Unexpected Alkene Isomerization during Iterative Cross-Coupling to Form Hindered, Electron-Deficient Trienes

Article abstract of DOI:10.1021/acs.orglett.8b00809

An iterative cross-coupling approach to conjugated trienes was explored as part of a planned stereoselective synthesis of bicyclic terpenes. Using a bifunctional bromoboronate building block, sequential Suzuki coupling reactions were employed to provide a conjugated trienone target containing a tetrasubstituted alkene. During the final cross-coupling step, an unexpected alkene isomerization was observed to give less hindered trans products. Examination of different substrates determined that conjugation to a ketone withdrawing group was responsible for isomerization, rather than steric hindrance of the tetrasubstituted alkene.

Full text of DOI:10.1021/acs.orglett.8b00809

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Unexpected Alkene Isomerization during Iterative Cross-Coupling To
Form Hindered, Electron-Deficient Trienes
Abigail Feceu, Lauren E. Sangster, and David B. C. Martin*
Department of Chemistry, University of California, Riverside, California 92521, United States
S
* Supporting Information
ABSTRACT: An iterative cross-coupling approach to conjugated trienes was explored as part of a planned stereoselective
synthesis of bicyclic terpenes. Using a bifunctional bromoboronate building block, sequential Suzuki coupling reactions were
employed to provide a conjugated trienone target containing a tetrasubstituted alkene. During the final cross-coupling step, an
unexpected alkene isomerization was observed to give less hindered trans products. Examination of different substrates
determined that conjugation to a ketone withdrawing group was responsible for isomerization, rather than steric hindrance of the
tetrasubstituted alkene.
wide variety of terpene natural products contain a decalin
substructure, often adorned with methyl or isopropyl
substituents, additional rings, and various patterns of
oxidation.1 In particular, many natural products share the
vicinal dimethyldecalin core structure 1 (>15000 natural
products), including a significant number of sesquiterpenes
(Figure 1).2 This class includes the eremophilane skeleton
challenge, and new synthetic approaches would be of significant
value.4−6
We were attracted to the possibility of generating the
dimethyldecalin substructure using a 6π-electrocyclization
reaction to forge the left-hand six-membered ring (7 → 8,
Figure 2), substantially simplifying the target.7,8 The proposed
A
Figure 2. Proposed 6π-electrocyclization strategy to either trans- or cis-
dimethyldecalin products using thermal or photochemical conditions,
respectively.
6π-electrocyclization reaction would allow the introduction of
both the tertiary and quaternary stereocenters in a single step,
where the relative stereochemical outcome would be
predictable based on the choice of reaction conditions (thermal
or photochemical) using the Woodward−Hoffmann rules.9
This strategy would potentially facilitate the synthesis of a
variety of eremophilane, nardosinane, and related sesquiter-
penes through a unified approach.
Figure 1. Dimethyldecalin core is found in many terpenes, including
the eremophilane and nardosinane sesquiterpenes.
With this idea in mind, we required an efficient synthesis of a
conjugated triene precursor incorporating functionality that
would allow for further elaboration to different targets.
Ketotriene 9 has been previously synthesized by Ramage and
(>1300 natural products, approximately) and nardosinane
skeleton (>160 natural products), represented by nootkatone
(4), periconianone F (5), and flavalin E (6).3 While the
syntheses of individual members of this family have been
reported and creative synthetic strategies beyond the often-used
Robinson annulation have been advanced, the construction of
the dimethyl decalin core 1 stereoselectively still poses a
Received: March 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00809
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Letter
Parker and Vosburg in modern approaches to kingianin A and
the endiandric acid scaffold, respectively.12,13 Here we report
our early efforts to apply MIDA-boronate cross-coupling to
stereospecifically synthesize the highly hindered E,Z-triene 9
and the observation of an unexpected Z to E alkene
isomerization process during a Suzuki coupling reaction. This
isomerization led to the loss of stereoselectivity and defines a
current challenge for the synthesis of conjugated polyenes that
are highly electron-deficient and sterically hindered using the
iterative cross-coupling strategy.
Scheme 1. Comparison of Reported Synthesis of Trienone 9
by Ramage and Proposed Iterative Cross-Coupling
Approach
Our route began with a slight modification of the known
synthesis of Z-2-bromovinylboronic acid MIDA ester (Z-14,
Scheme 2A).14 Hydroboration of commercially available
ethynyl MIDA boronate 16 gave E-diboronate 17. A two step
bromination/elimination sequence using Na2HPO4 as the base
gives the required Z-bromoboronate 14 with high stereo-
selectivity. A Suzuki coupling with propenylboronic acid 15
with Pd(OAc)2 and XPhos in THF led to dienyl MIDA
boronate 13 with retention of Z-configuration as expected.14,15
Two isomers are formed (in a 1:1 ratio) resulting from the
mixture of E- and Z-propenyl Grignard reagent used to
generate the E/Z-propenylboronic acid 15. Attempts to
separate the E,Z- and Z,Z-isomers of dienyl MIDA boronate
13 by crystallization and chromatography were unsuccessful.
