Asymmetric Transfer Hydrogenation of 1,3-Alkoxy/Aryloxy Propanones Using Tethered Arene/Ru(II)/TsDPEN Complexes

Article abstract of DOI:10.1021/acs.orglett.7b00756

A series of propanones containing combinations of aryloxy and alkoxy substituents at the 1- and 3-positions were reduced to the alcohols via asymmetric transfer hydrogenation using a tethered Ru(II)/TsDPEN catalyst. The enantioselectivities of the reductions reveal a complex pattern of electronic and steric effects which, when used in a matched combination, can lead to the formation of products of up to 68% ee (84:16 er) from this highly challenging class of substrate.

Full text of DOI:10.1021/acs.orglett.7b00756

Letter
pubs.acs.org/OrgLett
Asymmetric Transfer Hydrogenation of 1,3-Alkoxy/Aryloxy
Propanones Using Tethered Arene/Ru(II)/TsDPEN Complexes
Sam Forshaw,† Alexander J. Matthews,† Thomas J. Brown,† Louis J. Diorazio,‡ Luke Williams,†
and Martin Wills*,†
†Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, U.K.
‡Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: A series of propanones containing combinations of aryloxy and alkoxy substituents at the 1- and 3-positions were
reduced to the alcohols via asymmetric transfer hydrogenation using a tethered Ru(II)/TsDPEN catalyst. The enantioselectivities
of the reductions reveal a complex pattern of electronic and steric effects which, when used in a matched combination, can lead to
the formation of products of up to 68% ee (84:16 er) from this highly challenging class of substrate.
symmetric transfer hydrogenation (ATH) of ketones1 has
Abecomeamajorareaofasymmetriccatalysisresearch, largely
due to the pioneering work of Noyori et al.2 on the arene/Ru(II)/
TsDPEN class of catalysts typified by structure 1 (Figure 1).3,4 In
recent years “tethered” catalysts, for example 2 and 3, which
benefit from a high level of stability, have been developed by
ourselves5 and other groups.6
Figure 2. Classes of substrate and dominant directing effects in
reductions by catalysts 1−3.
Figure 1. Arene/Ru(II)/TsDPEN complexes used in asymmetric
transfer hydrogenation.
1−3. We focused our studies on 1,3-dialkoxy/aryloxy ketones,
where there is very little difference between the groups flanking
the ketone (Figure 3).
A closely related precedent can be found in the catalyst-
controlled diastereoselective reduction of complex ketones in
Certain classes of substrate are known to be highly compatible
with the arene/Ru(II)/TsDPEN catalysts 1−3, particularly
acetophenone derivatives,2,3 and propargylic ketones.2c,4 The
high level of electron density on the aromatic ring and triple bond
respectively engage in a constructive electrostatic interaction in
the ATH transition state (Figure 2), and this determines the
absolute configuration of the products.7 There is also evidence to
support the operation of an additional element of steric control in
the reaction selectivity.7f Very recent studies have revealed that
the hydrogen-transfer process is likely to be a stepwise process,
and that the selectivity is further influenced through destabiliza-
tion of the alternative transition state (TS) by an interaction with
the sulfonamide group.7h,i
Figure 3. Class of substrate studied and speculated directing effect.
Received: March 14, 2017
We wished to determine whether it might be possible to utilize
more distant electronic and steric differences within substrates to
controltheasymmetricselectivity ofketonereductionbycatalysts
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00756
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
which multiple interactions between the catalyst η6-arene and
multiple ethers in the substrate are important directing factors
(Supporting Information, Figure S1).8 The closely related
asymmetric reductions of 1-alkoxy-3-amino-propanones with
Ru(II)/TsDPEN complexes have previously been reported by
ourselves, using nontethered catalysts (Figure 2), and these
represent a relevant precedent, although on a distinct series of
substrates.9
We prepared a series of ketone substrates (Scheme S1, Table
S1) via the ring opening reactions of glycidyl ethers followed by
oxidation.10 The substrates were designed to contain contrasting
substituents with respect to both electronic and steric properties
in order to systematically examine the effect of each change.
Inthefirstseriesoftests(Figure4), theATHsofalkoxy vspara-
substituted aryloxy substrates were tested, to establish the
Figure 5. Modes of asymmetric reduction of ketones.
