High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates

Article abstract of DOI:10.1002/anie.201909308

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α-alkyl,β-aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates. Cyclobutanones with two stereogenic centers are obtained in good to high yield, with high enantioselectivity and diastereoselectivity. Vital to this advance are the development of a novel approach to α,β unsymmetrically disubstituted cyclobutenone substrates and the use of a high-throughput chiral ligand screening platform. The synthetic utility of both the boronic ester and ketone functionalities is displayed, with remarkable chemoselectivity for either group being possible in this small ring scaffold.

Full text of DOI:10.1002/anie.201909308

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: High-Throughput Ligand Screening Enables the Enantioselective
Conjugate Borylation of Cyclobutenones to Access Synthetically
Versatile Tertiary Cyclobutylboronates
Authors: Helen A. Clement, Michele Boghi, Rory M. McDonald, Louise
Bernier, Jotham W. Coe, William Farrell, Christopher J. Helal,
Matthew R. Reese, Neal W. Sach, Jack C. Lee, and Dennis
G. Hall
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909308
Angew. Chem. 10.1002/ange.201909308
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10.1002/anie.201909308
Angewandte Chemie International Edition
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COMMUNICATION
High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of
Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates
Helen A. Clement, Michele Boghi, Rory M. McDonald, Louise Bernier, Jotham W. Coe, William Farrell,
Christopher J. Helal, Matthew R. Reese, Neal W. Sach, Jack C. Lee,* Dennis G. Hall*
Abstract: Cyclobutane rings are important in medicinal chemistry,
yet few enantioselective methods exist to access this scaffold. In
particular, cyclobutylboronates are receiving increasing attention in
the literature due to the synthetic versatility of alkylboronic esters
and the increasing role of boronic acids in drug discovery. Herein, a
conjugate borylation of α-alkyl,β-aryl/alkyl cyclobutenones is
developed leading to the first synthesis of enantioenriched tertiary
cyclobutylboronates. Cyclobutanones with two stereogenic centers
are obtained in good to high yield, with high enantioselectivity and
diastereoselectivity. Vital to this advance are the development of a
novel approach to unsymmetrically α,β-disubstituted cyclobutenone
substrates and the use of a high-throughput chiral ligand screening
platform. The synthetic utility of both the boronic ester and ketone
functionalities is displayed, with remarkable chemoselectivity for
either group being possible in this small ring scaffold.
Compared to cyclopentane and cyclohexane homologs, much
fewer synthetic methods exist to produce functionalized chiral
cyclobutanes in high enantioselectivity.[3] Owing to the versatility
of the boronyl substituent as a precursor to C–O, C–N, C–C and
C–X bonds, there is significant interest in the development of
efficient methods to prepare chiral cyclobutylboronates in
optically enriched form. Moreover, the boronyl unit can be
employed as a potential handle to install a cyclobutyl unit into a
medicinal scaffold via transition metal catalyzed Suzuki-Miyaura
cross-coupling or O–/N–arylation.[4] However, stereoselective
methods to prepare optically enriched cyclobutylboronates are
scarce and generally limited in scope.[5] Matteson and co-
workers reported
a
multistep approach based on the
stereospecific cyclization of a stabilized carbanion onto a chiral
α-chloroalkylboronic ester.[6] Bach and co-workers reported the
enantiofacial-selective photochemical [2+2] cycloaddition
between an alkenylboronate and isoquinolone promoted by a