This sequence proceeds in 63% overall yield over four steps,
providing efficient access to this useful building block.
Sattar using the Stork−Danheiser protocol with alkyne 10 and
vinylogous ester 11 as building blocks (Scheme 1).8 This
classical synthesis relies on a partial reduction of the alkyne to
produce the Z-alkene but produces a mixture with starting
material and over-reduced alkane product that are not readily
separable. We wondered if we might take advantage of recent
developments in cross-coupling to stereospecifically synthesize
the desired triene through the Suzuki coupling of stereodefined
alkene building blocks.10 In particular, the iterative cross-
coupling strategy using bifunctional MIDA-boronates (N-
methyliminodiacetic acid boronate esters) recently described
by Burke and co-workers appeared to be an ideal method to
efficiently construct this triene with complete control of alkene
geometry.11 Stereospecificity would be critical to ensure the Z-
geometry about the central alkene that is necessary for
electrocyclization. This polyene cross-coupling/electrocycliza-
tion strategy has been pioneered by Trauner and Beaudry using
a Stille coupling/8π/6π electrocyclization cascade toward the
SNF4435 polyketides and recently employed independently by
We next investigated the Suzuki coupling of dienyl MIDA
boronate 13 with β-bromoenone 12 (Scheme 2B). We first
employed optimized conditions reported by Burke and co-
workers for in situ hydrolysis/coupling with catalytic Pd(OAc)2,
SPhos, and aqueous K3PO4 in THF or dioxane at room
temperature. Under these conditions, we observed the
conversion to a mixture of two triene products. The two
isomers differed at the double bond distal to the carbonyl
group, as was expected starting from the mixture of E- and Z-
1
MIDA boronates 13. However, close inspection of the H
NMR spectra suggested that both isomers have a central E-
3
alkene (E,E-9 and Z,E-9), with JHH values of 15.4 Hz in both
Scheme 2. Synthesis of Trienone Isomers Using Iterative Suzuki Cross-Coupling Reactions of MIDA-boronates
B
DOI: 10.1021/acs.orglett.8b00809
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Letter
Scheme 3. Suzuki Coupling of Less Hindered and More Electron-Rich Vinyl Bromides To Probe the Cause of Alkene
Isomerization
cases. This outcome was quite surprising, as it indicated that the
central Z-alkene had isomerized to the corresponding E-alkene
under the conditions of the Suzuki coupling. Carrying out the
reaction in the strict absence of light had no effect on this
process, suggesting that it is not a photochemical isomer-
ization.16 To verify this unexpected outcome, we synthesized
the corresponding E-dienyl MIDA boronate 13 and performed
a Suzuki coupling reaction with bromide 12 (Scheme 2C). We
obtained the same two triene products, again isomeric at the
alkene distal to the ketone, confirming their structure. While
the success of using a Suzuki coupling to produce the
tetrasubstituted alkene in trienone 9 is remarkable, the
accompanying isomerization reaction was problematic for the
planned electrocyclization that requires a Z-geometry of the
central double bond.
conditions yielded E,Z- and Z,Z-23 in 58% combined yield with
3
retention of stereochemistry. The coupling constants of JHH
=
11.6 Hz for both isomers support the assignment as cis double
bonds in both cases. Likewise, Suzuki coupling of more
hindered bromide 22 proceeded with retention of stereo-
chemistry to provide E,Z- and Z,Z-24. Clearly, while the
formation of the tetrasubstituted double bond in product 24
results in a reduced yield compared to triene 23, the steric
hindrance of this moiety does not lead to the isomerization of
the central tetrasubstituted alkene in the absence of the
conjugated ketone.19 Rather, the electron-withdrawing effect of
the ketone is solely responsible for the unwanted isomer-
ization.10,18 This behavior is most consistent with isomerization
of the product postcoupling after the alkene in question is
conjugated to the ketone group. At this stage, however, we
cannot exclude the possibility of isomerization prior to
reductive elimination.17b
One possible mechanism for isomerization is a deprotona-
tion/reprotonation process of the moderately acidic methyl
group in conjugated products 9 and 20, a process that requires
the presence of the ketone to acidify this position. To probe
this mechanism we synthesized the simpler Z-dienyl MIDA
boronate 2514 lacking the methyl group and subjected it to
Suzuki coupling with bromoenone 19 (Scheme 4). We again
observed isomerization (3JHH = 15.2 Hz), suggesting that
deprotonation is not required for isomerization.
