Remote Functionalization of α,β-Unsaturated Carbonyls by Multimetallic Sequential Catalysis

Article abstract of DOI:10.1021/jacs.9b09373

The remote functionalization of α,β-unsaturated carbonyls by an array of multimetallic sequential catalytic systems is described. The reactions are triggered by hydrometalation using [Pd-H] or [Ru-H] isomerization catalysts and driven by the formation of thermodynamically more stable 1,2-vinyl arenes. The Pd-catalyzed deconjugative isomerization was combined with a Cu-catalyzed β-borylation of the transiently generated styrenyl derivatives to deliver a range of products that would not be accessible with the use of a single catalyst. [Pd/Cu] catalytic systems were also identified for the highly enantioselective α-hydroboration and α-hydroamination of the styrenyl intermediates. Difunctionalization simultaneously at the benzylic and homobenzylic positions was achieved by combining the isomerization process with Sharpless asymmetric dihydroxylation (SAD) using [Pd/Os] or [Ru/Os] couples. Starting from a simple α,β-unsaturated ester, an isomerization/dihydroxylation/lactonization sequence gave access to a naturally occurring γ-butyrolactone in good yield, with excellent diastereo- and enantioselectivity.

Full text of DOI:10.1021/jacs.9b09373

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Article
Remote Functionalization of #,#-Unsaturated
Carbonyls by Multimetallic Sequential Catalysis
Ciro Romano, Daniele Fiorito, and Clément Mazet
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09373 • Publication Date (Web): 06 Oct 2019
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Remote Functionalization of -Unsaturated Carbonyls by Multi-
metallic Sequential Catalysis
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Ciro Romano, Daniele Fiorito, Clément Mazet*
† Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
ABSTRACT: The remote functionalization of -unsaturated carbonyls by an array of multimetallic sequential catalytic
systems is described. The reactions are triggered by hydrometallation using [Pd‒H] or [Ru‒H] isomerization catalysts and
driven by the formation of thermodynamically more stable 1,2-vinyl arenes. The Pd-catalyzed deconjugative isomerization
was combined with a Cu-catalyzed -borylation of the transiently generated styrenyl derivatives to deliver a range of prod-
ucts that would not be accessible with the use of a single catalyst. [Pd/Cu] catalytic systems were also identified for the
highly enantioselective -hydroboration and -hydroamination of the styrenyl intermediates. Difunctionalization simulta-
neously at the benzylic and homobenzylic positions was achieved by combining the isomerization process with Sharpless
asymmetric dihydroxylation (SAD) using [Pd/Os] or [Ru/Os] couples. Starting from a simple -unsaturated ester, an
isomerization/dihydroxylation/lactonization sequence gave access to a naturally occurring -butyrolactone in good yield,
excellent diastereo- and enantioselectivity.
The economic and environmental benefits associated
with sequential multimetallic catalysis has raised strong
■ INTRODUCTION
interest in academia and industry.9-11 The field emulates
from Nature’s ability to separate different reactive sites
within an enzyme, or different enzymes within a cell to ef-
fect a series of orthogonal transformations in a given se-
quence without the need to isolate unstable reactive inter-
mediates. The implementation of such strategies in syn-
thetic laboratories may ultimately enable chemists to read-
ily convert commodity chemicals into more complex mo-
lecular architectures with maximum efficiency - be it in
terms of atom-, step-, redox-economy, absolute and rela-
tive stereocontrol.12 A paramount challenge is to meet the
requirement for time resolution and compatibility of all re-
agents and catalysts to a single set of reaction conditions.
Recently, the Marek laboratory and our group inde-
pendently merged the concepts of remote functionaliza-
tion and multimetallic catalysis with the development of
complementary isomerization/cross-coupling sequences
using [Ir/Ni], [Pd/Ni] and [Ru/Ni] combinations.13 These
protocols afford highly substituted alkenes from readily
available alkenyl methyl ethers via the intermediacy of ste-
reodefined methyl vinyl ethers that would be difficult to
access and isolate by conventional methods.
