Inverting External Asymmetric Induction via Selective Energy Transfer Catalysis: A Strategy to β-Chiral Phosphonate Antipodes

Article abstract of DOI:10.1002/anie.201911651

Enantiodivergent, catalytic reduction of activated alkenes relays stereochemical information encoded in the antipodal chiral catalysts to the pro-chiral substrate. Although powerful, the strategy remains vulnerable to costs and availability of sourcing bo

Full text of DOI:10.1002/anie.201911651

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Accepted Article
Title: Inverting External Asymmetric Induction via Selective Energy
Transfer Catalysis: A Strategy to β-Chiral Phosphonate Antipodes
Authors: Carina Onneken, Kathrin Bussmann, and Ryan Gilmour
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10.1002/anie.201911651
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Inverting External Asymmetric Induction via Selective Energy
Transfer Catalysis: A Strategy to β-Chiral Phosphonate Antipodes
Carina Onneken, Kathrin Bussmann, and Ryan Gilmour*
Dedicated to Prof. Dr. Andreas Pfaltz
Abstract: Enantiodivergent, catalytic reduction of activated alkenes
relays stereochemical information encoded in the antipodal chiral
catalysts to the pro-chiral substrate. Although powerful, the strategy
remains vulnerable to costs and availability of sourcing both catalyst
α,β-unsaturated phosphonates were explored due to their
prominence in the pharmaceutical and agrochemical sectors,
biochemical significance and venerable history in synthesis
(Scheme 1).[15,16] Herein, the first photocatalytic
E → Z
enantiomers. Herein,
a
stereodivergent hydrogenation of α,β-
isomerisation of α,β-unsaturated phosphonates is disclosed
using an inexpensive organocatalyst. Merging this with a
stereospecific, Rh(I)-mediated hydrogenation[17] results in an
enantiodivergent paradigm to access the R- or S-configured β-
chiral phosphonate. Equal and opposite selectivity can be
attained using only one catalyst enantiomer.
unsaturated phosphonates is disclosed using a single enantiomer of
the catalyst. This enables generation of the R- or S-configured β-
chiral phosphonate with equal and opposite selectivity.
Enantiodivergence is regulated at the substrate level through the
development of a facile E → Z isomerisation. This has been enabled
for the first time by selective energy transfer catalysis using
anthracene as an inexpensive organic photosensitiser. Synthetically
valuable in its own right, this process enables subsequent Rh(I)-
mediated stereospecific hydrogenation to generate both enantiomers
of the product using only the S-catalyst (up to 99:1 and 3:97 e.r.).
This strategy out-competes the selectivities observed with the E-
substrate and the R-catalyst.
A defining feature of external asymmetric induction is that the
degree and direction of stereoselectivity may be regulated at the
catalyst / reagent level.[1] This general premise enables achiral
substrates to be processed to one of two chiral antipodes by
design under the auspices of catalyst control.[2] Expansive and
transformative, this strategy continues to profit from the breadth
and diversity of chiral pool entities available for inclusion in
catalyst scaffolds.[3] Although essential for life, homochirality[4]
intrinsically limits external asymmetric induction due to the
deficiency of unnatural biomolecules (e.g. L-sugars and D-amino
acids). This vulnerability often has a negative impact on
enantiodivergent synthesis[5] due to limited availability / higher
costs of one chiral stereodirecting element. It follows that
conceptual paradigms in which a second, synergistic external
stimulus may be harnessed to enable enantiodivergence would
be valuable and thereby mitigate the current reliance on an
enantiomeric catalyst pair.[6] Scenarios including elevated
temperature[7] or mechanical stress[8] may be considered, but the
operational simplicity of light irradiation prompted an
investigation of energy transfer-based stimuli.[9,10,11] Given the
value of alkenes as pro-chiral substrates in asymmetric catalysis,
and the renaissance of positional[12] and geometric
isomerisation[13] enabled by selective energy transfer,[14] an
isomerisation / stereospecific reduction sequence would provide
a useful platform to validate the working hypothesis. To that end,
M.Sc. C. Onneken, K. Bussmann, Prof. Dr. R. Gilmour
Organisch Chemisches Institut,
Westfälische Wilhelms-Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
Scheme 1. Top: External asymmetric induction approach to β-chiral
phosphonates requiring two enantiomeric catalysts. Bottom: An
enantiodivergent platform based on photocatalytic E→Z isomerisation to
generate the R- or S-configured product using the same catalyst enantiomer.