Figure 4. Reduction products of alkyoxy vs para-substituted aryloxy
ketones by ATH using catalyst (R,R)-2. *A standard of known
configuration was compared by chiral HPLC. **Comparison of the
sign of optical rotation to a standard. Others assigned by analogy.
Op(MeO)C6H4/OiPr substrate indicates competition for the
arene η6 position by the more electron-rich (e-rich) aromatic ring
(Figure 5b). On the other hand, the introduction of more
methoxy groups (in the dimethoxy derivative) to the alkoxy side
increased the selectivity of reduction, as would be expected by
analogy with the result of Nugent et al.8
The 7% ee obtained for the OPh/p(MeO)C6H4O substrate
suggests a very small electronic preference for reduction via a TS
with the more electron-rich ring marginally favoring the position
adjacent to the η6-arene. The electron-poor OpCl C6H4/OPh
gaveaproductofjust6%ee. Itwasgratifyingtofindthatreduction
of the OpClC6H4/p(MeO)C6H4O substrate gave a product of
12% ee which indicates a level of additivity in the directing effects,
and reduction via the TS shown in Figure 5c. The selectivities are
reflectedbytheHammett12 valuesforapara-OMegroupof−0.27
(electron-donating) and for a para-Cl group of +0.23 (electron-
withdrawing). A para-tBoc-amino group did not appear to
influence the sense of reduction at all however.
In the next series of tests, we reduced substrates containing two
aryloxy groups containing more hindered substituents (Figure 6).
To our surprise, the 2,6-dimethoxyphenoxy group appeared to
compete inthe reduction TS with the OiPr group (the eedropped
from 39% for OPh/OiPr 6 to just 16% for 15). To probe this
further, the OPh/2,6-(MeO)2C6H3O substrate was found to give
product 16 with 42% ee while the p(MeO)Ph/2,6-
(MeO)2C6H3O ketone gave a lower ee of 33%. Since it has
selectivity induced by purely electronic differences between
substituents. Catalyst (R,R)-2 was used throughout for
consistency (Scheme 1). Configurations were assigned based
either on a literature precedent (see below) or by analogy to a
structurally related reduction product in the series.
Scheme 1. Asymmetric Transfer Hydrogenation of 1,3-
Alkoxy/Aryloxy Ketones
The reduction of all the substrates containing a phenoxy vs any
alkoxy group (OMe, OnBu, OiPr, Oallyl) flanking the ketone gave
products with ee’s fairly consistently in the 30−40% range. The
absolute configurations of several products were determined by
comparison with authentic samples prepared following a
published synthetic method by Sharpless et al. (Scheme S2).11
This served to confirm the nature of the transition state leading to
the products; the slightly more electron-rich oxygen atom of the
alkoxide occupies the position proximal to the η6-arene group
(Figure 5a). The lower ee for the slightly more electron-rich
B
DOI: 10.1021/acs.orglett.7b00756
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
little or no enantioselectivity, possibly reflecting a balance of
electronic and steric effects in the dimethoxy-substituted ring. In
the final investigations in this study, a series of fluorine-containing
ketones were reduced to alcohols 26−29 and in each case the
absolute configurations matched those expected from the
fluorine-containing ring being in the distal position from the η6-
arene in the reduction TS. In the best case, the 2-trifluoromethyl-
phenyoxy substrate was reduced in 50% ee, reflecting the possible
additional contribution of a steric effect.
We were interested in establishing whether a correlation
existed between the difference in 1H NMR chemical shift (δΔ)
between the OCH2 groups adjacent to each ketone (other than
fluorinated examples) and the enantioselectivities of their
reductions (Table S1, Figure 7). Assuming that the groups on
Figure 7. Enantiomeric excess of reductions vs chemical shift difference
of methylene groups flanking the ketone in the substrates. Circles =
combinations of alkoxy and nonhindered (unsubstituted or p-
substituted) aryloxy. Diamonds = 2,6-dimethoxyphenoxy-containing
substrates. Triangles = o-NHtBoc-phenoxy-containing substrates.
Crosses = o-chloro, o-(dimethylamino) and 2,3-dimethoxyphenoxy-
containing substrates. 65% ee point is combination of o-NHtBoc and 2,6-
dimethoxyphenoxy dimethoxyphenyl.
