BIMP-Catalyzed 1,3-Prototropic Shift for the Highly Enantioselective Synthesis of Conjugated Cyclohexenones

Article abstract of DOI:10.1002/anie.202006202

A bifunctional iminophosphorane (BIMP)-catalysed enantioselective synthesis of α,β-unsaturated cyclohexenones through a facially selective 1,3-prototropic shift of β,γ-unsaturated prochiral isomers, under mild reaction conditions and in short reaction times, on a range of structurally diverse substrates, is reported. α,β-Unsaturated cyclohexenone products primed for downstream derivatisation were obtained in high yields (up to 99 %) and consistently high enantioselectivity (up to 99 % ee). Computational studies into the reaction mechanism and origins of enantioselectivity, including multivariate linear regression of TS energy, were carried out and the obtained data were found to be in good agreement with experimental findings.

Full text of DOI:10.1002/anie.202006202

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Accepted Article
Title: BIMP Catalyzed 1,3-Prototropic Shift for the Highly
Enantioselective Synthesis of Conjugated Cyclohexenones
Authors: Jonathan Golec, Eve Carter, John Ward, William
Whittingham, Luis Simon, Robert Paton, and Darren James
Dixon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006202
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10.1002/anie.202006202
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COMMUNICATION
BIMP Catalyzed 1,3-Prototropic Shift for the Highly Enantioselec-
tive Synthesis of Conjugated Cyclohexenones
Jonathan C. Golec,[a] Eve M. Carter,[a] John W. Ward,[b] William G. Whittingham,[c] Luis Simón,[d]
Robert S. Paton*[e] and Darren J. Dixon*[a]
Abstract: A bifunctional iminophosphorane (BIMP) catalyzed enanti-
oselective synthesis of α,β-unsaturated cyclohexenones via
a
facially selective 1,3-prototropic shift of β,γ-unsaturated prochiral
isomers, under mild reaction conditions and in short reaction times,
on a range of structurally diverse substrates, is reported. α,β-
Unsaturated cyclohexenone products primed for downstream
derivatisation were obtained in high yields (up to 99%) and
consistently high enantioselectivity (up to 99% ee). In-depth studies
into the reaction mechanism and origins of enantioselectivity,
including multivariate linear regression of TS energy, were carried
out computationally on the catalytic system and the obtained data
was found to be in good agreement with experimental findings.
Chiral conjugated cyclohexenones are valuable building blocks for
synthesis, offering great versatility across a broad spectrum of
reactions and applications.[1]
A
number of organocatalytic
approaches have been explored to construct such scaffolds in an
enantioselective manner, for example through the desymmetrisation
of cyclohexadienones or Robinson annulation.[2] However,
a
powerful yet underdeveloped approach for their enantioselective
synthesis is through the double bond migration of their β,γ-
unsaturated prochiral isomers. Such transformations have been
found to be catalyzed by a number of small molecule and enzymatic
pathways and their reaction kinetics have been well-documented.[3]
Until recently, chemocatalytic methods to accomplish this
transformation enantioselectively proved elusive.[4] Currently, Deng’s
approach to the enantioselective prototropic shift via cooperative
Brønsted base / iminium ion catalysis offers the best solution for
such a transformation, providing typically excellent yields and good
enantioselectivities (Scheme 1A).[5] Despite these attributes, the
reaction is limited in scope to alkyl / allyl-substituted substrates at
both the α- and β-positions and requires extended reaction times of
on average 85 hours. Furthermore – and relevant to the current
study – the Deng group reported that cinchona derived, bifunctional
Brønsted base / H-bond donor catalysts used previously to perform
related enantioselective isomerization of butenolides, were unable to
effect the transformation, owing to the low acidity of the ketone’s α-
proton.[6]
Attracted by the numerous synthetic applications of such an
enantioselective transformation, we sought to identify an
