Lipase-Catalyzed Dynamic Kinetic Resolution of C1- and C2-Symmetric Racemic Axially Chiral 2,2′-Dihydroxy-1,1′-biaryls

Article abstract of DOI:10.1002/anie.201804161

We have discovered that the racemization of configurationally stable, axially chiral 2,2′-dihydroxy-1,1′-biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35–50 °C. Combining this racemization procedure with lipase-catalyzed kinetic resolution led to the first lipase/metal-integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio-enriched C₁- and C₂-symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis.

Full text of DOI:10.1002/anie.201804161

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Accepted Article
Title: Lipase-Catalyzed Dynamic Kinetic Resolution of C1- and C2-
Symmetric Racemic Axially Chiral 2,2'-Dihydroxy-1,1'-biaryls
Authors: Gamal Moustafa, Yasuhiro Oki, and Shuji Akai
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804161
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10.1002/anie.201804161
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COMMUNICATION
Lipase-Catalyzed Dynamic Kinetic Resolution of C1- and C2-
Symmetric Racemic Axially Chiral 2,2’-Dihydroxy-1,1’-biaryls
Gamal A. I. Moustafa,[a,b] Yasuhiro Oki,[a] and Shuji Akai*[a]
applied to centrochiral substrates (Figure 1A).[8] To the best of
our knowledge, there is only one report from Bäckvall’s group
Abstract: We have discovered that the racemization of
configurationally stable, axially chiral 2,2’-dihydroxy-1,1’-biaryls
proceeds with a catalytic amount of a cyclopentadienylruthenium(II)
that uses this strategy on axially chiral compounds, in particular
complex at 35–50 °C. Combining this racemization procedure with
axially chiral allenes (Figure 1B).[9] With this background in mind,
lipase-catalyzed kinetic resolution led to the first lipase/metal-combo-
we now report the first chemoenzymatic DKR of C1- and C2-
symmetric atropisomeric 2,2’-dihydroxy-1,1’-biaryls that tend to
racemize during oxidative biaryl coupling.[10,11] Notably,
catalyzed dynamic kinetic resolution of racemic axially chiral biaryls.
The method was applied to the synthesis of various enantio-enriched
C1- and C2-symmetric biaryl diols in yields of up to 98% and
racemization, which is a critical problem in the biaryl coupling
strategy, is a favorable, and even crucial process in our present
DKR (Figure 1C).
enantiomeric excesses of up to 98%, which paves the way for new
developments in the field of asymmetric synthesis.
Homochiral 2,2'-dihydroxy-1,1'-biaryls (e.g., 1,1'-bi-2-
naphthols (BINOLs)) are widely used as chiral auxiliaries as well
as building blocks for versatile optically active natural products
and chiral ligands.[1] Hence, efficient enantioselective methods
for their syntheses have attracted considerable developmental
attention.[2] Typically, optically active BINOLs are synthesized by
enzymatic or chemical resolution of racemic substrates.[1a,c,3] In
addition, the enantioselective oxidative couplings of 2-naphthol
derivatives catalyzed by chiral, non-racemic copper, iron, and
vanadium complexes provides
a more direct and atom-
economical route to C2-symmetric BINOLs.[4] Unfortunately, the
latter approach can suffer from product racemization leading to a
drop in optical purity because this oxidative coupling proceeds
through the formation of radical intermediates and similar
coupling-product radicals are also generated under the same
reaction conditions, particularly in the case of BINOL itself and
its 6,6’-disubstituted derivatives.[4d-g] Substrates are also limited
when certain metal catalysts are used for oxidative coupling.[4e-g]
Similarly, the practical asymmetric synthesis of optically active
C1-symmetric, i.e., unsymmetrically substituted, BINOLs[1d,6] by
oxidative coupling is still underdeveloped, which is, in part, due
to the unavoidable formation of homocoupling products; in some
cases, the preferred cross coupling specifically requires the
coupling of 2-naphthol partners of sufficiently different oxidation
potential. Apart from Katsuki’s report on the asymmetric
syntheses of 3-substituted C1-symmetric BINOLs through the
iron(salen)-mediated cross couplings of 3-substituted 2-
naphthols with 6-substituted 2-naphthols,[7] the group of Pappo
reported an iron phosphate-catalyzed cross coupling en route to
enantio-enriched 3-unsubstituted C1-symmetric BINOLs.[4d]
However, undesired racemization in the latter approach
decreased the optical purity of the products. On the other hand,
chemoenzymatic dynamic kinetic resolution (DKR), which
combines enzyme-catalyzed kinetic resolution (KR) of
racemates with the in-situ rapid interconversion of both
enantiomers, has enabled the production of enantiopure
compounds in a single pot and in yields of up to 100%. To date,
the majority of chemoenzymatic DKRs have used a combination
of lipases and transition-metal-based catalysts and have been
Figure 1. Strategies for lipase-catalyzed dynamic kinetic resolution (DKR).
