Enantio- and Diastereodivergent Sequential Catalysis Featuring Two Transition-Metal-Catalyzed Asymmetric Reactions

Article abstract of DOI:10.1002/anie.202105800

This study demonstrates the feasibility and inherent benefits of combining two distinct asymmetric transition-metal-catalyzed reactions in one pot. The reported transformation features a Pd-catalyzed asymmetric allylic alkylation and a Rh-catalyzed enantioselective 1,4-conjugate addition, effectively converting simple allyl enol carbonate precursors into enantioenriched cyclic ketones with two remote stereocenters. Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to >99 % ee, exceeding those obtained from either of the individual asymmetric reactions. In addition, since the stereoselectivity of both steps is under catalyst control, this one-pot reaction is enantio- and diastereodivergent, enabling facile access to all stereoisomers from the same set of starting materials.

Full text of DOI:10.1002/anie.202105800

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Title: Enantio- and Diastereodivergent Sequential Catalysis featuring
Two Transition Metal-Catalyzed Asymmetric Reactions
Authors: Jeanne Masson-Makdissi, Liher Prieto, Xavier Abel-Snape,
and Mark Lautens
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Enantio- and Diastereodivergent Sequential Catalysis Featuring
Two Transition Metal-Catalyzed Asymmetric Reactions
Jeanne Masson-Makdissi,[a],† Liher Prieto,[a],[b],† Xavier Abel-Snape,[a] Mark Lautens*,[a]
[a]
J. Masson-Makdissi, Dr. L. Prieto, X. Abel-Snape, Prof. M. Lautens
Department of Chemistry, University of Toronto
80 St. George Street., Toronto, Ontario, M5S 3H6 (Canada)
*E-mail: mark.lautens@utoronto.ca
[b]
Dr. L. Prieto
Department of Organic and Inorganic Chemistry, University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao, Spain
†
These authors contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: This study demonstrates the feasibility and inherent
benefits of combining two distinct asymmetric transition metal-
catalyzed reactions in one-pot. The reported transformation features
a Pd-catalyzed asymmetric allylic alkylation and a Rh-catalyzed
enantioselective 1,4-conjugate addition, effectively converting simple
allyl enol carbonate precursors into enantioenriched cyclic ketones
with two remote stereocenters. Despite the anticipated challenges
associated with controlling stereoselectivity in such a complex system,
the products are obtained in enantiomeric excesses ranging up to >
99% ee, exceeding those obtained from either of the individual
asymmetric reactions. In addition, since the stereoselectivity of both
steps is under catalyst-control, this one-pot reaction is enantio- and
diastereodivergent, enabling facile access to all stereoisomers
starting from the same set of starting materials.
catalyzed asymmetric allylic alkylation was used to install the key
stereocenters.4a
The development of asymmetric transition metal catalysis
has played a pivotal role in modern synthetic chemistry. Despite
significant
achievements,
most
asymmetric
catalytic
transformations do not allow straightforward access to all possible
stereoisomers when the formation of more than one stereocenter
is of interest. In 2013, the Carreira group addressed this limitation
by introducing the concept of stereodivergent dual catalysis,
where two chiral catalysts work cooperatively to form two adjacent
stereocenters (Scheme 1a).1 In this type of reaction, each chiral
catalyst exhibits independent stereocontrol on one of the
stereocenters with no appreciable mismatch effects, thereby
enabling facile access to all four stereoisomers from a common
set of conditions.2
Aside from stereodivergence, another advantage of a
process forming two or more stereocenters with catalyst-
controlled stereoselectivity – as opposed to substrate control – is
statistical amplification of the enantiomeric excess.3 Although this
type of statistical amplification has classically been observed in
multi-step total syntheses, it can be used strategically in a single
pot operation. For instance, recent examples of “double
enantioselective catalytic reactions” have emerged, where a
single chiral catalyst performs the same reaction twice on distal
sites of the same molecule (Scheme 1b).4 Consequently, high
levels of enantiopurity can be obtained even if the individual
catalytic transformation is only moderately enantioselective. The
Stoltz group reported an elegant application of this concept for the
total synthesis of (-)-cyanthiwigin F, in which a double Pd-
Scheme 1. Stereodivergence and enantiomeric enrichment in asymmetric
catalysis
In theory, the combination of two different asymmetric
transition metal-catalyzed processes in one-pot could lead to
similar levels of statistical enantiomeric enrichment, while
significantly broadening the range of products that could be
formed via this approach (Scheme 1c). Yet, to the best of our
1
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knowledge, the realization of such
a
process remains
unreported.5 Finding a common set of reaction conditions
ensuring complete orthogonality of both steps while
simultaneously maintaining high yield and enantioselectivity for
each catalytic transformation is a significant challenge. With these
concerns in mind, we hypothesized that the benefits of statistical
amplification could outweigh the anticipated hurdles.