operationally simple, Brønsted base-catalyzed variant using our
highly modular and tuneable bifunctional iminophosphorane (BIMP)
superbase catalyst family. BIMP catalysts
– like many other
bifunctional organocatalysts – combine a Brønsted basic moiety with
a hydrogen bond donor group linked through a chiral scaffold
(Scheme 1B).[7] They have previously been demonstrated to impart
high levels of reactivity and enantiocontrol across a diverse range of
reactions including, ketimine nitro-Mannich reactions, sulfur-Michael
additions, conjugate additions to enone diesters, and – relating to
this work – the cascade heptenone isomerization / enantioselective
intramolecular Diels-Alder reaction key step of our group's total
synthesis of (‒)-himalensine A.[8]
[a]
[b]
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, United Kingdom, Mansfield Road, Oxford (UK) OX1 3TA E-mail:
darren.dixon@chem.ox.ac.uk
It was envisaged that in conjunction with the catalyst’s
hydrogen bond donor group, the superbasic iminophosphorane
moiety would provide sufficient activation to deprotonate the weakly
acidic α-position.[9,6] Kinetic and enantiodetermining reprotonation of
the extended enolate would then occur preferentially at the γ-
position in an enantioselective manner, to afford the desired
cyclohexenone product.[10] Our aim, was to identify a catalyst system
that would efficiently deliver excellent levels of enantioselectivity
across a wide range of substrates in a short reaction time, and
herein we wish to report our findings.
Leverhulme Research Centre for Functional Materials De-sign, The Materials
Innovation Factory, Department of Chemistry, University of Liverpool,
Liverpool L7 3NY, UK
[c]
[d]
[e]
Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY,
United Kingdom
Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los
Caídos 1-5, Salamanca 37008, Spain
Department of Chemistry, Colorado State University, 1301 Center Ave Ft.
Collins, CO 80523-1872 E-mail: Robert.Paton@colostate.edu
Supporting information for this article is given via a link at the end of the
document.
1
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We began our investigation using Hagemann’s ester-derived
β,γ-cyclohexenone 1a (see SI).[11] Guided by our previous work,
initially, we investigated for performance a range of 1st generation
BIMP catalysts (3a-d) including catalyst 3a used in the total
synthesis of (−)-himalensine A.[8] Each catalyst provided the product
in low to moderate yield (17-53%) with low levels of
enantioselectivity (1-14% ee). Notably, more basic P(PMP)3 derived
iminophosphoranes performed with improved catalytic activity in
comparison with those derived from PPh3 (Scheme 2). Accordingly,
we turned our attention to P(PMP)3 derived 2nd generation BIMP
catalysts and with catalyst 3e, substrate 1a underwent the 1,3-
prototropic shift in decent yield (67%) however enantiocontrol (18%
ee) remained poor. Replacing the tert-butyl substituent at
stereocentre a with methylnaphthyl group – to provide catalyst 3f –
unfortunately led to almost complete loss of reactivity and offered no
improvement in enantioselectivity. Consequently, the performance of
catalyst 3g, 3e’s diastereomer, was investigated which interestingly
led to a significant uplift in both enantioselectivity (85% ee) and yield
(97%). Two configurationally related catalysts, 3h and 3i, possessing
phenyl and methylnaphthyl groups at stereocentre b respectively
were synthesized and their performance investigated. Impressively,
methylnaphthyl containing catalyst 3i resulted in the formation of 2a
in near quantitative yield after 24 hours and 99% ee.
In further exploration of the reaction scope we looked at the
effect of pendant-heteroatom variance on reactivity and selectivity
(Scheme 3A). N-Boc protected amines 2i and 2j were found to
perform particularly well in the 1,3-prototropic shift with both high
yields and enantioselectivities being obtained in both cases. We
turned our attention to more complex amine-based functionalities to
introduce further structural diversity. Accordingly, hydrazine and
hydroxylamine functionalized substrates 1k and 1l were synthesized.