stoichiometric chiral hydrogen-bonding template.[7] Reports of
catalytic enantioselective methods are equally rare. A copper-
catalyzed enantioselective formal hydroboration of symmetrical
2,3-disubstituted cyclobutenes was reported by Tortosa and co-
workers (Figure 2a).[8] Because of its distinctive feature as a
desymmetrization, this method is limited to symmetrically
disubstituted cyclobutenes. Recently, Yu and co-workers
described a directed catalytic enantioselective CH borylation of
cyclobutyl carboxamides that provides cyclobutylboronates in
high enantioselectivity with a distinct substitution pattern (Figure
2b).[9],[10] To develop a general, complementary approach to
access cyclobutylboronates, we envisioned using a copper-
catalyzed conjugate borylation of
Cyclobutane rings are embedded in the structure of numerous
natural products and medicines (Figure 1).[1] In drug discovery,
cyclobutyl moieties are often employed to impose spatial
pharmacophore rigidification and have also been shown to be
O
Me
Me
MeO2C
MeO
MeO
OMe
O
H
Et
Et
OMe
OH
Et
Et
O
MeO
HO
O
OMe
H
MeO
norlignan cyclobutane
endiandrin A
O
hippolachnin
H
N
H2N
O
F
Me
Me
N
Me
N
F
N
EtHN
H
N
O
O
Me
HO
OH
O
Pfizer's clinical H3 histamine
receptor antagonists[1]
rumphellaone A
lobucavir (antivial)
non-traditional bioisosteres of arenes.[2]
Figure 1. Examples of stereochemically complex cyclobutane-containing
natural products and pharmaceutical drugs.
[*]
H. A Clement, Dr. M. Boghi, R. M. McDonald, Prof. Dr. D. G. Hall
Department of Chemistry, 4-010 CCIS
University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
E-mail: dennis.hall@ualberta.ca
L. Bernier, W. Farrell, N. W. Sach
Pfizer Worldwide Research and Development
La Jolla Laboratories
10770 Science Center Drive, San Diego, CA 92121 (USA)
M. R. Reese, Dr. J. W. Coe, Dr. C. J. Helal, Dr. J. C. Lee
Pfizer Worldwide Research and Development
Eastern Point Road
Groton, CT 06340, USA
Figure 2. Known (a,b) and proposed (c) catalytic enantioselective methods to
prepare cyclobutylboronates.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909308
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COMMUNICATION
cyclobutenones. Pioneering work by Hosomi has shown that
conjugate borylation provides an extremely efficient entry into
optically enriched cyclopentyl- and cyclohexylboronates,[11]
however the cyclobutane equivalent is lacking in the
literature.[12,13] To address this void, we targeted the conjugate
borylation of α,β-disubstituted cyclobutenones (Figure 2c), which
would provide the first examples of enantioenriched tertiary
cyclobutylboronates. Furthermore, it would also allow access to
(a)
polysubstituted
enantioselective approaches remain scarce.[14][15] The expected
keto-boronate products can undergo bidirectional
cyclobutanones,
for
which
catalytic
(d)
functionalizations, making them valuable medicinal chemistry
intermediates.
(c)
(b)
Although enantioselective conjugate borylations of β-substituted
cyclopentenones and cyclohexenones have been successfully
realized,[13,16] the steric congestion in tetrasubstituted α,β-
72 ligands
ee (%)
disubstituted enones makes their borylation
a significant
challenge. In fact, no example of catalytic enantioselective
conjugate borylation of a tetrasubstituted alkene exists in the
literature.[17] To surmount this challenge we envisioned using a
ligand high-throughput screening (HTS) approach, since it has
recently been demonstrated to be effective in addressing
notoriously difficult cases of catalytic enantioselective
hydrogenations of tetrasubstituted alkenes.[18] Herein, we report
a successful application of this strategy, which provides richly-
functionalized, optically enriched tertiary boronyl-cyclobutanones
that can be transformed into new sub-classes of cyclobutanes
by functionalization of the boronic ester and/or ketone groups.