This type of isomerization, while fairly uncommon under the
mild conditions of a typical Suzuki coupling, has been observed
in some circumstances and particularly with certain electron-
deficient conjugated π-systems.17,18 An early report by Mavrov
outlined the synthesis of dienoate E,Z-18 (Scheme 2C) by a
Suzuki coupling of the corresponding E-vinylboron precursor
and Z-β-bromoacrylate.18 The stereochemical outcome of the
reaction depended on the reaction temperature and phosphine
ligand used, with dppe favoring isomerization, PPh3 giving a
mixture (at high temperature) and dppf giving the expected
product E,Z-18 with 95% stereochemical fidelity (at room
temperature). Given the similarity to our system, we therefore
tested dppf as an alternative ligand in our reaction at room
temperature, but the outcome was the same: the two major
With access to the cis-allylic alcohol products, we sought to
reach the target trienones by an alternative route and test their
1
products in the H NMR of the crude reaction mixture had
Scheme 4. Suzuki Coupling of Boronate Z-25 and Attempted
Oxidation of Allylic Alcohol 23
undergone isomerization (E,E-9 and Z,E-9, 48% combined
yield) and we could not identify the expected Z-products. It
seems that isomerization was too facile to be avoided with this
substrate under the conditions examined.
To probe the molecular features that lead to this unexpected
isomerization, we tested related substrates with specific
substituents removed (Scheme 3). Less hindered bromoenone
19, which lacks the α-methyl substituent, was coupled to dienyl
MIDA boronate 13 in 72% yield and we again observed
isomerization of the central double bond to give E,E- and Z,E-
20 (3JHH values = 15.6 Hz for both products). This result
suggests that the steric hindrance about the tetrasubstituted
double bond in trienone 9 is not the cause of isomerization. We
therefore tested more electron-rich vinyl bromides 21 and 22
lacking the conjugated ketone group. Suzuki coupling of
bromide 21 with dienyl MIDA boronate 13 under the same
C
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stability. As evidenced by the lower yields of alcohols 23 and
24 (Scheme 3), these intermediates were somewhat unstable
and decomposed under a variety of oxidation conditions. A
Dess−Martin oxidation of the alcohols E,Z- and Z,Z-23
appeared to give E,Z- and Z,Z-20, one of the original target
trienones, in low yield (Scheme 4). These two isomeric
products clearly differed from the previously synthesized E,E-
and Z,E-20 (Scheme 3), however we were unable to obtain a
pure sample and measure coupling constants accurately due to
the instability of this compound. While we hesitate to draw firm
conclusions, the decomposition of cis-trienes supports the
hypothesis of post-Suzuki coupling isomerization, facilitated by
the electron-withdrawing ketone and driven by the formation of
the more stable trans products. In the context of previous
reports and based on the available data described here, we
currently favor isomerization of the electron-deficient product
via a palladium hydride species or a Pd(II) species.20−22
Overall, while the unexpected isomerization of polyenes is not a
new phenomenon,23 the process observed here defines a
current challenge for the synthesis of conjugated polyenes that
are highly electron-deficient using the iterative cross-coupling
strategy. Further catalyst optimization and mechanistic studies
will be necessary to overcome these challenges and access the
full diversity of natural and synthetic polyenes using this
versatile approach.11
In conclusion, we have reported the synthesis of a series of
trienes and trienones containing tri- and tetrasubstituted
alkenes using an iterative Suzuki coupling strategy. An
unexpected isomerization process of electron-poor conjugated
trienones occurs under the mild conditions of a Suzuki cross-
coupling reaction. This isomerization led to the loss of
stereoselectivity and complicated the exploration of an
electrocyclization strategy to the dimethyldecalin substructure
of many terpene natural products. The isomerization reaction
was not observed for a substrate lacking the conjugated ketone
group, indicating that electronics play the major role in favoring
isomerization rather than sterics.
D.B.C.M. is a member of the UC Riverside Center for
Catalysis.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00809.
1
Experimental procedures, characterization data, H and
13C NMR spectra of all new compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dave.martin@ucr.edu.
ORCID
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David B. C. Martin: 0000-0002-8084-8225
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous start-up funds from the
University of California, Riverside. NMR instrumentation for
this research was supported by funding from the U.S. Army
(W911NF-16-1-0523). We thank Eric Woerly (Burke Group,
UIUC) for helpful advice in the preparation of boronate Z-14.
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