Enantioselective Synthesis of Bicyclopentane-Containing Alcohols via Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.1c00889

Compounds a containing bicyclo[1.1.1]pentane (BCP) adjacent to a chiral center can be prepared with high enantiomeric excess through asymmetric transfer hydrogenation (ATH) of adjacent ketones. In the reduction step, the BCP occupies the position distant from the η6-arene of the catalyst. The reduction was applied to the synthesis of a BCP analogue of the antihistamine drug neobenodine.

Full text of DOI:10.1021/acs.orglett.1c00889

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Letter
Enantioselective Synthesis of Bicyclopentane-Containing Alcohols
via Asymmetric Transfer Hydrogenation
Vijyesh K. Vyas, Guy J. Clarkson, and Martin Wills*
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ABSTRACT: Compounds a containing bicyclo[1.1.1]pentane (BCP) adjacent to a chiral center can be prepared with high
enantiomeric excess through asymmetric transfer hydrogenation (ATH) of adjacent ketones. In the reduction step, the BCP
occupies the position distant from the η6-arene of the catalyst. The reduction was applied to the synthesis of a BCP analogue of the
antihistamine drug neobenodine.
complexes (Figure 1b).5a The methodology was particularly
ompounds that contain a bicyclo[1.1.1]pentane (BCP)
1,2
Care valuable structures for pharmaceutical research.
Examples include cases where a BCP is bioisosteric with a
para-substituted aromatic ring,1b−d a tBu group,1e,f or an
alkyne2 (Figure 1a). Pellicciari et al. reported the asymmetric
synthesis of an amino acid bearing a BCP, prepared via
separation of diastereomeric cyanohydrins, that exhibited
activity as an mGlu1 receptor antagonist.1b Compound 1 is a
BCP analogue of a γ-secretase inhibitor that exhibits improved
aqueous solubility and oral absorption characteristics.1c
Compound 2 is a BCP analogue of darapladib, a cardiovascular
disease drug, in which the isostere exhibited an improved
physiochemical profile.1d
effective for the synthesis of alkene-containing derivatives (e.g.,
7), and an example of an amine-containing derivative, 8, was
achieved using a procedure reported by Baran et al.5b Baran et
al.6a and Qin et al.6b reported the selective synthesis of
functionalized BCP derivatives.
Asymmetric catalytic methods for the synthesis of BCP
derivatives have been reported,7a−c but not to our knowledge
for the formation of adjacent α-oxo stereocenters.7d Therefore,
we investigated the introduction of a chiral center adjacent to
the group through asymmetric transfer hydrogenation (ATH)
of a ketone. This would permit the synthesis of BCP
compounds analogous to benzhydrols and their derivatives
such as neobenodine, carbinoxamine, and levocetrizine
(antihistamines) in enantiomerically pure form (Figure 2).8
Benzhydrols and their imine derivatives are challenging
substrates for ATH because of the often minimal differences
in steric and/or electronic properties of the aryl rings in the
precursor benzophenones, although a number of successful
strategies have been reported.8,9 We reasoned that BCP versus
an aromatic or alkyne flanking the ketone in a substrate would
offer a greater chance of differentiation due to their contrasting
structural properties and therefore would be suitable for ATH.
Knochel et al. described the formation of BCP isosteres of
alkynes including tazarotene and MPEP (3 and 4, respectively)
using coupling of Zn-BCP reagents (formed by the reaction of
a Grignard reagent with [1.1.1]propellane) with aromatic and
heteroaromatic halides (Figure 1a).2,3
Anderson et al. reported innovative routes to several BCP
derivatives.4 One example features a versatile synthesis of
disubstituted BCP derivatives through the reaction of [1.1.1]-
propellane with organic iodides under photochemical con-
ditions, followed by an iron-catalyzed Kumada cross-coupling
reaction with an aromatic or heteroaromatic Grignard
reagent.4a Syntheses of BCP-flubiprofen 5 (where the BCP
replaces a fluorinated aromatic ring in the anti-inflammatory
drug) and BCP-brequinar 6 (where the BCP replaces a
bridging aromatic ring) were reported (Figure 1b).
