropselective O-alkylation.
OMe
N
Ar2
Br–
nBu
Br–
OR1
H
Catalyst
Base
+
N +
nBu
N
O
OBn
OMe
Ar1
OMe
Solvent
Bn-X
Ar2
3 Ar1 = Ph, R1 = H
4 Ar1 = 3,5-(CF3)2-C6H3, R1 = H
5 Ar1 = 2-naphthyl, R1 = H
(S)-7
Ar2 = 3,4,5-F3-C6H2
1
2
6 Ar1 = 2,3,4-F3-C6H2, R1 = H
8 Ar1 = 2,3,4-F3-C6H2, R1 = Bn
Cat.
Base
Solvent
Temp.
Electrophile
e.r.*
3
3
4
5
6
7
6
6
6
8
6
6
KOH (aq.)
CsOH (aq.)
CsOH (aq.)
CsOH (aq.)
CsOH (aq.)
CsOH (aq.)
K2CO3 (s)
K3PO4 (s)
K3PO4 (s)
K3PO4 (s)
K3PO4 (s)
K3PO4 (s)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
C6H6
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0 °C
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnI
60:40
73:27
80:20
83:17
88:12
53:47
89:11
90:10
92:8
C6H6
66:34
94:6
96:4
C6H6
C6H6/CH2Cl†2
BnI
*Determined by chiral HPLC analysis. †Ratio of solvents is 4:1. Cat., catalyst; temp., temperature.
functional group is capped as a benzyl ether. This catalyst delivered Information, page 82). Using this highly enantioenriched material,
product in significantly lower enantioselectivity (66:34 e.r.), consist- we decided to probe the barrier to rotation in enol ether 2 by reflux-
ent with observations from us37 and others38 that Brønsted acidic ing in m-xylene (139 °C) and measuring the erosion in e.r. over time.
groups can play a key role in both catalytic activity and selectivity This demonstrated that t1/2rac (in solution at 139 °C) is 64 min, which
of phase-transfer catalysts. We finally considered whether the reac- corresponds to a barrier to rotation of 134 kJ mol−1 at 139 °C.
tivity of the electrophile could play a role in this process, which A barrier to rotation of this magnitude is sufficiently high to
demonstrated that the use of benzyl iodide increased selectivity essentially preclude any room temperature racemization.
further (to 94:6 e.r.), which could be augmented (to 96:4 e.r.) by
With optimized conditions for the enantioselective generation of
running the reaction at 0 °C using a benzene/dichloromethane enol ether 2 in hand, we examined its in situ oxidation to a differ-
solvent mixture. By employing a pseudoenantiomeric quinine- entially protected BINOL. Our attempts to combine the alkylation
derived catalyst, the opposite absolute configuration could be pro- and oxidation reactions using DDQ were successful, but the
duced with only a small drop in e.r. (6:94 e.r., see Supplementary process was slow and conversion was inconsistent. Consequently,
2
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Table 2 | Scope of enantioselective cation-directed O-alkylation.
BnI, K3PO4
ARTICLES
5
4
OMe
N
R1
R1
OH
R1
R2
2
C6H6/CH2Cl2
DDQ
+
O
OBn
OR3
OBn
OR3
2'
N
OR3
CH2Cl2
r.t., 2 h
+
H
Br–
R4N
R2
R2
+
R4N
F
F
0 °C, 48 h
F
OBn
OMe
OBn
OBn
OBn Ph
Me
OBn
OMe
F
OBn Cl
OMe
OBn Br
OMe
OBn
OMe
9
10
11
12
13
14
15
95% yield; 96:4 e.r. 70% yield; 96:4 e.r. 30% yield; 75:25 e.r.
86% yield; 96:4 e.r.
99% yield; 96:4 e.r. 93% yield; 96:4 e.r.
87% yield; 96:4 e.r.