The remote functionalization of an organic molecule
consists in interconverting two distant functional groups
by a relay process either through (i) space or (ii) across the
constitutional skeleton.1 The former usually requires the
elaboration, installation and subsequent removal of often
complex directing templates to achieve the desired distant
functionalization.2 The latter is typically accomplished by
alkene migration along a hydrocarbon chain and driven by
a thermodynamically favorable termination process.3 This
enabling strategy has gained increased momentum over
the last few years, leading to the development of particu-
larly innovative transformations (Figure 1, A).4-8 Two key
notions must be taken into consideration for the successful
realization of remote functionalization protocols based on
alkene migration. First, the initiation phase, which de-
pends on: (i) the triggering event that initiates olefin mi-
gration; (ii) the extent of substitution of the olefin, a crucial
parameter for reactivity. Second, the driving force of the
process, which includes: (i) the ability of the catalyst to sus-
tain olefin migration along the hydrocarbon chain, inde-
pendently of its length (favorable kinetics); (ii) the nature
of the terminal functional group undergoing refunctional-
ization (favorable thermodynamic). This last aspect is inti-
mately associated with the nature and thermodynamic sta-
bility of the organometallic intermediate which usually
precedes product formation. Specifically, metallo-carbinol
species such as A were found to intervene before reinstal-
lation of the unsaturation in several reactions, including in
deconjugative processes (Figure 1, B).4 A complementary
approach consists in intercepting a -benzyl organometal-
lic (B),5 a primary alkyl organometallic (C),6 or a C-bound
metal-enolate (D) with an appropriate coupling partner
(Figure 1, C-D).7-8
As an extension of this approach, we hypothesized that,
if judiciously designed, remote functionalization by se-
quential multimetallic catalysis may enable (i) to react the
intermediates resulting from alkene isomerization at posi-
tions that are not imposed by the thermodynamically fa-
vored organometallic species generated upon chain-walk-
ing, and (ii) to further diversify the scope of refunctionali-
zations by use of a second transition metal. These subse-
quent orthogonal transformations would not be conceiva-
ble with the catalyst used for isomerization (Figure 1, E).
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Figure 1. (A) Remote functionalization by transition metal-catalyzed alkene migration. (B) Remote functionalizations in-
volving Pd-carbinol intermediates. (C) Remote functionalizations involving transition metal-benzyl intermediates. (D) Re-
mote functionalizations involving primary alkyl transition metal intermediates and transition metal C-enolates. (E) Princi-
ple of remote functionalization by sequential multimetallic catalysis. (F) This study: deconjugative remote functionaliza-
tions based on the enantioselective -hydrofunctionalization, -borylation and asymmetric dihydroxylation of the transi-
ently generated 1,2-vinyl arenes using [Pd/Cu], [Ru/Os], [Pd/Os] catalytic sequences.
Herein we report the validation of this approach with the
devise of several multimetallic sequences initiated by the
■ RESULTS AND DISCUSSION
We have previously established that the refunctionaliza-
tion of an alcohol into a ketone or an aldehyde constitutes
a sufficiently strong driving-force to effect the deconjuga-
tive isomerization of ,-unsaturated carbonyls by palla-
dium catalysis.4k We decided to explore the possibility to
extend this process to substrates terminated by an aro-
matic ring to access the corresponding vinylarenes by in-
vestigating the isomerization of the ,-unsaturated ester
(E)-1a with a selection of well-established isomerization
catalysts 3a-e (Table 1). Satisfactorily, product formation
was observed in all cases. Only moderate conversion into
styrenyl 2a were achieved with the Pfaltz modified version
of Crabtree catalyst 3a activated by H2 and with
[(Ph3P)3Ru(H)2(CO)] 3b (Entry 1-2).14 With the neutral rho-
dium hydride complex [(Ph3P)3RhH(CO)] 3c, conversion
into 2a was also incomplete. Nearly 16% of a 4:1 E/Z mixture
of the intermediate internal alkenes was observed. The ru-
thenium monohydride [(Ph3P)3RuH(CO)(Cl)] 3d and our
home-made palladium precatalyst 3e afforded 2a in 92%
long-range deconjugative isomerization of -unsatu-
rated carbonyls catalyzed by either a ruthenium or a palla-
dium complex and driven by the formation of a remote vi-
nylarene. These intermediates were typically generated
with high levels of stereoselectivity and engaged in a sub-
sequent functionalization in the same reaction vessel.