Both compounds underwent the 1,3-prototropic shift in high yield and
excellent enantioselectivity. Heterocyclic appendages incorporated
into the starting material, for example, an indole substituent attached
at the δ-position (2m), performed consistently. Introduction of an
amido furan moiety was easily achieved and subjection to the
standard reaction conditions afforded 2n and 2o in high yield and
99% and 97% ee, respectively. Pleasingly β,γ-diphenyl substrate 1p
performed equally well with the product 2p being obtained in 76%
yield and impressive 94% ee.
A significant drop in reactivity was encountered with β,γ-diethyl
substrate 1q. Based on a previous study by Whalen and co-workers
it was more than likely that the rate-limiting step of the prototropic
shift would show Brønsted base strength dependence.[3] Thus, to
further augment Brønsted base strength we surveyed a range of
iminophosphoranes whilst maintaining the chiral H-bond donor
scaffold (see SI).[8] An uplift in reactivity with a tributylphosphine-
derived iminophosphorane was observed although the conversion
was poor over the standard reaction time and the selectivity
decreased significantly (20% yield, 87% ee).
With optimal catalyst and conditions identified, the scope of
the enantioselective prototropic shift was investigated (Scheme 3A).
Wide variation to the ether substituent was well-tolerated with high
yields and enantioselectivities (>95% ee) being obtained for
products 2b-e. Almost complete enantiocontrol and conversion to O-
TBS protected product 2f was witnessed even upon scale up to 1.5
g. Furthermore, unprotected alcohol 1g was a viable substrate
providing 2g in good yield and 85% ee. We sought to apply our
method to the synthesis of a key building block in the construction of
both (‒)-reserpine and (‒)-penitrem D, achieved by Stork and co-
workers and Smith et. al. respectively (Scheme 3B).[12] Isomerization
substrate 1h was synthesized in a single step using methodology
developed by Hilt,[13] and smoothly underwent the 1,3-prototropic
shift to afford 2h in 62% yield and 94% ee shortening 2h’s previously
reported synthesis.[12]
Pleasingly, switching the hydrogen bond donor motif to a urea
group provided the uplift in reactivity we desired. After re-
optimization of the reaction conditions we were able to perform the
1,3-prototropic shift on substrate 1q to afford 2q in 63% yield and
impressive 97% ee. We trialled more challenging substrates
(Scheme 3C). β,γ-dipropyl substrate 1r underwent the prototropic
shift in 50% yield and 97% ee. Replacement of the β-substituent with
a phenyl group provided 2s in 63% yield and 95% ee and analogous
substrate 1t with an electron rich phenyl ring performed equally well.
2
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Derivatisation of the enantioenriched products was realized
through the removal of 2f’s TBS group and activation of the free
alcohol through tosylation in high yield, to provide 4a in 99%
enantiopurity (Scheme 3D, see SI).[14] The tosylate could then be
used to introduce further functionality including azide 4b and
thioether 4c which were obtained in 99% ee and 97% ee,
respectively. The free alcohol could also be transformed into
xanthate ester 4d and subsequently enantiopure cyclic thionolactone
4e.[15] Prolonged heating of 2n effected an intramolecular Diels-Alder
reaction to afford the stereochemically congested tricyclic scaffold 4f
with high ee.
experimental observations, the (S)-enantiomer is favored in this step
by 2.2 kcal/mol, equivalent to a computed ee value of 95%.
Computations also predict that α-deprotonation will occur reversibly,
consistent with deuterium exchange between labelled and unlabelled
substrates at the α-position that we observe experimentally (see SI).
The catalyst:dienolate ion-pair can reversibly dissociate prior to the
irreversible protonation taking place.[17] We performed a systematic
conformational analysis of competing TSs, including varied substrate
ring conformations and rotations about single bonds. In the preferred
TSs, the thiourea binds the substrate oxygen while the
iminophosphorane participates as proton acceptor and then donor.