Supporting information for this article is given via a link at the end of the
document.
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To establish conditions for the geometrical isomerisation, the
conversion of E-1 to Z-1 was investigated as a model reaction,
due to the ease with which the substrate can be prepared
selectively. It was envisaged that selective energy transfer from
a simple organic photosensitiser would facilitate isomerisation of
To investigate the scope and limitations of this method, a series
of E-vinyl phosphonates modified at R1, R2 and the aryl ring
fragments were investigated under the optimised conditions
(Figure 1). Gratifyingly, para-substitution was well tolerated (Z-1-
7) with selectivities up to Z:E 94:6 having been observed. The
meta-bromo product Z-8 was also generated with a high degree
of selectivity (Z:E 91:09) and, like Z-4, provides a versatile
building block for subsequent derivatisation via cross coupling.
the E-isomer.[18] In contrast, 1,3-allylic strain (A1,3 [19]
in the
)
product Z-isomer would inhibit re-excitation thereby endowing
the transformation with the desired directionality (Table 1, top).
Due to the closely similar absorption spectra of the isomers at ca. Variation in R2 had no impact on the reaction efficiency or
220-270 nm, attention was focused on the more attractive UV-
visible region (ca. 365 nm and above). Excitation in this range is
highly compatible with a diverse array of common small
molecule photocatalysts (see SI).[20] A concise screen conducted
in acetonitrile quickly eliminated Ir(ppy)3 (450 nm), (-)-riboflavin,
and benzil (both 402 nm) due to poor selectivities (Z:E 13:87,
66:34 and 25:75, respectively (entries 1-3). Only thioxanthone
showed a promising 86:14 Z:E ratio (entry 4), but since this
process is part of a stereodivergent sequence, a more efficient
catalyst was required. Switching to benzophenone (at 365 nm)
preserved the selectivity (entry 5), but the best Z:E ratio was
observed with anthracene (92:08, entry 6).
selectivity as is evident from Z-9 and Z-10 (92:8 and 90:10,
respectively). Importantly, highly electron rich aryl systems such
as those found in Z-11 and Z-12 were found to compromise
selectivity. This is likely
a consequence of contributing
resonance forms partially facilitating bond rotation and relaxation
to the starting E-isomer.
Table 1. Optimisation of the E → Z isomerisation of vinyl phosphonate E-1.[a]
1
E-isomer c = 0.2 mM
0.8
Z-isomer c = 0.2 mM
0.6
anthracene c = 0.05 mM
0.4
0.2
0
200
250
300
350
400
λ [nm]
Entry
Photocatalyst
Irradiation
Wavelength / nm
Isolated
Z:E
Yield / %
quant.
quant.
98
ratio[b]
13:87
66:34
25:75
86:14
86:14
92:08
1
2
3
4
5
6
Ir(ppy)3
(-)-Riboflavin
Benzil
450
402
402
402
365
365
Thioxanthone
Benzophenone
Anthracene
94
quant.
quant.
[a] All reactions were performed on a 0.1 mmol scale using 5 mol% catalyst in
1.5 mL MeCN at ambient temperature for 18 h; [b] determined by 1H NMR and
confirmed by 31P NMR spectroscopy.
Figure 1. Development of the E → Z isomerisation of vinyl phosphonates via
selective energy transfer catalysis using anthracene. Reactions performed on
a 0.1 mmol scale. aScale up: 95%, 92:8 Z:E (0.4 mmol) and 97%, 83:17 Z:E
(1.0 mmol). For full details see the SI.