First, a challenging Cu-catalyzed borylation at the homo-
benzylic position was achieved for a variety of derivatives
providing access to multifunctional scaffolds that could
not be prepared with a single transition metal catalyst.
Next, conditions compatible with Cu-catalyzed enantiose-
lective -hydroboration and enantioselective -amination
reactions were identified when a Pd catalyst was used for
the deconjugative process. Finally, a [Ru/Os] catalytic
combination enabled highly selective dihydroxylation of
the in situ generated vinylarene. The possibility to increase
molecular complexity using this strategy was established in
an isomerization/dihydroxylation/lactonisation sequence
providing access to a naturally occurring -butyrolactone.
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Table 1. Catalyst identificationa
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Figure 2. Remote functionalization of 1a by a [Pd/Cu]-cat-
alyzed deconjugative isomerization/-borylation se-
quence.
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Entry Substrate
Catalyst
Conv. (%)b
46
E/Z 2b
creasing molecular complexity. The catalytic and site-selec-
tive -functionalization of 1,2-vinylarenes constitute a con-
temporary challenge in itself and the number of successful
examples of such processes remains quite limited. Due to
the robustness of the reaction conditions, we reasoned that
the Cu-catalyzed -borylation of 1,2-vinylarenes pioneered
by Hoveyda may constitute a suitable entry point for the
development of a multimetallic sequence.15 Upon testing
this hypothesis, we were pleased to find that the two cata-
lytic systems were compatible. Indeed, only marginal ad-
justment of the original reaction conditions of the pro-
toboration were necessary to perform sequentially, in the
same reaction vessel, and without solvent switch, the Pd-
catalyzed deconjugative isomerization of 1a and the Cu-
catalyzed -selective functionalization of the transiently
generated vinyl arene 2a. Gratifyingly, using [(IMes)CuCl],
NaOtBu, B2pin2 and MeOH at room temperature in the
second part of the sequence, the final borylated product 3a
could be isolated in pure form in 73% yield after purifica-
tion by column chromatography and separation from the
product of conjugate addition to 1a (Figure 2). Formation
of the product of -borylation was not observed.
1
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1b
(E)-1b
(Z)-1a
(E)-2a
(E)-2a
3a
>20:1
2
3
3b
3c
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31
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
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5
6
7
8
9
10
3d
3ec
3d
3ec
3ec
3d
3ec
92
94
58
88
93
8
6
a 0.15 mmol scale. b Determined by 1H NMR using an inter-
nal standard. c 3e activated using 5.5 mol% of NaBArF.
and 94% conversion with very high levels of stereocontrol
(E/Z >20:1) (Entry 3-5). Only partial conversion was
achieved for the deconjugative isomerization of the steri-
cally more demanding -substituted -unsaturated ester
(E)-1b using the ruthenium precatalyst 3d. With the palla-
dium complex 3e, the styrenyl derivative 2b was generated
in 88% and E/Z >20:1 (Entry 6-7). Isomerization of (Z)-1a
afforded (E)-2a with excellent stereoselectivity, highlight-
ing the stereoconvergent nature of the isomerization pro-
cess (Entry 8). Both for 1a and 1b, despite the excellent cat-
alytic efficiency observed with 3d and 3e, physical separa-
tion of the styrenyl product from the substrate could not
be achieved. Attempts to reach complete conversion by
systematic variation of the reaction parameters (catalyst
loading, reaction time, temperature…) were not met with
success, thus severely limiting the practicality of the pro-
cess. When 2a (prepared by an independent route) was
subjected to the optimized catalytic conditions using ei-
ther 3d or 3e, formation of the -unsaturated ester was
observed in 8% and 6% respectively (Entry 9-10). These re-
sults indicate that the isomerization reaction is reversible
and under thermodynamic control, with preference for the
formation of the styrenyl derivatives 2 when 3d and 3e are
employed.