Herein, we report a fully enantio- and diastereodivergent
one-pot reaction featuring a Pd-catalyzed asymmetric allylic
alkylation6 and
a Rh-catalyzed enantioselective conjugate
addition of boronic acids (Scheme 1c).7 This process meets the
expected benefits of orthogonal one-pot catalysis, which aims to
maximize efficiency in synthesis by skipping intermediate
purification steps, therefore minimizing waste and saving time.8
When we initiated this investigation, allyl enol carbonate 1a
was selected as the model substrate in order to control the
sequence of events when both catalysts are present at the outset
of the reaction. In contrast to allyl β-keto esters, allyl enol
carbonates have the added benefit of having the enone
functionality masked until it is revealed by the asymmetric
allylation step. Although each individual asymmetric
transformation is precedented in the literature, development of a
one-pot process required optimization to account for compatibility
issues between the two reactions. We examined each step, while
actively looking for conditions employing a common base, solvent,
and temperature.
For the Pd-catalyzed allylation step, the use of (S)-BINAP
afforded 2a in good yield, but in very low enantiomeric excess
(Scheme 2a, entry 1). On the other hand, (S)-tBuPHOX was found
to be an efficient ligand for the transformation (entry 2), in
accordance with several reports using this metal-ligand
combination. We opted for a Pd(II) catalyst with pre-bound ligand
as opposed to more standard conditions involving Pd2dba3 and a
slight excess of (S)-tBuPHOX, to reduce the risk for formation of
Rh(I)-tBuPHOX, which was shown to be an inactive catalyst in the
second step (Scheme 2b, entry 2). In the absence of base, the
Pd(II) pre-catalyst is inactive (Scheme 2a, entry 3). A combination
of cesium carbonate and methanol was found to facilitate the
reduction of the Pd pre-catalyst, leading to a satisfactory yield of
2a (entry 4).9
Chiral diene ligand A, first developed by the Carreira
laboratory10 and repurposed for Rh-catalyzed 1,4-additions by the
Darses group,7b was found to be efficient for the Rh-catalyzed
transformation (Scheme 2b, entry 3). However, this chiral diene is
difficult to separate from 3a using column chromatography. To
alleviate purification issues, a more polar chiral diene ligand B
was used (entry 4).
In spite of the enantioselectivity of each step being less than
ideal (i.e. <90% ee), the combination of both steps in a sequential
one-pot protocol leads to outstanding enantiomeric excess of the
major diastereomer (Scheme 2c), through statistical amplification.
Assuming complete orthogonality and catalyst-controlled
stereoselectivity for both steps, the expected diastereomeric ratio
and enantiomeric excess are calculated to be 6.4:1 dr and 99%
ee for the major diastereomer (see Figure S1 in S.I. for
calculations). In fact, allyl enol carbonate 1a is converted to
ketone 3a in 88% NMR yield (7:1 dr), and the major diastereomer
can be isolated in 71% yield and 99% ee.
Scheme 2. Optimization of the sequential protocol. All reactions performed on
a 0.20 mmol scale under argon atmosphere, see S.I. for experimental details.
1H NMR yields are reported; isolated yield of major diastereomer in parentheses.
[a] % ee of the anti diastereomer is reported and matched the % ee of the syn
diastereomer within measurement error.
We next turned our attention to determining the reaction
scope (Scheme 3). A variety of aryl boronic acids could be
employed. Both electron-poor (3d, 3i) and electron-rich (3e-f, 3j)
boronic acids performed well under the reaction conditions.
Boronic acids with para-halogens, such as fluoro (3b) and chloro
(3g), were coupled successfully. Notably, boronic acids with
functional groups such as acetyl (3d), Boc-protected amine (3f)
and nitrile (3i) participated in the reaction. Additionally, an ortho-
substituted boronic acid afforded enantiopure product (3h), albeit
in a modest isolated yield of 43%. Heteroaromatic, vinyl, and
aliphatic boronic acids were also screened but were found to be
incompatible with this protocol (see S.I., Figure S2).