Figure6. ReductionproductsofaryloxyvsaryloxyketonesbyATHusing
catalyst (R,R)-2. *A standard of known configuration was compared by
chiral HPLC, others assigned by analogy.
already been shown that the more electron-rich p(MeO)C6H4
group favors the position adjacent to the η6-arene, the conclusion
must be that the reduction in ee results from the 2,6-
dimethoxyphenoxy dominating this position over both PhO
andp(MeO)C6H4O, butnotoverthe iPrO. Takentogether, these
results suggested that, despite the steric hindrance, the 2,6-
dimethoxyphenyoxy is competing for the position adjacent to the
η6-arene in the TS (Figure 5d and 5e). This may be the result of
the inability of the C(alkyl)−O bond on this group to become
coplanar with the aromatic ring due to steric clashes, thus
reducing the ability of the lone pair to delocalize into the aromatic
ring (Figure S2).
Improving the ee by purely electronic effects in such a
challenging system is quite difficult, however we reasoned that a
very sterically hindered group on the “electron-poor” side in the
TS could increase the reduction selectivity further. In the event,
using a ketone containing ortho-NtBocC6H4O vs OPh, OiPr or
2,6-(MeO)2C6H3O gave products of 46%, 68%, and 65% ee,
respectively, in favor of the predicted enantiomers based on
combined steric and electronic effects (Figures 5f−6h). These
represent the highest recorded enantioselectivities for such a
challenging system for ATH. The contrast with the para-tBocNH
substrate, which gave essentially no enantioselectivity (Figure 4),
underlines the feeble electronic directing effect contrasting with
the strong steric effect of the NHtBoc group. The reductions of
ortho-chloroaryloxy substrates also proceeded to give products of
predictable configuration based on the combined directing
effects. In the case of the o-ClC6H4)/OiPr combination. A good
ee of 59% was generated in the product. PhO vs 2,3-
dimethoxyphenoxy or 2-dimethylaminophenoxy substrates gave
the oxygen atoms can influence the electron-richness of the
adjacent methylene group, its chemical shift should reflect this,
and thus its ability to interact with the η6-arene ring of the catalyst.
In the event, the results appear to fall into a number of groups.
First, a group at the center of Figure 7 (black circles, highlighted
within an oval) are the alkoxy vs unhindered aryloxy substrates.
Anothergroup, blackcirclesinthelowerleftsegment(lowee),are
the substrates containing unhindered aryloxy groups on either
side of the ketone; the remote and weak electronic effects have
only minor influence over the reduction enantioselectivity.
More interesting are the 2,6-dimethoxyphenoxy-containing
substrates (diamonds) and ortho-NHtBocC6H4O- substrates
(triangles; the 65% ee point is the substrate containing both
these groups). Notably, the oNHtBoc-containing substrates
generally give higher ee’s than the chemical shift differences alone
might suggest, which reflects the effect of the steric hindrance on
the selectivity. In contrast, the 2,6-dimethoxyphenoxy- substrate
results correlate fairly closely to the earlier set of results (circles),
indicating the contribution of a primarily electronic directing
effect. The final set of results, for the remaining substrates
(crosses), again reflect the higher than average ee’s for the more
sterically congested ortho-chloroaryl-substrates. While not
quantitative, there is broadly a relationship between the chemical
shift difference of the methylene groups flanking the ketone and
the induced ee’s of the reductions. 2,6-Dimethoxyaryl groups also
fit this trend, despite their extra steric hindrance effects.
In conclusion, we have prepared and examined in detail the
ATH of a series of 1,3-dialkoxy/aryloxy propanones, which are
C
DOI: 10.1021/acs.orglett.7b00756
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Vries, J. G.; Rutjes, F. P. J. T. Chem. Commun. 2015, 51, 14462.
(k) Nicolaou, K. C.; Wang, Y.; Lu, M.; Mandal, D.; Pattanayak, M. R.; Yu,
R.; Shah, A. A.; Chen, J. S.; Zhang, H.; Crawford, J. J.; Pasunoori, L.;
Poudel, Y. B.; Chowdari, N. S.; Pan, C.; Nazeer, A.; Gangwar, S.; Vite, G.;
Pitsinos, E. N. J. Am. Chem. Soc. 2016, 138, 8235.