The generality of this sequential multimetallic catalytic
process was explored using the optimized conditions (Fig-
ure 3). To fully appreciate the combined efficiency of the
two catalysts when operating in sequence, Figure 3 also
contains the ratio between the -unsaturated carbonyl
and the vinyl arene measured when the Pd-catalyzed de-
conjugative isomerization reaction is performed inde-
pendently. In most cases, variation of the terminal aro-
matic ring had only a limited impact on the ratio between
the -unsaturated ester and the vinyl arene remained
very high, ranging from 7:93 to 1:99 (2a,c-h). All styrenyl
products were obtained with excellent stereoselectivity
(E/Z >20:1). The furan and Boc-indole derivatives (1i,j) led
to much reduced chemoselectivity (21:79 and 40:60 respec-
tively), and 2j was generated with decreased stereoselectiv-
ity (E/Z = 7.2:1). When these reactions were run in se-
quence, the borylation products were isolated in moderate
to high yields. Starting from 1b, the product of -borylation
4b was isolated in 79% (dr 1:1) after conducting the [Pd/Cu]
catalytic sequence. In contrast, the presence of a -substit-
uent on the -unsaturated ester drastically affected the
efficiency of the isomerization process and consequently
the yield of the Cu-catalyzed borylation reaction (4k: 37%,
dr 1.7:1). Isomerization of 1l to generate the styrenyl deriv-
ative 2l, featuring a trisubstituted alkene, was quantitative.
In line with our initial objectives, we subsequently
sought to identify a catalytic transformation for the in situ
-functionalization of the styrenyl derivatives obtained
upon deconjugative isomerization. Ultimately, this would
not only allow us to potentially circumvent purification is-
sues but, more importantly, to functionalize the products
of isomerization at a less conventional position while in-
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Figure 3. Scope of the Pd-catalyzed deconjugative isomerization of -unsaturated carbonyls and scope for the [Pd/Cu]-
catalyzed deconjugative isomerization/-borylation sequence. The 1:2 ratio was determined by 1H NMR using an internal
standard. Reactions performed on a 0.2 mmol scale. (A) Variations of the arene end-group. (B) Variations of the alkene
substitution pattern. (C) Effect of chain length on catalytic efficiency. (D) Variation of the carbonyl head group. a Isomeri-
zation run at 60 °C for 24 h. b Isomerization run at 120 °C for 18 h. c Not determined. d No reaction. e Contains ca. 40% of
f
g
h
i
internal olefins. Not compatible. 1:2.3 mixture of 2q and 4q. Contains ca. 5% of internal olefins. Using 1.1 equiv. of
B2pin2.
Consistent with literature precedents, Cu-borylation of the
congested C=C bond was ineffective. We established that
the Pd-catalyzed deconjugative isomerization is essentially
insensitive to the chain length between the carbonyl func-
tion and the remote aryl group, and could perform the re-
mote borylation of 1m and 1n with selectivity similar to
that of the model substrate (7:93 and 8:92 respectively; 4m:
74% yield; 4n: 48% yield after purification). Nonetheless,
in the case of the 9-C atom substrate 1n, nearly 40% of in-
ternal olefin isomers were observed after the isomerization
step. Finally, we found that -unsaturated alkyl ketone
(1o), aryl ketone (1p), tertiary amide (1q), phosphate (1r)
and sulfone (1s) are all competent functional groups in the
deconjugative isomerization, affording the corresponding
vinyl arenes with good to excellent 1:2 ratios. Even though
the ketone derivatives are not compatible with the reaction
conditions for borylation, we were able to isolate the prod-
ucts of isomerization in high yield (2o: 82%; 1p: 80%). Even
when the stoichiometry and catalyst loading were ad-
justed, only partial borylation was achieved with the amide
derivative 4q, leading to an intractable mixture of isomer-
ization and borylation products. Satisfactorily, 4r and 4s,
the products of the deconjugative isomerization/boryla-
tion sequence of the corresponding -unsaturated phos-
phate and sulfone were obtained in high yield (85% and
75% respectively).