The central challenge in the present study was the discovery
of a suitable racemization process that is compatible with lipases
while maintaining its catalytic activity in a single flask.[12] We set
out to examine various transition metal complexes that smoothly
racemize optically pure BINOL ((R)-1a) as a model substrate
(Table 1). In anticipation that racemization can proceed by a
redox process between (R)-1a and (S)-1a, readily available
redox catalysts that transfer either one or two electrons were
examined.[1c,4,8] A significant decrease in the optical purity (% ee)
of (R)-1a was observed when Pd/C (10 mol%), Ru/C (10 mol%),
or CuCl(OH)•TMEDA complex[13] (10 mol%) was used (Table 1,
entries 1, 3, and 4). However, the use of these catalysts was
hampered by their low compatibilities with lipases and/or poor
racemization reproducibilities (see Supporting Information, SI);
consequently, other transition-metal catalysts were examined.
Catalyst 2, activated in situ by partial decarbonylation with
trimethylamine-N-oxide,[14] and 3[15] were ineffective (entries 5
and 6). Moreover, the activity of 3 was not improved by the
addition of 1,4-bis(diphenylphosphino)butane (dppb) (entry 7).[16]
(R)-1a slowly racemized in the presence of Shvo’s complex 4,[17]
retaining 62% ee after 24 h (entry 8). Gratifyingly, RuII
complexes 5[18] and 6[19] were highly efficient (entries 9 and 10).
In particular, catalyst 6, activated in situ by t-BuOK, promoted
the racemization of 1a at 35 °C, resulting in an ee of 8% after
only 4 h (racemization half-life = 72 min at 35 °C; for
racemization time course, see SI). The best result was obtained
in toluene, whereas relatively polar ethereal and halogenated
solvents dramatically reduced the racemization rate (for solvent
screening, see SI).
[a]
[b]
Dr. G. A. I. Moustafa, Y. Oki, Prof. Dr. S. Akai, Graduate School of
Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka,
Suita, Osaka 565-0871, Japan. E-mail: akai@phs.osaka-u.ac.jp
Dr. G. A. I. Moustafa
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia
University, Minia 61519, Egypt.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804161
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To gain insight into the mechanism for the racemization of
1a by catalyst 6, a competitive kinetic study of BINOL derivatives
1b and 1c, bearing an electron-donating MeO and an electron-
withdrawing alkoxycarbonyl group, respectively, was carried out.
The relative rates of racemization followed the order: 1b > 1a >
1c (Scheme 2; for details, see SI), indicating the electron density
of the aromatic moiety has a significant impact, and supporting a
redox mechanism in which the oxidation step leading to the
disruption of aromaticity is rate-limiting. Since catalyst 6 is
known to racemize sec-alcohols by transfer hydrogenation,[20]
we initially proposed a similar mechanism in which (R)-1a is
oxidized to intermediate I followed by hydride reduction to
generate racemic 1a (Scheme 3A). However, such a proposal
was not validated by any experimental evidence. There
remained the possibility that racemization proceeds by a radical
mechanism, by analogy with the recently reported FeCl3/t-
BuOOt-Bu-catalyzed racemization of BINOLs.[4d,21]. Hence, we
assume that a single electron transfer (SET) process in the RuIII
binaphtholate complex III, generated through the oxidation of the
RuII complex II by oxygen, leads to radical intermediate IV
bearing an sp3 carbon at the C1 position, which enables free
rotation around the chiral axis leading to racemic 1a (Scheme
3B). The formation of the RuIII species from the RuII catalyst 6a
and its ability to facilitate SET were supported by our study in air
or oxygen, in which 6a promoted the oxidative coupling of 2-
naphthol to afford 2,2’-binaphthol through an SET mechanism
(for details and additional studies on the racemization
mechanism, see SI).[22]
Scheme 2. Kinetic study for racemization of (R)-BINOLs 1a-c.