F
Br
Me
3,4-Cl2C6H3
Ph
Me
OBn
OMe
OBn
OMe
OBn
OMe
OBn
OMe
OBn
OMe
OBn
OMe
OBn
OMe
16
17
18
77% yield; 94:6 e.r.
19
20
21
22
92% yield; 96:4 e.r. 63% yield; 93:7 e.r.
94% yield; 96:4 e.r.
96% yield; 96:4 e.r. 55% yield; 96:4 e.r.
69% yield; 93:7 e.r.
Me
Me
OBn
OMe
OBn
OMe MeO
OBn
OMe
OBn
OMe
OBn
OMe
OBn
OMe
Ph
Me
Ph
26
X-ray
23
24
25
53% yield; 92:8 e.r.
26
99% yield; 98:2 e.r.
27
84% yield; 97:3 e.r.
28
81% yield; 91:9 e.r. 40% yield; 91:9 e.r.*
61% yield; 97:3 e.r.
Reaction conditions: (i) 0.2 mmol ketone, 3 equiv. BnI, 10 equiv. K3PO4 (s), 10 mol% catalyst 6, 4:1 C6H6/CH2Cl2 (v/v), 0 °C, 48 h; then 3 equiv. DDQ, CH2Cl2, 2 h. e.r. determined by chiral HPLC analysis.
Yields are for isolated material and are quoted over two steps from ketone starting materials. Positions around the BINOL core are indicated with red numerals. *DDQ oxidation required 24 h.
we switched solvents to dichloromethane for the oxidation, and Introduction of an alkyl group at this position was also tolerated;
under these conditions a clean reaction was observed in under 2 h 7-methyl BINOL derivative 16 was generated in 92% yield and
at room temperature, leading to the synthesis of 2-O-methyl-2′-O- 96:4 e.r. Exchanging one hemisphere of the BINOL core from
benzyl-BINOL 9 in 95% yield and 96:4 e.r., demonstrating that 2-naphthol to 2-phenanthrenol (as in 17) had only a minor impact
there was no erosion of e.r. during the oxidation process (Table 2). on enantioselectivity (93:7 e.r.) but this demonstrates that the intro-
We were able to establish that the absolute configuration of 9 is duction of sterically demanding substituents in this position is poss-
(S) through comparison with both literature optical rotation values ible. We next examined substitution in the 5-position, and were
and with an authentic sample prepared from (S)-BINOL. With an pleased to observe that halogens such as fluorine (19, 96:4 e.r.,
optimal procedure achieved, we assessed the scope of this catalytic 94% yield), and bromine (20, 96:4 e.r., 96% yield) could be intro-
enantioselective reaction. Changing the phenolic group from a duced whilst maintaining high levels of enantioselectivity and reac-
methyl ether to a benzyl ether (as in 10) did not impact on the selec- tion yield. A 5-methyl derivative, 21, was also generated in high
tivity of the overall process (70% yield and 96:4 e.r.). We were inter- enantiomeric purity (96:4 e.r.) and good yield. Introduction of
ested whether the 2′ oxygen substituent was essential for reactivity groups in the 4-position is also possible: 4-aryl substituted com-
and enantioselectivity, and replaced it with a methyl group. This pound 22 was synthesized in 93:7 e.r. and 69% yield, and
substrate led to biaryl 11 in moderate enantioselectivity (75:25 e.r.) 4-methyl derivative 23 was generated in 91:9 e.r. and 81% yield.