Considering the importance of methylation in medicinal
chemistry[19] and the structural simplicity of a methyl substituent,
we were particularly interested in targeting the borylation of α-
methyl-β-aryl/heteroaryl cyclobutenones using 1a as a model
substrate (Scheme 1). Although cyclobutenones have proven to
be useful substrates in various contexts,[20] preparative methods
for unsymmetrically disubstituted alkene derivatives were lacking
in the literature. Inspired by pioneering work of Ghosez and co-
Figure 3. Summary of HTS results for ligand optimization. The data points are
slightly skewed for visualization purposes.[24]
With an efficient access to 1a developed, a HTS of a library of
118 chiral ligands was explored under pre-optimized conditions
using Cu(MeCN)4PF6 as the catalyst with NaOtBu as base in
THF at 25 °C.[24],[25] By far, the highest enantioselectivity was
obtained
with
(2S,4S)-2,4-bis(diphenylphosphino)pentane
(BDPP) leading to the formation of 2a as a single diastereomer
in 55% conversion and 88% ee ((a), Fig. 3). Most of the
remaining materials was leftover 1a, leaving room for further
optimization. The HTS results clearly highlight the notorious
challenge provided by the cyclobutenone substrate (Figure 3).
Out of 118 ligands, only two afforded over 50% ee, with the
second best result having a low 15% conversion and 69% ee
((b), Fig. 3). Remarkably, Taniaphos and QuinoxP*, which were
reported to be efficient ligand scaffolds for the copper-catalyzed
borylation of cyclopentenones and cyclohexenones, were
inadequate with cyclobutenone 1a ((c) and (d), Fig. 3).[12],[13]
Furthermore, over half of the ligands screened were found to
give no conversion under the reaction conditions used (72
ligands, 61%).[24]
workers,[21] cyclobutenone 1a was prepared by
a [2+2]
cycloaddition between an amide-derived keteniminium
intermediate and phenylacetylene, followed by an isomerization
to the thermodynamically favored alkene.[22] The optimal
conditions allowed for the synthesis of 1a on a 50 mmol scale
with a 44% yield over the three steps (Scheme 1). It should be
noted that Jiao and co-workers recently described an elegant
complementary synthesis of cyclobutenone 1a using a novel
triflic anhydride mediated [2+2] cycloaddition between activated
acetonitrile and internal, unsymmetrically disubstituted
alkynes.[23] Although Jiao’s method features a mild work-up
suitable for base-sensitive substituents, the approach of Scheme
1 allows the direct use of arylacetylene derivatives, which are
more commercially prevalent than the corresponding internal
alkynes.
With an optimal ligand, validation of the HTS conditions and
screening of the remaining reaction parameters were
undertaken. Thus, when the reaction was performed at 0 °C with
5 mol% catalyst on a standard reaction scale (0.3 mmol), there
was no loss of enantioselectivity with full consumption of
cyclobutenone 1a (entry 1). Increasing the steric bulk of the
alcohol did not improve the diastereoselectivity, nor the
enantioselectivity (entry 2). A less sterically hindered base
resulted in a lower yield (entry 3), yet LiOtBu produced a cleaner
reaction and higher diastereoselectivity than its sodium
equivalent. Aromatic solvents, such as toluene, were less
efficient (entry 4), while acetonitrile resulted in a very clean
Scheme 1. Preparation of α,β-disubstituted cyclobutenone 1a.
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COMMUNICATION
reaction with a high 17:1 dr, albeit with a lower conversion and
enantioselectivity (entry 5). Changing the Cu(I) source to CuCl
lowered the stereoselectivity (entry 6), as did using the more
sterically bulky m-xyl-BDPP derivative (entry 7). Surprisingly,
excess B2pin2 was detrimental to the yield with multiple
unidentified side products forming (entry 8). Maintaining the
reaction temperature at 0 °C did not result in any improvement
to the enantioselectivity (entry 9). Finally, using the optimal
parameters and 1.4 equivalents of B2pin2, the reaction was
complete after 3 hours, providing more reproducible results
A representative scope of the conjugate borylation is displayed
in Table 2. In general, the isolated yields are moderate to high
(44–88%). Screening of all three tolyl substrates showed the
general steric effect of different substitution patterns – the
reaction is not significantly affected by substitution at the para
position; however, for both meta and ortho methyl substitution
the enantioselectivity decreased slightly to 93.0:7.0 er (2b–d).