Alternative modes of N-H proton transfer from the catalyst to
substrate from the (thio)urea were much higher in energy and are
not expected to contribute to the observed reactivity (see SI). We
located 112 different TS conformers and used statistical modeling to
identify the most important structural features that influence their
stability. Multivariate linear regression was performed to predict the
conformational energy (R2 0.85 (train), 0.80 (test), 0.80 (5-fold CV)),
from which the statistically significant geometric features,
automatically selected during model construction, are shown in the
SI.[18]
Having succeeded in the development of an enantioselective
Brønsted base catalyzed 1,3-prototropic shift, we then turned our
investigation to the mechanistic pathway and origins of
enantioselectivity using in-depth computational analysis. Transition
structures (TSs) were located for substrate 1a undergoing
successive α-deprotonation and γ-reprotonation by BIMP catalyst 3i,
resulting in the Gibbs energy profile shown in Figure 1. The
reprotonation TSs are higher in energy, making this the rate- and
enantio-determining step.[16] Along this reaction coordinate the
bifunctional catalyst engages the substrate oxygen with a dual H-
bonding interaction from both thiourea N-H protons. Consistent with
3
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distortion energy[19] is 1.6 kcal/mol greater in this TS, which is
disfavored (G‡) by 2.2 kcal/mol overall.
The γ-substituent plays an important role in influencing
enantioselectivity. It must adopt different conformations in response
to the catalyst (principally to avoid clashes with the P-substituents)
protonating either enantioface. As
a consequence, substrate
conformational strain dictates the sense of enantioselectivity, rather
than significant differences in the noncovalent interactions between
substrate and catalyst. From these findings, we can predict that a
flexible γ-substituent is helpful for high levels of enantioselectivity
since this creates the potential for differential allylic strain between
the two pathways. Furthermore, it also follows that although a β-
substituent is not essential for enantioselectivity, its absence will
reduce allylic strain in the TS. Accordingly, we compute a reduced
G‡ of 1.9 kcal/mol (92% ee) for substrate 2h.
In summary, we have uncovered a new Brønsted base
catalyzed 1,3-prototropic shift for the synthesis of enantioenriched,
functionalized cyclohexenones using our BIMP family of catalysts
and have investigated the mechanistic pathway and origins of
enantioselectivity in detail using DFT. The isomerization was found
to proceed in high yield within a short time frame and demonstrates
impressive levels of enantioselectivity across a range of functionally
interesting substrates which could be further derivatized to introduce
more diversity and functionality. The catalyst itself has been shown
to be versatile enough to overcome reactivity issues through the
modification of its Brønsted base strength, whilst maintaining good
enantiocontrol;
a design feature we hope to exploit in other
challenging synthetic transformations.
Acknowledgements
J. G. is grateful to the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1) for a
studentship, generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB and Vertex. R. S. P. acknowledges support from
the NSF (CHE-1955876) L. S. also thanks the MINECO
(CTQ2017-87529-R) for financial support. Dr. Heyao Shi is also
The substrate conformation is decisive in terms of
enantioselectivity. The more favorable (S)-TS has less torsional
strain and less 1,3-allylic strain. As shown in Figure 2 the (R)-TS has
greater eclipsing interactions in the ring and, due to the orientation of
the alkoxy group, greater A1,3-strain. Indeed, the computed substrate
4
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Keywords: chiral cyclohexenone • prototropic shift • BIMP
catalysis • enantioselective • superbase
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10.1002/anie.202006202
Angewandte Chemie International Edition
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Getting a shift on: The enantioselective BIMP catalyzed 1,3-prototropic shift of structurally diverse β,γ-unsaturated cyclohexenones
is reported. The reaction is high yielding (up to 99%) in a short time span and occurs with a high level of selectivity (up to 99% ee) on
a wide range of substrates. To complement the data, in-depth computational studies were undertaken including multivariate linear
regression of TS energy.
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