Unprecedented cobalt-catalyzed isomerization reactions to single skipped 2,4,7-trienes applied in the synthesis of urushiol

Article abstract of DOI:10.1002/asia.201402323

The cobalt-catalyzed isomerization of 1,3-dienes to 2Z,4E-dienes was realized for the very challenging substrates with an additional double bond in the side chain. An isomerization to the conjugated 3,5,7-triene derivative was not observed, which is in stark contrast to observations with many other isomerization catalysts. Accordingly, the synthesis of the natural product urushiol, which has a sensitive 2Z,4E,7Z-triene subunit in the side chain, was investigated. The O-protected urushiol derivative was generated selectively without isomerization to the conjugated 3,5,7-triene or Z/E-isomerization of the double bond at position 7.

Full text of DOI:10.1002/asia.201402323

COMMUNICATION
DOI: 10.1002/asia.201402323
Unprecedented Cobalt-Catalyzed Isomerization Reactions to Single Skipped
2,4,7-Trienes Applied in the Synthesis of Urushiol
Anastasia Schmidt and Gerhard Hilt*[a]
Abstract: The cobalt-catalyzed isomerization of 1,3-dienes
to 2Z,4E-dienes was realized for the very challenging sub-
strates with an additional double bond in the side chain. An
isomerization to the conjugated 3,5,7-triene derivative was
not observed, which is in stark contrast to observations with
Scheme 1. Asymmetric rhodium-catalyzed isomerization of an internal al-
lylic amine into a chiral enamine.
many other isomerization catalysts. Accordingly, the synthe-
sis of the natural product urushiol, which has a sensitive
2Z,4E,7Z-triene subunit in the side chain, was investigated.
The O-protected urushiol derivative was generated selec-
tively without isomerization to the conjugated 3,5,7-triene
or Z/E-isomerization of the double bond at position 7.
which terminal alkenes were isomerized to the 2Z-alkenes
as the major products.[5]
Prior to this publication, we reported the stereoselective
cobalt-catalyzed isomerization of the E/Z-mixtures of 1,3-
dienes 3 to the 2Z,4E-isomers 4.[6] Remarkably, a further
isomerization of the double bonds to the corresponding 3,5-
dienes 5 were not observed (Scheme 2).
The isomerization of the configuration as well as the mi-
gration of double bonds are reactions where in sum neither
a new bond is formed nor any atom is added or lost in the
products. However, these reactions can be very useful in or-
ganic synthesis, particularly when the isomerization or the
migration of double bonds starts from readily available
starting materials and leads to more valuable products. In
general, the formation of the thermodynamically more
stable isomer is the predominant driving force. Accordingly,
the isomerization of an alkene from the Z-configuration to
the E-alkene has been disclosed several times[1] while the re-
verse reaction is more challenging.[2] For double bond migra-
tion reactions the thermodynamic driving force can be
either a higher degree of substitution or the formation of
a more stable double bond, such as those in carbonyl
groups, imines or to double bonds which are then in conju-
gation to another unsaturated functionality.[3] One of the
benchmark transformations in this respect is the asymmetric
isomerization of the allylic amine 1 by chiral rhodium com-
plexes for the formation of the chiral enamine 2 in the syn-
thesis of the tocopherol side-chain as described by Noyori
and co-workers (Scheme 1).[4]
Scheme 2. Cobalt-catalyzed isomerization of terminal 1,3-dienes to 4.
In the course of our ongoing investigation concerning
cobalt-catalyzed isomerization reactions of 1,3-dienes, we
identified the urushiol 6,[7] a main component of East Asian
lacquer (japanese: urushi),[8] as a highly interesting bench-
mark target molecule. Lacquerware has been used in East
Asia for thousands of years for the preservation of wooden
materials that can be found in everyday items as well as for
decorative purposes. The main components of the non-poly-
merized lacquer have been identified to consist of catechol
derivatives with a long side chain that show different grades
of unsaturation. By far the highest content (up to 67%) of