(4) Propargylic ketones: (a) Nakayama, A.; Kogure, N.; Kitajima, M.;
Takayama, H. Angew. Chem., Int. Ed. 2011, 50, 8025. (b) Dias, L. C.;
Ferreira, M. A. B. J. Org. Chem. 2012, 77, 4046. (c) Reddy, K. S. N.;
Sabitha, G. Tetrahedron Lett. 2017, 58, 1198. (d) Brandt, D.; Dittoo, A.;
Bellosta, V.; Cossy, J. Org. Lett. 2015, 17, 816.
(5) ‘3C’ tethered: (a) Nedden, H. G.; Zanotti-Gerosa, A.; Wills, M.
Chem. Rec. 2016, 16, 2623. (b) Soni, R.; Jolley, K. E.; Clarkson, G. J.;
Wills, M. Org. Lett. 2013, 15, 5110. (c) Fang, Z.; Wills, M. Org. Lett. 2014,
16, 374. (d) Mangion, I. K.; Chen, C.-Y.; Li, H.; Maligres, P.; Chen, Y.;
Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.;
Reamer, R. A.; Sherry, B. D.; Zavialov, I. Org. Lett. 2014, 16, 2310.
(e)Vyas, V.K.;Bhanage, B. M.Org.Lett. 2016,18,6436. (f)Soni,R.;Hall,
T. H.;Mitchell, B. P.;Owen, M.R.;Wills, M. J. Org.Chem. 2015,80, 6784.
regarded as highly challenging substrates for ATH using catalysts
1−3. Purely electronic effects (e.g., two differently substituted
aromatic rings) generally lead to product formation in low ee’s,
although gratifyingly the results reflect the Hammett values for
the substituents. Steric factors, particularly of ortho-substituted
aromatics, can be significant and additive to the enantioselectivity
ofthereductionsincertaincases. Productsofgoodee(upto68%)
can be obtained in cases where electronic and steric effects are
matched to the catalyst. To some extent, the ee’s of the reductions
relate to electronic differences between aromatic substituents.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00756.
Allexperimentaldetails, copiesofNMRspectra, andHPLC
data (PDF)
̌
(g) Hodgkinson, R.; Jurcík, V.; Zanotti-Gerosa, A.; Nedden, H. G.;
Blackaby, A.; Clarkson, G. J.; Wills, M. Organometallics 2014, 33, 5517.
(h) Wakeham, R. J.; Morris, J. A.; Williams, J. M. J. ChemCatChem 2015,
7, 4039. (i) Su, Y.; Tu, Y.-Q.; Gu, P. Org. Lett. 2014, 16, 4204.
AUTHOR INFORMATION
■
(6) Other tethered catalysts: (a) Touge, T.; Hakamata, T.; Nara, H.;
Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc.
2011, 133, 14960. (b) Parekh, V.; Ramsden, J. A.; Wills, M. Catal. Sci.
Technol. 2012, 2, 406. (c) Kisic, A.; Stephan, M.; Mohar, B. Org. Lett.
̌ ́
2013, 15, 1614. (d) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.;
Ikariya, T. J. Am. Chem. Soc. 2016, 138, 10084. (e)Cotman, A. E.;Cahard,
Corresponding Author
*E-mail: m.wills@warwick.ac.uk.
ORCID
Martin Wills: 0000-0002-1646-2379
Notes
̌ ́
D.;Mohar, B. Angew. Chem., Int.Ed. 2016,55,5294. (f)Kisic, A.;Stephan,
M.; Mohar, B. Adv. Synth. Catal. 2014, 356, 3193. (g) Chung, J. Y.L.;
Scott, J. P.; Anderson, C.; Bishop, B.; Bremeyer, N.; Cao, Y.; Chen, Q.;
Dunn, R.; Kassim, A.; Lieberman, D.; Moment, A. J.; Sheen, F.; Zacuto,
M. Org. Process Res. Dev. 2015, 19, 1760. (h) Komiyama, M.; Itoh, T.;
Takeyasu, T. Org. Process Res. Dev. 2015, 19, 315.
(7) Molecular modelling: (a) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.;
Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580. (b) Yamakawa, M.;
Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466. (c) Noyori, R.;
Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931.