Received: March 15, 2021
Published: April 5, 2021
Aggarwal et al. reported the trapping of BCP-containing
Grignard reagents with boronic esters to form BCP-boronate
https://doi.org/10.1021/acs.orglett.1c00889
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3179−3183
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the reduction,10 we focused on the use of the “tethered”11
catalyst (R,R)-9 (Figure 3b), which we have previously found
to be very versatile in ATH applications. [1.1.1]Propellane was
initially converted to the ketone via reaction with PhMgBr
followed by trapping of the Grignard reagent with PhCOCl.
However, a significant amount of benzophenone was also
formed, which could not be separated from 10. We found that
10 could be made more cleanly through addition to an
aldehyde followed by oxidation with MnO2. ATH of BCP
ketone 10 gave the desired alcohol 11 with 97% ee, which
confirmed the sharp difference in directing effects between the
two groups flanking the ketone. Subsequent X-ray crystallo-
graphic analysis of a chiral derivative (see the Supporting
Information) confirmed that the product configuration was R
using (R,R)-9. Applying the model previously proposed for
ATH indicates that reduction likely proceeds with the BCP
distal from the η6-arene (Figure 3c).12
The methodology was successfully extended to a number of
aromatic substrates and one enone (Figure 4). Alkyl
substitution on the aromatic ring was tolerated, giving products
with 99% ee for para-substituted substrates and slightly lower
for the m-methyl substrate. Substrates containing electron-
withdrawing groups such as p-CF3 and p-F were reduced with
lower ee, possibly reflecting a weaker η6-arene interaction.
Substrates containing electron-donating OMe groups were also
generally highly enantioselective in reductions (88−98% ee),
although a p-phenoxy substrate was reduced with a lower ee of
just 85%.
Figure 1. (a) BCP analogues of therapeutics where the BCP replaces
either an aromatic ring (1 and 2) or an alkyne (3 and 4). (b) BCP
analogues of therapeutics prepared by Anderson et al. (5 and 6) and
BCP derivatives containing alkenes reported by Aggarwal et al. (7 and
8).
A sharp contrast was exhibited by the formation of the
product of ATH of the o-OMe derivative (i.e., 19), which was
reduced with just 2% ee. This result reflects the lower
enantioselectivities observed for substrates such as 2-
methoxyacetophenone.11a This can be attributed to disruption
of the approach of the substrate to the catalyst due to a likely
twist of the aromatic ring out of planarity with the ketone. A p-
amino substrate was also tolerated, forming the alcohol with
97% ee, while a p-bromo substrate gave the alcohol with 81%
ee. Heterocycle-containing substrates were also enantioselec-
tively reduced by ATH, with furan (99% ee), thiophene (99%
ee), and pyridine (91% ee) all being compatible with the
conditions. The configurations were assigned by analogy with
that of the unsubstituted example, but in the case of 28, which
was reduced with just 41% ee, the configuration was not
established.
We also examined the reductions of ketones flanked by a
combination of BCP and an alkyne (Figure 4).13 We obtained
products with high ee (95−99% for all of the examples tested).
Hence, the reaction conditions were shown to be tolerant of
groups such as p- and o-methoxy, an alkyl group, trimethylsilyl,
and chloro. An X-ray crystal structure of 33 (see the
Supporting Information) served to confirm the configuration
as R when (R,R) 9 was used in the reductions. This outcome
would correspond to the proposed mode of reduction of
propargylic ketones by this class of catalyst (Figure 3c).
To highlight the value of the BCP as an isostere of aromatic
rings and triple bonds that can facilitate the synthesis of highly
enantiomerically enriched products via ATH, we examined the
reduction of a range of comparator compounds (Figure 5);
products were formed with only moderate ee. The
combination of alkyne versus aromatic in ketones is also
known to be challenging.13b However, known and important
exceptions are provided by substrates containing ortho-
substituted aromatic rings, which give products with high ee
Figure 2. Potential BCP analogues of antihistamine therapeutics.
