Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones

Article abstract of DOI:10.1002/anie.202004658

The sulfone functional group has a strong capacity to direct the asymmetric transfer hydrogenation (ATH) of ketones in the presence of [(arene)Ru(TsDPEN)H] complexes by adopting a position distal to the η⁶-arene ring. This preference provides a

Full text of DOI:10.1002/anie.202004658

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Accepted Article
Title: The sulfone group as a versatile and removable directing group
for the asymmetric transfer hydrogenation of ketones
Authors: Martin Wills, Vijyesh K Vyas, and Guy C Clarkson
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The sulfone group as a versatile and removable directing group
for the asymmetric transfer hydrogenation of ketones
Vijyesh K. Vyas,[a] Guy J. Clarkson[a] and Martin Wills*[a]
[a]
Dr Vijyesh K. Vyas, Dr Guy J. Clarkson, Prof Dr Martin Wills*
Department of Chemistry
The University of Warwick
Coventry, CV4 7AL, UK.
E-mail: vijyesh.vyas@warwick.ac.uk; G.clarkson@warwick.ac.uk; m.wills@warwick.ac.uk
Supporting information for this article is given via a link at the end of the document.
Abstract: The sulfone functional group has a strong capacity to
direct the asymmetric transfer hydrogenation (ATH) of ketones by
[(arene)Ru(TsDPEN)H] complexes by adopting a position distal to
the 6-arene ring. This preference provides a means for the
prediction of the sense of asymmetric reduction. The sulfone group
also facilitates the formation of a range of reduction substrates and
its ready removal provides a route to enantiomerically-enriched
alcohols which would otherwise be extremely difficult to prepare by
direct ATH of the corresponding ketones.
reduction, followed by its removal, to ‘unmask’ what would
previously have represented a very difficult target for ATH. In
this regard, sulfones seemed promising, since they have been
reported to be effective partners for ATH reactions (Figure 2).
Zhang et al. reported, in 2009, the Dynamic Kinetic Resolution
(DKR)/ATH of cyclicsulfone-substituted ketones
4 with
catalyst (S,S)-1 to products 5 in high dr and ee (Figure 2A).7
Cyclic examples including the conversion of 6 to 7, were
exceptionally selective (Figure 2B).7 In 2009, Wang et al.
reported the use of catalyst (R,R)-3 for asymmetric
hydrogenation (AH) of sulfonyl and sulfonamidyl ketones 8
(Figure 2D) to alcohols 9 and the DKR/AH of related cyclic
substrates.8 The majority of examples contained an aryl
substituent and gave >90% ees, although the reduction of
EtCOCH2SO2Ph in 84% ee8/80% ee9 and MeCOCH2SO2Ph in
82% ee8/91% ee9 were also reported.8 Later reports featured a
one-pot formation, and then ATH, of sulfone-substituted ketones
under aqueous conditions,9,10 and the application of a silica-
supported variant.11 Bhanage and Vyas reported DKR/ATH of
cyclic -sulfone ketones using a proline-derived catalyst.12
Asymmetric transfer hydrogenation (ATH) is a highly practical
method for the synthesis of enantiomerically-enriched alcohols,
being effective under mild conditions and avoiding the need for
the
use
of
high
pressure
hydrogen
gas.1
The
[(arene)Ru(TsDPEN)Cl] class of catalysts first reported by
Noyori et al. (e.g. 1, Figure 1) are very efficient in this application,
and reduce many classes of ketones, notably acetophenone
derivatives and progargylic ketones, in high ee.2 We, and others,
have reported ‘tethered’ derivatives of the Noyori catalysts (e.g.
2, Figure 1) which in some applications exhibit higher activity
and stability.3 Catalysts such as 1 and 2 have been employed in
ATH for the synthesis of pharmaceutically relevant targets,4
including multikilo applications4a and uses in high-volume flow
chemistry.4b The triflate derivative, 3, which readily ionizes in
methanol, has been employed in closely related asymmetric
hydrogenation (AH) of ketones.5
Figure 1. Noyori-Ikariya catalyst 1, 3C-tethered derivative 2 and
the Noyori-Ikariya triflate-derivative catalyst 3. The active
catalysts are generated through HCl elimination when the
catalysts are activated.