We next optimized the lipase-catalyzed KR process. The
previously reported enzymatic KR of racemic 1a[23] was revisited
to improve its relatively low reaction rate and to identify ideal
conditions for combination with the racemization process. Hence,
various commercially available lipases, acyl donors, and
solvents for the KR of (±)-1a were screened (for details, see SI);
the highest enantioselectivity (E value > 100) and reaction rate
were obtained with immobilized Pseudomonas sp. lipoprotein
lipase (Toyobo LIP301) (4 w/w) (Scheme 4). Moreover, the KR
was faster in nonpolar solvents such as iPr2O and toluene using
vinyl acetate or isopropenyl acetate as the acyl donor. Although
a higher conversion was observed in iPr2O, toluene was
selected for the DKR study because it was the best racemization
solvent.
Table 1. Survey of racemization catalysts via plausible redox mechanism.
entry metal [M][a] (eq) additive (eq)
solvent
temp
(°C)
time ee (%)
(h) of 1a
1
2
3
4
Pd/C (0.10)
Ru/C (0.10)
Ru/C (0.10)
-
toluene
toluene
toluene
toluene
50
50
50
35
6
6
6
4
38
78
28
13
-
under H2
under O2
Cu(OH)Cl•
TMEDA (0.10)
Scheme 3. (A) Our initial proposal for racemization of (R)-1a via transfer
hydrogenation. (B) A more plausible mechanism of racemization of (R)-1a via
a single electron transfer (SET) process.
Me3NO (0.1),
Na2CO3 (1)
5
2 (0.10)
anisole
50-90
16
99
6
7
3 (0.08)
3 (0.10)
Et3N (1)
toluene
THF
50
6
8
99
99
dppb (0.1),
t-BuOK (0.1)
35-50
8
9
4 (0.05)
5 (0.04)
6 (0.04)
-
toluene
toluene
toluene
70
35
35
24
29
4
62
23
8
t-BuOK (0.05)
t-BuOK (0.05)
10
[a] Catalysts used in this study are shown below.
Scheme 4. Lipase-catalyzed KR of racemic 1a-c.
With the optimized conditions for both racemization and
KR in hand, we next combined the two processes in one pot. In
our initial attempt, the DKR of (±)-1a was carried out using
catalyst 6 and LIP, which resulted in up to 60% yield of ester
(R)-7a with low enantioselectivity even after prolonged reaction
time or increased temperature (Table 2, entries 1 and 2). The
high optical purity of recovered (S)-1a indicated that
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Table 3. LIP/Ru 6 combo-catalyzed DKR of (±)-1a–p.
racemization did not take place, presumably due to catalyst
poisoning by the moisture in LIP301. However, the reaction was
unsuccessful even when LIP301 was azeotropically dried with
toluene under vacuum prior to use (entry 3). Increasing the
loading of 6 was also not beneficial (entry 4). The effect of
molecular sieves (MS) 4Å in toluene was next examined,[19] but
neither the ee of (R)-7a nor the racemization process was
significantly improved (entry 5). Notably, increasing the amount
of 6 to 10 mol% in the presence of MS 4Å slightly promoted
racemization and increased the ee of (R)-7a; however, a longer
reaction time was required (entry 6). Under these conditions,
increasing the temperature to 50 °C resulted in decomposition of
1a (entry 7). Other types of activated MS were then examined at
35 °C (entries 8 and 9). To our delight, racemic 1a was
successfully converted into (R)-7a in 83% isolated yield and
93% ee in the presence of MS 5Å (3 w/w), 6 (10 mol%), LIP301
(5 w/w), and isopropenyl acetate (20 equiv.) (entry 10, for
additional details, see SI). It should be noted that the acylated
product 7a does not undergo any racemization by catalyst 6 (for
details, see SI)．To the best of our knowledge, this is not only
the first example of the lipase-catalyzed DKR of an axially chiral
biaryl but also the first time that Pseudomonas sp. lipoprotein
lipase has been used in a DKR process. The addition of MS 5Å
was crucial for accelerating the reaction rate and augmenting
the compatibility of the two catalytic systems (for details, see SI).