and only poor conversion to product (25%). This is indicative of Installing a substituent in the 3-position is also possible; 24 can
the oxygen substituent playing an important role for both reactivity be synthesized in 91:9 e.r. and 40% yield. The relatively low yield in
and selectivity. We subsequently examined the impact of introdu- this case is probably a consequence of slow reaction during the
cing substituents in the BINOL 7-position. 7-Phenyl compound DDQ oxidation; the prolonged reaction times required to consume
12 was generated in 96:4 e.r. and 86% yield, implying that introdu- both diastereoisomers of the intermediate enol ether led to deleterious
cing steric bulk at this position was unlikely to be deleterious to side reactions (see Supplementary Information page 100). Introduction
the reaction. This was confirmed by the reaction of substrates of a substituent at the 7ʹ position is possible, as demonstrated by
with halogens in the 7-position, which proceeded smoothly and methoxy derivative 25 (53% yield; 92:8 e.r.), and groups such as
with high levels of enantioselectivity to afford 7-fluoro (13, 96:4 e.r.), phenyl and methyl can also be introduced in the 6ʹ position (26:
7-chloro (14, 96:4 e.r.) and 7-bromo derivatives (15, 96:4 e.r.). 99% yield, 98:2 e.r.; 27: 84% yield, 97:3 e.r.). The formation of 7ʹ
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ARTICLES
Axially chiral enol ether 2 (96:4 e.r.) underwent diastereoselective
oxidation with m-chloroperoxybenzoic acid to afford an intermedi-
ate epoxide that rearranged to point chiral 1-alkoxy-2-tetralone 29
(93:7 e.r.) in the presence of catalytic ytterbium triflate. The absolute
configuration of 29 was confirmed by single crystal X-ray diffraction
(see Supplementary Information page 123). The BINOL derivative 9
could be globally dealkylated with boron tribromide to afford 30
(99% yield, 96:4 e.r.) or selectively debenzylated by hydrogenolysis
in the presence of palladium on carbon yielding 31 (96% yield,
96:4 e.r.). Treatment of BINOL 9 with n-butyllithium in diethyl
ether led to a diastereoselective [1,2]-Wittig rearrangement,
affording 32 as a single diastereoisomer without compromising
enantioselectivity (96:4 e.r.)39.
DDQ
CH2Cl2
BBr3
CH2Cl2
OBn
OMe
OBn
OMe
OH
OH
2
9
30
99% yield, 96:4 e.r.
96:4 e.r.
99% yield, 96:4 e.r.
mCPBA, CH2Cl2,
then Yb(OTf)3
n-BuLi
Et2O
H2, Pd/C
MeOH/EtOAc
Ph
O
OH
OH
OMe
OBn
OMe
OMe
Mechanistic considerations: a counterion-directed dynamic
kinetic resolution. The reaction probably proceeds by initial
interfacial deprotonation of the racemic 2-tetralone 1 with solid
potassium phosphate to generate axially chiral and racemic
potassium enolates (Fig. 3). These stereoisomeric potassium
enolates can interconvert through rapid and reversible
protonation and deprotonation via tetralone 1. We expect that
counterion metathesis with the chiral ammonium salt generates
soluble diastereoisomeric ion pairs 33 and 34, which are alkylated
at different rates to give the observed atropselectivity, with 2 as
the major enantiomer (and 35 as the minor enantiomer).
This selectivity could be augmented through selective transport
to the solution phase of one enantiomer of the axially chiral potass-
ium enolate by the ammonium salt to generate 33 (in a higher con-
centration than 34), which is subsequently alkylated. It has been
previously observed in the enantioselective alkylation of Schiff
bases that the phase-transfer catalyst becomes alkylated during the
reaction, and that this is the active catalytic species19. Alkylation
of catalyst 6 to give 8 is slow under the reaction conditions, and
the e.r. of the product is constant throughout, indicating that the
active catalyst does not change during the reaction. Running the
reaction at different concentrations of electrophile (over a 40-fold
29
94% yield, 93:7 e.r.
32
31
96% yield, 96:4 e.r.
85% yield, 96:4 e.r.