As a following challenge, we decided to investigate
whether the Pd-deconjugative isomerization could be
combined with enantioselective hydrofunctionalizations
of the vinyl arenes generated in situ.16 Not only are these
reactions particularly sensitive to subtle changes in the ex-
perimental conditions, but the association of two metal-
hydride catalysts may constitute an additional hurdle to
the successful development of such multimetallic se-
quences.
The enantioselective -hydroboration of 1,2-substituted
vinyl arenes that produces benzylic boronic esters finds
limited precedents in the literature.17 We initiated our in-
vestigations by testing the optimum system described by
Yun and coworkers for the Cu-catalyzed hydroboration of
-methyl styrene17a on the independently prepared styrenyl
derivative 2a and were pleased to isolate the targeted ben-
zyl boronate 5a in 57% yield and 95% ee (as compared to
71%, 95% ee for the product of -methyl styrene) (Figure 4,
A). The remote functionalization of 1a performed by apply-
ing the Pd-catalyzed isomerization/Cu-catalyzed hydrobo-
ration sequence in one-pot afforded 5a in only 48% yield
and with a much reduced enantioselectivity (86% ee) (Fig-
ure 4, B). Several chelating bis-phosphine ligands were
evaluated using the conditions for sequential catalysis (See
Supporting Information). Gratifyingly, another P-stereo-
genic ligand, BenzP* (L2) delivered 5a in low yield but with
excellent enantioselectivity (27% yield, 97%).
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Figure 5. (A) Enantioselective access to -butyrolactone 7a
by [Pd/Os]-catalyzed deconjugative isomeriza-
a
tion/SAD/lactonization sequence. (B) Enantioselective ac-
cess to -butyrolactone 7a by a [Ru/Os]-catalyzed deconju-
gative isomerization/SAD/lactonization sequence. (C) Re-
mote functionalization of 1n by a [Ru/Os]-catalyzed de-
conjugative isomerization/SAD sequence.
To further demonstrate the potential of remote func-
tionalization strategies by sequential multimetallic cataly-
sis, we turned our attention to the Sharpless asymmetric
dihydroxylation of alkenes (SAD),19 a protocol that could
potentially allow to orthogonally functionalize the in situ
generated 1,2-vinyl arenes both at the benzylic and homo-
benzylic positions. The mechanism of the SAD has been
extensively studied and is relatively well understood. A less
enantioselective secondary cycle in which the osmium cat-
alyst is not bound to the chiral ligand has been identified.
We anticipated that if any perturbation of the chiral os-
mium catalyst during the isomerization/SAD sequence
(e.g. ligand exchange) might increase the contribution of
the secondary cycle and, consequently, deplete the enanti-
omeric excess of the product. To test the viability of the
[Pd/Os]-catalytic combination, our model substrate 1a was
subjected to deconjugative isomerization using 2.5 mol%
of 3e and subsequently to the prototypical reaction condi-
tions for SAD using AD-mix- (0.2 mol% in [Os]). Pleas-
ingly, not only both protocols were found to be compatible,
but a lactonization between the methyl ester and the newly
generated homobenzylic alcohol delivered syn-(S,S)-7a in
44% yield, dr >20:1 and >99% ee (Figure 5, A). Interestingly,
-butyrolactone syn-(S,S)-7a is a naturally occurring prod-
uct originating from sponge-derived fungi, which was
found to display anti-nematodal activity.20 Substituting
AD-mix- by mCPBA in the second part of the sequence
provided access to another natural product isolated from
fungi which displays antimicrobial activity: Cytospora-
none A (anti-7a: 56% yield and dr >20:1).21 In contrast to
Figure 4. (A) Cu-catalyzed enantioselective -hydrobora-
tion of 2a. (B) Sequential [Pd/Cu]-catalyzed deconjugative
isomerization/-hydroboration of 1a. Effect of relative cat-
alyst loading. (C) Remote functionalization of 1n by a
[Pd/Cu]-catalyzed deconjugative isomerization/-hydrob-
oration sequence. (D) [Pd/Cu]-catalyzed deconjugative
isomerization/-hydroamination of 1a.
When the catalyst loading in 3e was halved to minimize
potential interactions between the in situ generated [Pd‒
H] catalyst and the Cu catalyst, a reduced reactivity was
observed with L1 but, remarkably, boronate 5a could be iso-
lated in 58% yield and 97% ee with L2.