2
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It was found that, although traces of methanol can likely
assist in the activation of the palladium catalyst, too much
methanol leads to a significant decrease in enantioselectivity and
a modest decrease in yield (Scheme 4a, entry 1). Phenyl boronic
acid was also found to interfere, leading to low conversion and
only 16% yield of enone 2a (Scheme 4a, entry 2). By contrast,
phenyl pinacol borate was compatible in the first step (Scheme 4a,
entry 3). However, phenyl pinacol borate is unreactive in the
second step at 25 °C (Scheme 4b, entry 1), but good conversion
can be obtained at 60 °C (entry 2).
Scheme 3. Scope of the reaction. All reactions performed on a 0.20 mmol scale
under argon atmosphere, see S.I. for experimental details. First step carried out
at 25 °C for allyl enol carbonates, 35 °C for allyl β-keto esters [a] Isolated in 9:1
dr. [b] Isolated in 8:1 dr. [c] Isolated in 7:1 dr. [d] Hydrogens not shown; carbons
shown in light gray, oxygen in dark gray, nitrogen in black.
Scheme 4. Development of an assisted-tandem variant. All reactions performed
on a 0.20 mmol scale under argon atmosphere, see S.I. for experimental details.
1H NMR yields are reported; isolated yields of major diastereomer in
parentheses. [a] 2.0 equivalents in total. [b] %ee of the anti diastereomer is
reported. [c] Diene* A was used. [d] Isolated in 8:1 dr. [e] Isolated in 10:1 dr. [f]
Isolated in 12:1 dr.
When investigating the scope of the carbonates, we also
studied the more easily prepared allyl β-keto esters to broaden
the applicability of the methodology. A methyl (3a) or benzyl (3k)
substituent was tolerated at the alpha position.
A more
challenging scaffold, derived from heptanone, also gave the
desired product in excellent stereoselectivity, albeit in lower yield
(3l). Starting from allyl β-keto esters, products bearing aliphatic
chains with functional groups such as nitrile (3m), ester (3n), and
TBS-protected alcohol (3o) could be formed, all in good yields.
Next, we sought to determine whether the sequential pro-
tocol could be translated to a one-pot process where all reagents
are present from the outset of the reaction. The previously
described conditions cannot be directly converted to a tandem
process; less than 5% of the desired product is obtained if
reagents from the second step are added from the outset (see S.I.,
Section 2.4). To understand the origins of the problem, we
conducted an interference (alternatively called a robustness)
screen approach to evaluate which reagents from the second step
were incompatible in the first step (Scheme 4a).11
Incorporating a temperature change in the assisted-tandem
protocol was key to achieve a correct balance between reagent
compatibility in the first step and reactivity in the second step. In
addition, it was found that switching methanol for a combination
of water and cesium fluoride could afford product 3a in a moderate
combined yield of 52% (Scheme 4c). Notably, the
stereoselectivity of the reaction remained high: the major
diastereomer could be isolated in 39% yield and 99% ee. Other
pinacol boronate reagents could be used, and major
diastereomers all showed excellent enantiomeric purity. However,
purification following this protocol was more challenging and only
low to moderate yields are obtained in contrast to the sequential
procedure. While we have demonstrated the feasibility of a one-
pot procedure where all the reagents are added from the outset
3
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Scheme 5. Demonstrating stereodivergence. All reactions performed on a 0.20
mmol scale under argon atmosphere, see S.I. for experimental details.
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Acknowledgements
We thank the University of Toronto, the National Science and
Engineering Research Council (NSERC), and Kennarshore Inc.
for financial support. J.M.M. thanks NSERC for a graduate
fellowship (PGS D). X.A.S. thanks NSERC for a CGS-M
scholarship and the Province of Ontario (OGS) for funding. L. P.
acknowledges the Basque Government (Grupos IT908-16) and
UPV/EHU for financial support. We thank Alan Lough (University
of Toronto) for X-ray crystallography of 3i (CCDC 2069849). We
also wish to thank Bijan Mirabi for proofreading the manuscript.
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Keywords: sequential catalysis • asymmetric allylic alkylation •
rhodium • palladium • stereodivergent
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Entry for the Table of Contents
Two catalysts are better than one. Two chiral transition metal catalysts are combined in one-pot to perform orthogonal asymmetric
transformations. Simple allyl enol carbonates are converted to ketones bearing two non-contiguous stereogenic centers via a Pd-
catalyzed asymmetric allylic alkylation followed by a Rh-catalyzed enantioselective Hayashi-Miyaura conjugate addition. This tandem
process is enantio- and diastereodivergent and exhibits statistical amplification of enantiomeric excess.
6
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