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To interrogate the influence of R1 in inhibiting re-conjugation of
the chromophore, Z-13 was prepared as a control. Although of
no significance for the subsequent reduction, this substrate
illustrates the structural importance of R1 (photostationary
composition 1:1). By extension, augmenting the size of R1 from
Me to Et caused a small increase in Z:E ratio from 92:8 to 96:4
(Z-14). The ortho-methyl derivative also furnished synthetically
useful levels of selectivity (93:7, Z-15). Indeed, the value of
ortho-substitution is evident from a screen of the halogens (Z-16,
17 and 18, up to 99:1 Z:E). Having established a robust protocol
to facilitate the geometrical E → Z isomerization of vinyl
phosphonates via energy transfer catalysis, the reaction was
then coupled to a stereospecific hydrogenation (Figure 2). For
that purpose, both the E- and Z-activated alkenes were exposed
to Rh(I)-catalysed hydrogenation conditions using a single
enantiomer of (Sc,Sp)-Walphos.[21]
To our delight, the reaction proved to be highly stereospecific
delivering R- or S-19 with equal and opposite selectivity [R:S 97:03
e.r. versus 01:99 e.r., from E-1 and Z-1, respectively]. This trend
proved to be general, resulting in a highly stereospecific reduction,
where enantioselectivity encoded at the catalyst level could be
inverted by geometrical isomerisation (Figure 3). In the case of the
para-substituted derivatives 20-25, the E-substrates furnished the
R-products in 97:03 e.r. and the Z-substrates led to the opposite S-
antipode in up to 01:99 e.r. This stereospecificity was mirrored by
the meta-bromo derivative R- and S-26 (97:03 and 01:99,
respectively). Modifying R2 was extremely well tolerated (27) as was
introduction of an electron rich para-OMe substituent (28) or
extended π-system (29). Switching R1 from Me to Et had no impact
on selectivity (30); R:S 97:03 e.r. versus 01:99 e.r.) and the
introduction of ortho-substituents 31-33 was equally well tolerated
(up to >99:1 from the Z-alkene). Interestingly, the selectivities
observed with the o-Br derivative 34 were inverted, again with
reduction of the Z-isomer out-competing the E-substrate (>01:99).
19 from E
19 from Z
20 from E
20 from Z
21 from E
21 from Z
22 from E
22 from Z
23 from E
23 from Z
24 from E
24 from Z
25 from E
25 from Z
26 from E
26 from Z
27 from E
27 from Z
28 from E
28 from Z
29 from E
29 from Z
30 from E
30 from Z
31 from E
31 from Z
32 from E
32 from Z
33 from E
33 from Z
34 from E
34 from Z
-100
-50
0
50
100
er
Figure 2. Stereospecific reduction of E- and Z-activated alkenes. Reactions
performed on a 0.1 mmol scale. aScale up to 1.0 mmol from E (99%, 97:03
e.r.); from Z (96%, 01:99 e.r.). For full details see the SI.
Figure 3. Graphical representation of the degree and direction of stereoselectivity.
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Classics in Stereoselective Synthesis. E. M. Carreira, L. Kvaerno, Eds.;
Wiley-VCH: Weinheim, 2009.
Since Z-configured substrates generally gave higher
enantioselectivities, the reaction with the opposite catalyst
antipode was performed (Figure 4, top). Geometrical
isomerisation constitutes a practical advantage enabling both
stereoisomers to be prepared in an optically pure manner (99:1
and 1:99 e.r.). Furthermore, the reaction could be executed in a
one-pot fashion from the E-isomer as is demonstrated in Figure
[2]
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geometrical isomerisation of vinyl phosphonates via selective
energy transfer catalysis using anthracene (up to Z:E 99:1).
Although valuable in its own right, this reaction provides a
stimulus prior to stereospecific hydrogenation allowing both
product enantiomers to be generated from a single optically
active catalyst (up to 99:1 e.r.). This additional dimension to
external asymmetric induction may prove to be expansive,
particularly where the opposite catalyst enantiomer is
prohibitively expensive or is unobtainable.
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Experimental Section
Full details are provided in the Supporting Information.
Acknowledgements
[18] E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry,
University Science Books: USA, 2005.
We acknowledge financial support from the WWU Münster, and
thank M.Sc. Tobias Morack for helpful discussions.
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Keywords: catalysis • energy transfer • hydrogenation •
organophotocatalysis • stereodivergence
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[21] (a) T. Konno, K. Shimizu, K. Ogata, S. Fukuzawa, J. Org. Chem. 2012,
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COMMUNICATION
Carina Onneken, Kathrin Bussmann and
Ryan Gilmour*
Page No. – Page No.
Inverting External Asymmetric
Induction via Selective Energy
Transfer Catalysis: A Strategy to
β-Chiral Phosphonate Antipodes
A stereodivergent hydrogenation of α,β-unsaturated phosphonates is disclosed using a single enantiomer of the
catalyst. This enables generation of the R- or S-configured β-chiral phosphonate with equal and opposite selectivity.
Enantiodivergence is regulated at the substrate level through the development of a facile E → Z isomerisation. This has
been enabled for the first time by selective energy transfer catalysis using anthracene as an inexpensive organic
photosensitiser.
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