Under the optimized DKR conditions, binaphthols bearing
methoxy (1b), methyl (1d), or bromo substituents (1e) were
converted into the corresponding optically active binaphthols
(R)-1b, (R)-1d, and (R)-1e in 85–98% isolated yields and
excellent ees (95–96%) after ester hydrolysis of the DKR
products (Table 3). In particular, clean and complete conversion
of 1b to (R)-1b was achieved with only 5 mol% of 6 and a
reaction time of 24 h, which is ascribed to electron-donating-
group-assisted rapid racemization of 1b. Binaphthol 1c bearing
an electron withdrawing alkoxycarbonyl group also underwent
DKR to give (R)-1c in 61% yield (98% ee). Similarly, slow-
racemizing substrates 1f and 1g were converted into (R)-1f
(62% yield, 89% ee) and (R)-1g (79% yield, 83% ee). The
method was also applicable to biphenol derivative 1h to give
(R)-1h (74% yield, 92% ee), which is difficult to access using
conventional asymmetric biaryl coupling reactions.
[a] 6 (5 mol%) was used and reaction time was 24 h. [b] Reaction was done at
50 °C. [c] 6 (5 mol%) was added in two portions (at the beginning and after 24
h); reaction temp. was 35 °C for the first 24 h and 50 °C for the next 24 h. [d] 6
(12 mol%) was used; substrate concentration was 0.033 M and MS 5Å (6 w/w)
was used. [e] 6 (5 mol%) was added in two portions (at the beginning and after
24 h). [f] Na2CO3 (1.5 eq.) was added. [g] 6 (2.5 mol%) was used. [h] 6 (5
mol%), 2.5 w/w LIP301 and 5 eq. isopropenyl acetate were used.
It is worth noting that this method was applicable to C1-
symmetric 2,2'-binaphthols that are also important chiral
auxiliaries.[1d,6] Hence, (±)-1i–p were converted into
(R)-1i–p in high chemical yields and optical purities.
In particular, (±)-1j,1l, and 1p, bearing electron-
donating MeO or 4-MeO-C6H4 substituents at the C6
position, were successfully converted into (R)-1j,
(R)-1l, and (R)-1p in 81–97% yields and with
excellent ees (93–97%); these compounds are
difficult to obtain in such high optical purities using
known enantioselective oxidative coupling methods
due to partial racemization of the products.[4d-g,7]
Moreover, asymmetric 2,2’-binaphthols bearing
bromo (1i) or alkyl (1k) substituents were efficiently
resolved to (R)-1i (92% yield, 93% ee) and (R)-1k
(77% yield, 94% ee). On the other hand, our method
still needs further improvement regarding the
reactivities and enantioselectivities of 2,2’-
binaphthols bearing substituents at the C3 position,
such as 1n.
Table 2. Selected results on the optimization of the LIP/Ru cat. 6-integrated DKR of (±)-1a.
entry
LIP301
(w/w)
additive
temp.
(°C)
time
(h)
(R)-7a
(S)-1a
yield
Ru cat. 6
(mol %)
yield
(%)[a]
ee
ee
(%)
(%)[a]
40
43
44
44
33
23
2
(%)
1
2
3
4
5
6
7
8
4
4
4
-
35
50
35
35
35
35
50
35
72 60
53
65
76
69
79
89
92
89
99
84
99
98
98
56
5
4
-
48 54
48 51
48 55
48 66
72 68
48 68
48 62
4
4[b]
4[b]
4[b]
4[b]
-
10
4
-
MS 4Å (3.0 w/w)
MS 4Å (3.0 w/w)
In conclusion, in contrast to the former lipase-
catalyzed DKR strategies that have been applied to
substrates with stereogenic centers, the present
study demonstrates, for the first time, the
applicability of the enzymatic DKR concept to axially
chiral 2,2‘-dihydroxy-1,1‘-biaryls. The combination of
10
10
10
4[b] MS 4Å (3.0 w/w)
4[b]
MS 3Å (3.0 w/w)
15
52
9
10
10
4[b] MS 13X (3.0 w/w) 35
5[b]
MS 5Å (3.0 w/w) 35
48 51
94
93
49
13
50
23
Ru-catalyzed
racemization
and
highly
enantioselective lipase-catalyzed KR facilitates the
practical atropselective synthesis of C2-symmetric,
as well as non-C2-symmetric binaphthols, in addition
10
48 76 (83)
[a] Determined by 1H-NMR analysis of a crude product, and the isolated yield is shown in
parenthesis. [b] LIP301 was azeotropically dried with toluene.