We prepared ketone precursors of the desired alcohols
through the reaction of Grignard reagents with [1.1.1]-
propellane2,3 followed by trapping with an appropriate
electrophile (as illustrated in Figure 3a for substrate 10). For
Figure 3. (a) Strategy for ATH of BCP ketones and their subsequent
asymmetric reduction using ATH, as illustrated for alcohol 11. (b)
Catalyst used in this study. (c) Likely modes of ATH.
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Figure 5. ATH products of non-BCP comparator compounds. (a)
Benzhydrols (configuration not determined). (b) Dialkynyl ketone
reduction products (configuration not determined). (c) Reported
aromatic/alkenyl reduction products. (d) Reported Ph/tBu ketone.14
Conversions were 100% unless otherwise stated.
Figure 6. Asymmetric synthesis of a BCP-containing derivative of
neobenodine. The conversion of 35 to (S)-36 was conducted on a 1
mmol scale.
would be challenging to prepare with high ee. The method-
ology was applied to an efficient asymmetric synthesis of the
BCP derivative of neobenodine.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00889.
■
Figure 4. Products of ATH of BCP derivatives of aromatic and alkyne
derivatives using a 1 mol % loading of catalyst (R,R)-9. Conditions are
as in Figure 3. Isolated yields are given; conversions were 100% unless
otherwise stated. Configurations other than that of 28 were assigned
by analogy with (R)-11 or (R)-33.
sı
Experimental procedures, NMR spectra, X-ray crystallo-
graphic data, and HPLC data (PDF)
due to steric hindrance and electronic differentials between
groups.8,9,13b
Accession Codes
CCDC 2067283 and 2067284 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
To illustrate the value of the methodology, its application to
the synthesis of BCP- neobenodine was undertaken (Figure 6).
Intermediate 353a was prepared via the BCP iodide (not
isolated). ATH of 35 was undertaken on a 1 mmol scale and
gave alcohol 36 with 94% ee in 90% isolated yield. Conversion
to the BCP analogue of neobenodine following the procedure
for neobenodine via the amide intermediate8a,b was success-
fully completed with minimal loss of ee. In this example, the
S,S enantiomer of catalyst 9 was used in order to form the BCP
with the analogous configuration to neobenodine.15
In conclusion, we have reported a highly enantioselective
reduction of BCP-ketones to alcohols using ATH, which we
believe represents the first example of a catalytic asymmetric
synthesis of BCP derivatives. Since the BCP group is a known
bioisostere of alkynes and aromatic groups, the methodology
provides an asymmetric route to analogues of structures that
AUTHOR INFORMATION
Corresponding Author
■
Martin Wills − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, U.K.; orcid.org/0000-
0002-1646-2379; Email: m.wills@warwick.ac.uk
Authors
Vijyesh K. Vyas − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, U.K.
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Route to Bicyclo[1.1.1]pentanes through Photoredox Catalysis. ACS
Guy J. Clarkson − Department of Chemistry, The University
of Warwick, Coventry CV4 7AL, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00889
Notes
The authors declare no competing financial interest.
The research data (and/or materials) supporting this
publication can be accessed at http://wrap.warwick.ac.uk/.
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ACKNOWLEDGMENTS
■
We thank The Royal Society (U.K.) and the Science and
Engineering Research Board (SERB, India) for funding V.K.V.
through an SERB−Newton International Fellowship (ref NIF
\R1\180142). Crystallographic data were collected using an
instrument (described in the Supporting Information)
purchased through support from Advantage West Midlands
(AWM) and the European Regional Development Fund
(ERDF). The authors thank Johnson Matthey (Cambridge,
U.K.) for a donation of catalyst 9 and Shweta Gediya
(University of Warwick) for assistance with the preparation
of [1.1.1]propellane.
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