A similar approach was followed for the development
of Pd-catalyzed deconjugative isomerization/Cu-catalyzed
enantioselective hydroamination sequence (Figure 4, C).
Using the protocol developed by Buchwald and co-workers
as starting point,18 we found that best performances were
achieved when the loading in 3e was reduced. This is pre-
sumably due to minimized detrimental interaction be-
tween both transition metal catalysts. Moreover, to be fully
operative, the system required to switch solvent from tol-
uene to THF after the isomerization reaction. The Cu-cat-
alyzed hydroamination was therefore conducted on the
crude reaction mixture resulting from deconjugative isom-
erization of 1a using diethoxymethylsilane, benzylamino-
4-(dimethylamino)benzoate as the amine transfer reagent
and (R)-DTBM-Segphos L6 as chiral ligand to afford the
product of remote functionalization 6a in 53% yield and
99% ee.
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* Prof. Clément Mazet. University of Geneva, Organic Chem-
istry Department. Quai Ernest Ansermet 30, Geneva 1211 -
Switzerland. clement.mazet@unige.ch
the previous multimetallic sequences, we found that
[[(Ph3P)3RuH(CO)(Cl)] 3d (2.5 mol%) could be successfully
associated with the osmium catalyst to afford syn-(S,S)-7a
in an improved 56% yield while maintaining similar selec-
tivity (dr 20:1 and >99% ee) (Figure 5, B). Overall, this se-
quence consisting of a deconjugative isomerization, an en-
antioselective dihydroxylation and a lactonization enabled
to substantially increase the level of molecular complexity
from a simple -unsaturated ester to a biologically active
natural product. This result underscores the potential of
remote functionalization by multimetallic catalysis.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the University of Geneva and the Swiss National Sci-
ence Foundation (project 200021_159199) for financial support
and Johnson Matthey for a generous gift of iridium and palla-
dium precursors. Stéphane Rosset (University of Geneva) is
warmly acknowledged for measuring HRMS analyses and for
his assistance with analytical instruments.
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In summary, we have developed a series of remote func-
tionalizations based on sequential multimetallic catalytic
reaction performed in a single reaction vessel. These se-
quences are initiated by Pd- or a Ru-catalyzed deconjuga-
tive isomerizations of -unsaturated carbonyl com-
pounds. Although reversible, the isomerization is under
thermodynamic control and driven by the formation of the
more stable styrenyl derivatives. Consistent with previous
observations from our laboratory, the palladium complex
was found to be less sensitive to higher steric demand from
the olefinic substrate. Therefore, the scope of the Pd-cata-
lyzed deconjugative isomerization was investigated in de-
tails and successfully combined with a Cu-catalyzed -
borylation of the transiently generated 1,2-vinyl arenes.
Each elementary reaction is challenging when considered
independently and remote functionalization at the homo-
benzylic position would not be conceivable with the exclu-
sive use of known isomerization catalysts. The sequence
was found to be compatible with a variety of carbonyl de-
rivatives, several sensitive functional groups and to tolerate
various olefinic substitution patterns. Two isomeriza-
tion/enantioselective -hydrofunctionalization sequences
using [Pd/Cu] combinations have also been developed. We
demonstrated that the combination of the isomerization
system with established protocols is not necessarily
straightforward. Aside from the identification of a suitable
chiral ligand, we showed that adjustment of the relative
catalyst loadings is crucial to reach satisfactory reactivity
and attain excellent enantioselectivity levels. Products re-
sulting from formal remote -hydroboration and -hy-
droamination were thus obtained in practical yield and
very high ee. Finally, a naturally occurring -butyrolactone
with anti-nematodal activity was accessed in enantiopure
form starting from a simple -unsaturated ester by ef-
fecting a sequence of three consecutive events consisting
in an isomerization, an asymmetric dihydroxylation and a
final lactonization. The [Ru/Os] catalytic combination
proved slightly superior to the [Pd/Os] couple.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, charac-
terization of all new compounds and spectral data. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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Journal of the American Chemical Society
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