Figure 2. Reported classes of asymmetric reductions of sulfone-
substituted ketones A: DKR/ATH of acyclic substrates, B:
DKR/ATH of cyclic substrates, C: mode of hydride transfer for A
and B, D: AH of sulfone-substituted acetophones, E: mode of
hydride transfer for D.
However, despite its high value and practicality, this class of
catalyst does not work well for all substrates. For example, in the
asymmetric reduction of alkyl/alkyl ketones or substrates with
minimal electronic or steric differences between the groups
flanking the ketone,6 the catalysts are less enantioselective. To
Zhang et al. reported the reduction of -sulfonamide ketones in
very high ee and conversion using the ‘3C’ tethered catalyst 2.13
Asymmetric hydrogenation of sulfone-containing acetophenone
address this shortcoming, we investigated the use of
a
temporary directing group to influence the selectivity of a
1
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derivatives has also been reported using other catalysts
including Ru/diphosphine catalysts, and CBS reagents.14(a)-(d)
In reductions with [(arene)Ru(TsDPEN)Cl] complexes 1-3,
where acetophenone derivatives are most commonly studied,
the sense of reduction indicates that the sulfone adopts a
position in the transition state for ATH15 in which it is positioned
distal from the 6-arene ring on the ruthenium hydride which is
the active catalyst form in the reaction (Figure 2C and 2E). The
6-arene is presumed to engage in a productive electrostatic
interaction with the aromatic substituent on the substrate.
that reported (see Supporting Information) and also to the
reported precedents.7-13 The configurations of 11f, the OPh
derivative of 11f, and of 11i were also confirmed by optical
rotation comparisons with those reported and the other products
were assigned by analogy.
The results suggest that the sense of reduction of the examples
follows the model for the earlier-reported (predominantly
aromatic) substrates, i.e. in which the sulfone group favours the
position in the t.s. in which it is distal from the 6-arene of the
complex (Figure 5B).7-13
In contrast, very few reductions of alkyl-containing, -sulfonyl
ketones have been reported, possibly due to the perceived lack
of fit to the traditional ‘acetophenone-based’ reduction model.15
The potential for the use of a sulfone as a temporary directing
group prompted us to examine what range of substituents could
successfully partner a sulfone and whether it could hence be
used as a removable group to facilitate the synthesis of
otherwise challenging alcohol target molecules (Figure 3).
Figure 3. Investigations in this report, and strategy for synthesis
of challenging alcohols in high ee.
Results and discussion.
We first prepared a diverse range of sulfonyl ketones 10a-10i
and studied their reductions using the 3C-tethered catalyst
(R,R)-2 (Figure 4).3 The majority of these were prepared from
the bromoketone using PhSO2Na. Racemic 11h was prepared
by addition of PhSO2CH2 anion to PhCCCHO, and subsequently
oxidised to the ketone 10h. The ketone precursor to 11i (i.e. 10i)
was prepared by addition of PhSO2CH2 anion to the Weinreb
amide PhCH2CONMe(OMe).
Figure 4. ATH of -sulfonyl ketones with a tethered ATH
catalyst and resulting products 11a-11i, and comparisons to ees
of corresponding ATH products containing sulfides and ethers in
place of the sulfone.