Figure 2 | Chemoselective derivatization of axially chiral enol ether
intermediate and BINOL products. Orthogonal functional groups lead to
chemo- and stereoselective derivatization. Axially chiral enol ether 2
undergoes oxidation with m-chloroperoxybenzoic acid (mCPBA) to furnish
point chiral 1-alkoxy-2-tetralone 29 following rearrangement in the presence
of ytterbium triflate. The BINOL derivative 9 could be globally dealkylated,
selectively debenzylated by hydrogenolysis, or undergo a diastereoselective
[1,2]-Wittig rearrangement, providing access to a variety of functionality
from a common precursor.
aryl derivative 26 could also be performed on a gram scale without
significantly compromising yield or e.r. (96% yield, 98:2 e.r.). We
were also able to crystallize 26 and confirm absolute stereochemistry
through single crystal X-ray diffraction (see Supplementary Information
page 122). Installation of a 3′ substituent was also possible; we were able
to synthesize 28 in 61% yield and 97:3 e.r.
With an enantioselective route to enol ether 2 and BINOL
derivative 9 in hand, we examined whether these intermediates
could be derivatized chemoselectively (Fig. 2).
a
+
Br–
K3PO4 (s), R4N
+
O–
Fast
BnI
OBn
OMe
R4N
Major enantiomer
OMe
33
2
O
Point chiral
and racemic
Axially chiral
enolates
OMe
1
+
O–
OBn
OMe
R4N
Slow
BnI
Minor enantiomer
OMe
+
Br–
K3PO4 (s), R4N
34
35
b
D
D
+
Br–
K3PO4 (s),
R4N
F
O
+
O
F
O
O
D
OMe
+
D
H
D
OMe
OMe
OMe
C6H6/CH2Cl2, 0 °C
36 1:9, H:D
1 10:0, H:D
37 5:1, H:D
38 5:1, H:D
Figure 3 | Proposed mechanism for observed enantioselectivity by variable rates of O-alkylation. a, Rapid and reversible interconversion of the point chiral
and racemic 2-tetralone to axially chiral diastereoisomeric ammonium enolates, which are then O-alkylated at different rates, is proposed. Biased populations
of diastereoisomeric ammonium enolates 33 and 34 could be generated under these conditions. b, Transfer of deuterium between substrates under the basic
reaction conditions is consistent with enolate equilibration. Ratios for 37 and 38 reflect total deuteration across C-1 and C-3.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2710
ARTICLES
17. Armstrong, R. J. & Smith, M. D. Catalytic enantioselective synthesis of
concentration change) does not change the enantioselectivity of the
process, consistent with the rate of alkylation being slow relative to
interconversion of the axially chiral enolates. To probe whether
enolate equilibration occurs under the reaction conditions, we pre-
pared deuterated compound 36 (90% D). Treatment of a 3:1 mixture
of 36 and non-deuterated 2-tetralone 1 in the presence of catalyst 6
and solid potassium phosphate base led to distribution of the deu-
terium label across both tetralones, leading to 37 and 38, in which
deuterium is predominantly present at C-3 (see Supplementary
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leading to highly enantioselective O-alkylation. This dynamic
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Received 29 April 2016; accepted 30 November 2016;
published online 23 January 2017
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Acknowledgements
The European Research Council has provided financial support under the European
Community’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement
no. 259056. We are grateful to EPSRC for a DTP award (to J.D.J.). We are grateful to
J. Wickens and B. Odell (Oxford Chemistry) for their valuable assistance with
spectroscopic techniques.
Author contributions
M.D.S., J.D.J. and R.J.A. conceived and designed the study. J.D.J. and R.J.A. performed the
synthetic experiments and analysed data for all compounds. M.D.S., J.D.J. and R.J.A.
co-wrote the paper.
Additional information
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atropisomers via peptide-catalyzed asymmetric bromination. Science 328,
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Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to M.D.S.
16. Shirakawa, S., Wu, X. & Maruoka, K. Kinetic resolution of axially chiral 2-
amino-1,1′-biaryls by phase-transfer-catalyzed N-allylation. Angew. Chem. Int.
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Competing financial interests
The authors declare no competing financial interests.
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