Steric hindrance at the para position can be increased without
erosion of enantioselectivity (2e–h), however electron
withdrawing (2i-k) and meta substitution (2l, 2m) led to lower
levels of enantiomeric purity (89.5:10.5 to 93.5:6.5 er). Both β-2-
naphthyl and α-ethyl substitution led to high yields and
enantioselectivity of 95.0:5.0 er (2n, 2o). In contrast, the
enantioselectvity was eroded in the case of α-benzyl substitution
(2p) to 91.5:8.5 er, but the dr remained high. Both heterocyclic
(2q) and alkyl (2r) β-substituted enones (R1) resulted in highly
enantioenriched products in good diastereoselectivity. The
single failed substrate was a para-cyanophenyl R1 derivative,
which gave protodeboronation as the major product.[24]
Table 1. Condition optimization for the conjugate borylation of cyclobutenone
1a.
Entry
Changes from above
Yield of
2a[a]
dr[b]
er[c]
Table 2. Substrate scope of the stereoselective conjugate borylation.
1
2
NaOtBu (50 mol%)
70%
7 : 1
7 : 1
96.0 : 4.0
95.5 : 4.5
Entry
1
with iPrOH
68%
instead of MeOH
NaOMe (50 mol%)
toluene
3
57%
59%
43%
82%
57%
28%
63%
96%
4 : 1
95.0 : 5.0
94.5 : 5.5
83.5 : 16.5
92.5 : 7.5
14.5 : 85.5
N.D.
4
5 [d]
10 : 1
17 : 1
9 : 1
MeCN
6
CuCl
7
(R,R)-m-xyl-BDPP
2.0 equiv of B2pin2
0 °C reaction temp.
1.4 equiv B2pin2, 3
h, sealed vial
6 : 1
8
6 : 1
9
7 : 1
95.0 : 5.0
95.0 : 5.0
10
16 : 1
[a] 1H NMR yield of the major diastereomer from the crude reaction mixture by
integration of CH2Br2 as an internal standard. [b] dr was determined by relative
[c]
1H NMR integration of the Me groups after the first column.
Enantiomeric
ratios (er) are determined by chiral HPLC after isolation of
a single
diastereomer. [d] Only 62% conversion of 1a. N.D. = not determined.
when a sealed vessel with a tight cap was used rather than a
septum (entry 10). Overall, the optimized reaction allowed for
1
formation of the desired borylated product 2a in a high H NMR
yield (96%), with excellent diastereoselectivity (16:1 dr) and
enantioselectivity (95.0:5.0 er). The absolute and relative
configuration of cyclobutylboronate 2a and other analogs was
assigned based on the X-ray analysis of an optically enriched
crystalline derivative of 2a (cf. Scheme 2). Based on a control
experiment demonstrating a lack of isomer equilibration, the
observed diastereoselectivity is proposed to arise from
a
sterically-controlled, irreversible protodecupration away from the
larger Bpin group (Figure 4).[24]
[b]
[a] Isolated yield after column chromatography with water deactivated silica.
1H NMR yield of the major diastereomer from the crude reaction mixture by
integration of CH2Br2 as an internal standard. [c] Determined by chiral HPLC
[d
after isolation of a single diastereomer. dr was determined by relative 1H
NMR peak height of the Me groups after the first column. [e]10 mol%
Figure 4. Proposed rationale for the observed diastereoselectivity.
Cu(MeCN)4PF6, 11 mol% (S,S)-BDPP.
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COMMUNICATION
MeOH, -78 °C; NaOMe, -78 °C; k) (1) LiC(OCb)=CH2, THF, -78 °C; I2, MeOH,
-78 °C; (2) LDA, THF, -78 °C; MeOH -20 °C; l) LiC(OEt)=CH2, THF, - 78 °C; I2;
NaOMe, MeOH, -78 °C; NH4Cl.