The ATH (using formic acid/triethylamine
– FA/TEA 5:2
azeotrope) of substrates 10a-10d revealed an unexpected trend
in which the product ee increased as the ring became smaller in
the series from cyclohexyl (11a, 87% ee) to cyclopropyl (11d,
99% ee), although it remained high in each case (Figure 4). In
representative cases, the results were compared with those for
the ATH of the analogous thiol- or ether-containing substrates. It
was found that these were consistently reduced in lower
enantioselectivity in every case. The reduction of sulfone-
containing cyclopropyl ketone 10d gave product 11d in a very
high 99% ee, whereas the thiophenyl-substituted analogue gave
a product in a reasonable ee of 87% whereas the phenoxy
substrate gave a product of just 36% ee. Substrates containing
sulfones and linear alkyl chains (10e, 10f) were also reduced;
the product ees increased with the length of the chain, and were
higher than for the reported reductions of substrates containing
Me and Et substituents. Even a substrate containing a hindered
t-butyl group, i.e. 10g, was reduced in a valuable 86% ee. The
substrate containing a triple bond, 10h, was reduced in
particularly high enantioselectivity to 11h (99% ee) although the
benzyl-substituted substrate 10i gave a product 11i of just 72%
ee.
A
B
Figure 5. A. Structure of 11a functionalised using (S)-1-
phenylethylisocyate (X-ray structure is in Supporting
Information). B. Proposed mode of reduction of sulfone-
substituted alkyl ketones.
The cyclopropyl group is a particularly compatible substituent in
substrates for ATH reactions, with reports having been
published of applications to natural product synthesis in which
ketones adjacent to cyclopropanes are reduced in high ee.16 The
sense of induction suggests that it is compatible with an
interaction with the 6-arene, which accords with our results
(Figure 6A). We also found that product 12 was formed as a
53:47 mixture of two enantiomerically-enriched diastereosiomers
(90 and >99% ee respectively) through reduction of the racemic
trans-cyclopropane substrate (Figure 6B). Another example of a
related ketone, bearing a phthalimide group (and hence a
precursor to 2-hydroxy amines) was reduced in 96% ee by ATH
to product 13 (Figure 6C) to further highlight the value of the
cyclopropyl group.
A derivative of the major enantiomer of the cyclohexyl-containing
reduction product 11a was prepared through reaction with (S)-1-
phenylethylisocyate and the X-ray crystallographic structure of
this (Figure 5A) allowed the product configuration to be assigned
as S, in agreement with the comparison of the optical rotation to
2
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hence the preferred reduction of the R- enantiomer of the
substrate when (R,R)-2 catalyst was used.
Figure 6. Cyclopropyl-functionalised ketones are also excellent
substrates for ATH reactions. A. Likely mode of hydrogen
transfer by ATH using (R,R)-2. B. ester-functionalized
cyclopropane ATH product 12. C. Phthalimide-containing ATH
product 13 (ATH conditions as given in Figure 4).
Encouraged by these results, we investigated further derivatives
with more challenging functionalisation. Previous studies in our
group had revealed that aryloxy- and alkoxy- groups can adopt
positions adjacent to the 6-arene of the catalyst during
reductions and it seemed that the pairing of these with a sulfone
could create an ideal substrate for reduction. In the event, we
found that oxygen-containing groups were tolerated well in ATH
substrates; PhOCH2COCH2SO2Ph was reduced to 14 in 96 %
ee and two related ketones were also converted in similarly high
enantioselectivity to products 15 and 16 (Figure 7). Again, a
corresponding sulfide-containing substrate was reduced in lower
ee (81% ee), underlining the importance of the sulfone group to
the control of the reduction (Figure 5C). A sulfone group one
carbon further away from the ketone was less effective at
directing the reaction, and a product 17 of 27% ee was formed.
The reduction of a substrate containing a tBoc- protected amine
opposed to a sulfone gave a product 18 of just 53% ee however.
Figure 8. A. Diastereoselective ATH products with DKR where a
racemizable center was present in the substrate. B. ATH/DKR
products. The product ee is in each case of the major
diastereoisomer. Products 20a-20g were formed in 100%
conversion. C. Products 21-25 of sulfone reduction. D. Proposed
mode of reduction of 19a-19g in the ATH/DKR reaction.