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10.1002/anie.201804161
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to biphenol derivatives, from readily available racemic substrates.
A key feature of this study was the identification of ruthenium
c) J. R. Zbieg, E. Yamaguchi, E. L. McInturff, M. J. Krische, Science
2012, 336, 324.
complex
6 that facilitates racemization through a radical
[7] H. Egami, K. Matsumoto, T. Oguma, T. Kunisu, T. Katsuki, J. Am. Chem.
Soc. 2010, 132, 13633.
intermediate that attenuates the configurational stability of the
axially chiral biaryl diols under mild conditions even at 35 °C.
Well-investigated enantioselective oxidative biaryl couplings
sometimes suffer from decreases in optical purity of products
through radical-mediated racemization.[4,5] In contrast, such
undesired racemizations are advantageous in our DKR. Another
key feature of our method is sufficient stability of the acylated
products against racemization under the DKR conditions.
Therefore, our method reliably produces 3- and 7-unsubstituted
BINOLs that are difficult to obtain in optically pure form by
asymmetric oxidative coupling.[4] We believe this method will
open new avenues in the field of asymmetric synthesis based on
enzymatic and organocatalytic DKR strategies.
[8] For reviews, see: a) S. Akai, in Future Directions in Biocatalysis (Ed.:
Tomoko Matsuda), 2nd Ed., Elsevier, Amsterdam, 2017, pp. 337; b) Z. S.
Seddigi, M. S. Malik, S. A. Ahmed, A. O. Babalghith, A. Kamal,
Coordination Chem. Rev. 2017, 348, 54; c) O. Verho, J.-E. Bäckvall, J.
Am. Chem. Soc. 2015, 137, 3996; d) S. Akai, Chem. Lett. 2014, 43, 746.
[9] J. Deska, C. del Pozo Ochoa, J.-E. Bäckvall, Chem.-Eur. J. 2010, 16,
4447.
[10] The only example for the enzymatic DKR of axially chiral biaryls has
been reported by enantioselective ketoreductase-catalyzed reduction of
rapidly racemizing 2-formyl biaryls to produce configurationally stable 2-
hydroxymethyl biaryls. See: S. Staniland, R. W. Adams, J. J. W.
McDouall, I. Maffucci, A. Contini, D. M. Grainger, N. J. Turner, J.
Clayden, Angew. Chem. Int. Ed. 2016, 55, 10755; Angew. Chem. 2016,
128, 10913.
Acknowledgements
[11] For selected reviews on desymmetrization/organocatalytic or transition-
metal-mediated DKR approaches to atropisomeric biaryls, see the
following reviews and references cited therein: a) P. Renzi, Org. Biomol.
Chem. 2017, 15, 4506; b) J. Wencel-Delord, F. Colobert, Synthesis 2016,
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53, 12822; Angew. Chem. 2014, 126, 13036. Also, see ref. 2a and 3b.
For recent examples, see: d) J. Zhang, J. Wang, Angew. Chem. Int. Ed.
2018, 57, 465; Angew. Chem. 2018, 130, 474; e) J. D. Jolliffe, R. J.
Armstrong, M. D. Smith, Nat. Chem. 2017, 9, 558.
This research was supported by JSPS KAKENHI [Grant
Numbers: 15H04631, 16H01151 (Middle Molecular Strategy),
and 18H02556] and AMED (Grant Number 17am0101085j0001).
We acknowledge Toyobo Co. Ltd. for supplying LIP301. We
thank Professor Hiroaki Sasai and Professor Shinobu Takizawa
at Osaka University for valuable discussion.
Keywords: biaryls • dynamic kinetic resolution • lipase •
racemization •ruthenium.
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10.1002/anie.201804161
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Gamal A. I. Moustafa, Yasuhiro Oki,
Shuji Akai*
Page No. – Page No.
Lipase-Catalyzed Dynamic Kinetic
Resolution of C1- and C2-Symmetric
Racemic Axially-Chiral 2,2’-
Dihydroxy-1,1’-biaryls
The first lipase-metal integrated dynamic kinetic resolution of axially-chiral racemic
biaryls has been established. A highly compatible combination of ruthenium-
catalyzed racemization and atropo-enantioselective lipase-catalyzed kinetic
resolution provides an access to valuable C1- and C2-symmetric biaryl diols in up to
98% yield and up to 98% ee.
This article is protected by copyright. All rights reserved.