(d) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001,
40, 2818. (e) Casey, C. P.; Johnson, J. B. J. Org. Chem. 2003, 68, 1998.
(f) Brandt, P.; Roth, P.; Andersson, P. G. J. Org. Chem. 2004, 69, 4885.
(g) Handgraaf, J.-W.; Meijer, E. J. J. Am. Chem. Soc. 2007, 129, 3099.
(h) Dub, P. A.; Ikariya, T. J. Am. Chem. Soc. 2013, 135, 2604. (i) Dub, P.
A.; Gordon, J. C. Dalton Trans. 2016, 45, 6756.
(8) Bligh, C. M.; Anzalone, L.; Jung, Y. C.; Zhang, Y.; Nugent, W. A. J.
Org. Chem. 2014, 79, 3238.
(9) Kawamoto, A. M.;Wills, M. J. Chem. Soc., Perkin Trans 1 2001, 1916.
(10) Seth, K.; Roy, S. R.; Pipaliya, B. V.; Chakraborti, A. K. Chem.
Commun. 2013, 49, 5886.
(11) (a) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett.
1993, 34, 2267. (b) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
10515.
(12) Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.;
Oxford University Press: pp 1042−1043.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Warwick University is thanked for partial funding of S.F. and
A.J.M. L.W. was supported by a Warwick University Under-
graduate Research Support Scheme (Warwick URSS) award. We
thank the EPSRC and Astrazeneca Ltd. for funding (to T.J.B.) via
the EPSRC Industrial CASE Programme. We thank Johnson-
Matthey Catalysts for a donation of catalyst 2.
REFERENCES
■
(1) Reviews: (a) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621.
(b) Wang, C.; Wu, X.; Xiao, J. Chem. - Asian J. 2008, 3, 1750. (c) Ito, J.-I.;
Nishiyama, H. Tetrahedron Lett. 2014, 55, 3133. (d) Robertson, A.;
Matsumoto, T.; Ogo, S. Dalton Trans. 2011, 40, 10304. (e) Vaclavik, J.;
Sot, P.; Vilhanova, B.; Pechacek, J.; Kuzma, M.; Kacer, P. Molecules 2013,
18, 6804. (f) Foubelo, F.; Naj
2015, 26, 769.
́
era, C.; Yus, M. Tetrahedron: Asymmetry
(2) Early reports: (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.;Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(c) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. (d)Haack, K. J.;Hashiguchi, S.;Fujii, A.;Ikariya, T.;
Noyori, R. Angew. Chem. 1997, 109, 297; Angew. Chem., Int. Ed. Engl.
1997, 36, 285.
(3) Recent applications: (a) Corbett, M. T.; Johnson, J. S. J. Am. Chem.
Soc. 2013, 135, 594. (b) Steward, K. M.; Corbett, M. T.; Goodman, C. G.;
Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 20197. (c) Hems, W. P.;
Jackson, W. P.; Nightingale, P.; Bryant, R. Org. Process Res. Dev. 2012, 16,
461. (d) Lemke, M.-K.; Schwab, P.; Fischer, P.; Tischer, S.; Witt, M.;
Noehringer, L.; Rogachev, V.; Jager, A.; Kataeva, O.; Frohlich, R.; Metz,
̈
̈
P. Angew. Chem., Int. Ed. 2013, 52, 11651. (e) Hong, Y.; Chen, J.; Zhang,
Z.; Liu, Y.; Zhang, W. Org. Lett. 2016, 18, 2640. (f) Tissot, M.; Phipps, R.
J.; Lucas, C.; Leon, R. M.; Pace, R. D. M.; Ngouansavanh, T.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2014, 53, 13498. (g) Vyas, V.; Bhanage, B. M. Org.
Chem. Front. 2016, 3, 614. (h) Kumaraswamy, G.; Narayanarao, V.;
Shanigaram,P.;Balakishan, G.Tetrahedron2015,71,8960.(i)Cheng,T.;
Ye, Q.; Zhao, Q.; Liu, G. Org. Lett. 2015, 17, 4972. (j) Verkade, J. M. M.;
Quaedflieg, P. J. L. M.; Verzijl, G. K. M.; Lefort, L.; van Delft, F. L.; de
D
DOI: 10.1021/acs.orglett.7b00756
Org. Lett. XXXX, XXX, XXX−XXX