The synthetic potential and versatility of bifunctional
cyclobutylboronates 2 is displayed in Scheme 2 with 2a as a
model substrate. Unless otherwise noted, all products were
obtained as a single diastereomer according to 1H NMR analysis. established
stereoselective
lithiation-1,2-boryl
migration
Remarkably, chemoselective functionalization of the ketone is
possible without affecting the pinacol boronic ester. Divergent
diastereoselectivity of the ketone reduction was accomplished
by either using Luche conditions or L-selectride to obtain
secondary alcohols 3 and 4 in 85% and 73% yield, respectively.
Oxidation with sodium perborate resulted in diol 5 in high yield
(97%), while benzoyl ester protection allowed for unambiguous
stereochemical assignment of 6 by X-ray crystallography.[26]
Furthermore, Grignard addition with phenylmagnesium bromide
occurred cleanly to form tertiary alcohol 7 in 86% yield.
Protodeboronation resulted in the formal anti cyclobutenone
hydrogenation product 8 in moderate yield and 10:1 dr. The
potassium trifluoroborate salt 9 was obtained in a high 94% yield
and was found to be a suitable substrate for a rhodium catalyzed
aldehyde addition to obtain diketone 10 as a mixture of
chemistry, which has been largely developed by Aggarwal and
co-workers.[28]
In summary, a catalytic enantioselective approach to novel
tertiary cyclobutylboronates by conjugate borylation of α-alkyl,β-
aryl/alkyl cyclobutenones has been successfully developed.
Keys to this advance include a new and practical access to
unsymmetrically disubstituted cyclobutenones
1
and the
application of HTS of 118 chiral ligands for efficient optimization
of the desired reaction in up to 98:2 er. Both the ketone and
boronic ester moieties in cyclobutylboronates
2 can be
transformed orthogonally, in high stereoselectivity, to access
novel cyclobutane scaffolds of potential pharmaceutical interest.
diastereomers
upon
oxidation.[27]
Alternatively,
the
Acknowledgements
corresponding ketal 11 can serve as a viable substrate for a
number of carbon-carbon bond forming processes. Zweifel
olefination, alkynylation and acetylation were possible in good to
high yields (12–14), using previously
This research was generously funded by Pfizer Inc, the Natural
Sciences and Engineering Research Council (NSERC) of
Canada (Discovery Grant to D.G.H., Canada Graduate
Scholarship-Master’s to H.C.) and the University of Alberta
(Queen Elizabeth II scholarships to H.C.). We thank Dr. Yuqiao
Zhou (X-ray Crystallography Laboratory, University of Alberta)
for X-ray crystallographic analysis of compound 6, and Mr. Ed
Fu for help with chiral HPLC analyses.
O
O
i
O
Ph
pinB
Ph
pinB
Me
Me
2a
(±)-
11
, 91%
OH
Me
OH
Me
O
c
a
b
e
f
j
O
Ph
pinB
Ph
HO
Ph
Ph
Me
5
, 97%
3
, 85%
Conflict of interest
12
, 56%
Ar
OH
O
d
L. B., J. W. C., W. F., C. J. H., M. R. R., N. W. S. and J. C. L. are
employees of Pfizer Inc. and may own stocks in the company.
O
Ph
pinB
Ph
pinB
O
Me
Me
k
O
4
6
, 73%
, 91%
(Ar = 4-Br-C6H4)
Me
Keywords: asymmetric catalysis • cyclobutylboronates •
Ph
OH
13
, 74%
cyclobutanones • conjugate borylation • cyclobutenones
Ph
pinB
Me
, 86%
O
[1] a) Review of cyclobutane-containing natural products: V. M. Dembitsky,
Phytomedicine 2014, 21, 1559–1581.; b) T. T. Wager, B. A. Pettersen, A. W.