As previously outlined, this transformation provides access to a
strategy for the synthesis of otherwise highly challenging
asymmetric alcohol products in high ee. In order to demonstrate
this, we reductively removed the sulfone group17 from a
representative number of products to generate the unsubstituted
products 21 – 25 in high ee, which in each case was an alcohol
with very little steric or electronic difference between the groups
flanking it (Figure 9C). Traditionally such targets would be
regarded as very difficult to prepare through direct ketone ATH.
For each case, comparisons of enantioselectivities of reductions
of the direct ketone precursors are included for comparison (see
Supporting information). Product 21 was formed as a racemate
by direct ketone reduction, and 23 was formed in just 5% ee.
Direct reduction of the ketone precursor to 22 gave the best
result of 64% ee, and in the same sense, resulting from the
electronic difference between phenyl and phenoxy substituents.
Compounds 24 and 25 have previously been reported by us,6a
with ees of just 30% and 7% ee respectively obtained by direct
ketone reduction. In the case of 25, the opposite enantiomer of
alcohol is formed by direct reduction (using the same
configuration of catalyst), thus serving to confirm that the
absolute sense of reduction of ketone 19g matches that
predicted by the model in Figure 8D. However by proceeding
Figure 7. ATH products formed from alkoxy and amino-
substituted ketone substrates containing sulfone groups (ATH
conditions as given in Figure 4).
With the directing factors established, the dynamic kinetic
resolution (DKR) of sulfone-containing substrates 19a-g was
examined next. This also proved successful, with products 20a-
20g of high dr and ee being obtained, i.e. where the substituent
was adjacent to the ketone and able to racemize rapidly in order
to facilitate the DKR process (Figure 8A and 8B). The absolute
stereochemistry of 20c was be confirmed by X-ray
crystallography (Supporting Information) and others were
assigned by analogy. In these examples, the starting materials
19a-19g were prepared by addition of the corresponding sulfone
anion to the precursor aldehyde followed by oxidation. In all
cases, the sense of reduction to 20a-20g followed that in the
model previously described (Figure 5B) with the additional
requirement for the avoidance of steric clashes between the
substituent adjacent to the sulfone and the catalyst (Figure 8D),
3
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through the sulfone intermediate, products of >99% ee (24) and
95% ee (25) respectively were obtained. The sharp contrast
illustrates how a sulfone acts as a temporary group for
achievement of the required syntheses. Attempted removal of
the sulfone from 20e did not yield the required alcohol product,
possibly due to debenzylation and decomposition.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, NMR
spectra, X-ray crystallographic data and HPLC data (PDF).
In cases where the existing chiral center was located distal from
the sulfone), i.e. in 26 and 27, a DKR was not achieved, and
both product diastereoisomers were formed, with variable results
(Figure 9) and some differences between the matched and
mismatched substrate/catalyst enantiomer combinations.
Data sharing statement. The research data (and/or materials)
supporting
this
publication
can
be
accessed
at
http://wrap.warwick.ac.uk/TBA.
Notes
The authors declare no competing financial interests.
Acknowledgements
We thank The Royal Society for funding VKV through an SERB-
Newton International Fellowship. 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).
Figure 9. Attempted ATH/DKR where a racemizable centre was
not present in the substrate. ATH conditions are as given in
Figure 8. Relative stereochemistry was not confirmed.
In an extension of this strategy (Figure 10), an allylic alkene was
prepared through reduction of the heterocyclic sulfone 28
(prepared from the anion of 2-(methylsulfonyl)benzo[d]thiazol-6-
ylium and 2-phenoxyacetyl chloride) to alcohol 29 in 94% ee.
Protection of the alcohol gave 30 and this step was followed by
a Julia-Kocienski olefination reaction with benzaldehyde and
deprotection to give E-31 in 91% ee.18
Keywords: Asymmetric catalysis • ketone reduction • sulfones;
alcohols • ruthenium.
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5
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Entry for the Table of Contents
The sulfone group facilitates the formation of a range of reduction substrates through asymmetric transfer hydrogenation (ATH) of
ketones and its ready removal provides a route to challenging enantiomerically-enriched alcohols.
6
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