Schmidt, D. K. Spracklin, S. Mente, T. W. Butler, H. Howard, Jr, D. J. Lettiere,
D. M. Rubitski, D. F. Wong et al., J. Med. Chem. 2011, 54, 7602–7620.
[2] Rigidification: a) M. L. Wrobleski, G. A. Reichard, S. Paliwal, S. Shah, H.-C.
Tsui, R. A. Duffy, J. E. Lachowicz, C. A. Morgan, G. B. Varty, N.-Y. Shiha,
Bioorg. Med. Chem. Lett. 2006, 16, 3859–3863.; Bioisostere: b) A. F. Stepan,
C. Subramanyam, I. V. Efremov, J. K. Dutra, T. J. O’Sullivan, K. J. DiRico, W.
S. McDonald, A. Won, P. H. Dorff, et al., J. Med. Chem. 2012, 55, 3414–
3424.; c) K. C. Nicolaou, D. Vourloumis, S. Totokotsopoulos, A. Papakyriakou,
H. Karsunky, H. Fernando, J. Gavrilyuk, D. Webb, A. F. Stepan,
ChemMedChem 2016, 11, 31–37.
7
l
O
Ph
Me
O
Me
O
Ph
Me
14,
60%
8
, 56%
6
(ORTEP of )
(10:1 dr)
O
O
g
h
Ph
Ar
Ph
KF3B
Me
Me
, 94%
O
9
10
, 66%, 5:1 dr
(Ar = 4-NO2-C6H4)
[3] M. Weng, P. Lu, Org. Chem. Front. 2018, 5, 254–259.
Scheme 2. Synthetic versatility of the cyclobutylboronate products.
[4] D. G. Hall, Chapter 1 in Boronic Acids – Preparation and Applications in
Organic Synthesis, Medicine and Material (Ed.: D. G. Hall), 2011, Wiley-VCH,
1–133.
Reaction conditions: a) NaBH4, CeCl3●7H2O, EtOH, -78 °C; b) L-selectride,
THF, -78 °C; c) NaBO3●4H2O, THF/H2O; d) 4-Br-BzCl, DMAP, Et3N, DCM; e)
PhMgBr, THF, 0 °C; f) Bu4NF●3H2O, toluene, 45 °C; g) KHF2, MeCN/H2O;
h)(1) pNO2-PhCHO, [Rh(COD)Cl]2, dioxane/H2O, 80 °C; (2) DMP, DCM i)
PTSA●H2O, (HOCH2)2, HC(OMe)3, toluene; j) H2C=CH-MgBr, THF, -78 °C; I2,
[5] V. Martín-Heras, A. Parra, M. Tortosa, Synthesis 2018, 50, 470–484.
[6] H.-W. Man, W. S. Hiscox, D. S. Matteson, Org. Lett. 1999, 1, 379–381.
[7] S. C. Coote, T. Bach, J. Am. Chem. Soc. 2013, 135, 14948–14951.
This article is protected by copyright. All rights reserved.

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COMMUNICATION
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[12] X. Feng, J. Yun, Chem. Commun. 2009, 6577–6579.
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[14] For a recent approach to prepare non-chiral tertiary cyclobutylboronates,
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10.1002/anie.201909308
Angewandte Chemie International Edition
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Title
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Helen A. Clement, Michele Boghi, Rory
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Jack C. Lee, Dennis G. Hall*
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The conjugate borylation of α,β-disubstituted cyclobutenones allows access to
tertiary cyclobutylboronates in up to 98:2 er with high diastereoselectivity. The
synthetic versatility of the products is displayed by the orthogonal functionalization
of both the ketone and boronic ester.
High-Throughput Ligand Screening
Enables the Enantioselective
Conjugate Borylation of
Cyclobutenones to Access
Synthetically Versatile Tertiary
Cyclobutylboronates
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