such derivatives in urushiol was assigned to the 2Z,4E,7Z-
isomer 6 shown in Figure 1.
Recently, Weix, Holland and co-workers described an out-
standing application of a cobalt-catalyzed isomerization in
[a] A. Schmidt, Prof. Dr. G. Hilt
Fachbereich Chemie
Figure 1. Structure of 6, the main component of urushiol.[8c]
Philipps-Universitꢀt Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
Fax : (+49)64212825677
E-mail: Hilt@chemie.uni-marburg.de
The synthesis of urushiol 6 from a corresponding 1,3,7-
triene, such as 7, implies specific challenges (Scheme 3):
1) The cobalt catalyst should isomerize the terminal 1,3-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402323.
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G. Hilt and A. Schmidt
stants and is in accordance with the previously reported re-
sults.[6] The determination of the E-configuration of double
1
bond 7 by H NMR spectroscopic analysis could not be ac-
1
complished because the H NMR resonances were overlap-
ping and coupling constants could not be deduced. The con-
figuration of double bond 7 was assigned based on the
13C NMR specroscopic data since the 13C NMR chemical
shifts of the carbon atoms adjacent to the double bond in 11
are an excellent measure for the assignment of the 7E-
double-bond configuration: C6: 36.0 ppm; C9: 32.7 ppm.[10]
We then turned our attention to a more challenging triene
with an internal Z-configured double bond (Scheme 5).
Therefore, the commercially available aldehyde 12 was se-
lected and transformed in a Julia-Kocienski olefination into
the E/Z-mixture of triene 13 in 72% yield (E:Z=5:4).
Scheme 3. Outline of the desired transformation of the terminal 1,3-diene
subunit in 7 to the single skipped triene 8.
diene subunit to the desired 2Z,4E-moiety. 2) A further iso-
merization to the thermodynamically more favored conju-
gated 3,5,7-triene in 8 has to be avoided. 3) The 7Z-double
bond should not be altered by the cobalt catalyst, neither in
its position nor in its configuration.
Before addressing the synthesis of urushiol 6, we decided
to examine the cobalt-catalyzed isomerization reaction on
simple, easily accessible substrates. For this purpose, the
triene 10 with an internal E-double bond was synthesized as
outlined in Scheme 4. The commercially available ester 9
was reduced to the corresponding alcohol and transformed
into the aldehyde through pyridinium chlorochromate
(PCC) oxidation. The synthesis of the 1,3-diene was realized
in a Julia–Kocienski olefination with 2-(allylsulfonyl)benzo-
thiazole and sodium hexamethyldisilazane (NaHMDS) to
afford 10 as a E/Z-mixture (E:Z=10:7) in 66% overall
yield.
Scheme 5. Synthesis of 7Z-configured 13 and isomerization towards
triene 14.
The cobalt-catalyzed migration afforded the desired
triene 14 in 73% yield as a single product. As before, the
configuration of double bond 7 could not be deduced from
1H NMR coupling constants. The analysis of 13C NMR data
of 14 for C6 (30.7 ppm) and C9 (20.7 ppm) confirms the un-
changed 7Z-double bond configuration. Accordingly, this
data analysis revealed that the requirements outlined before
for the double-bond migration were fulfilled. Firstly, the 1,3-
diene unit migrated selectively to the 2Z,4E-position and
configuration, and secondly the configuration and position
of the double bond 7 remained unchanged.
With these promising results in hand, we investigated the
synthesis of the natural product, urushiol 6. The precursor
21 for the cobalt-catalyzed isomerization reaction was ob-
tained in a straightforward reaction sequence outlined in
Scheme 6. Starting from the commercially available alkyne
15, the triple bond was migrated to the terminal position ap-
plying a procedure described by Brown followed by an
Appel bromination to afford the bromo-alkyne 16 in a good
overall yield of 73%. In a one-pot reaction sequence, the
bromo-alkyne 16 was treated with an excess of the ortho-
lithiated catechol 17 (3.5 equiv), thus leading to the carbon–
carbon bond formation and the deprotonation of the termi-
nal alkyne proton: Subsequently, the second carbon–carbon
bond formation was realized by addition of the alkyl bro-
mide derivative 18. The internal alkyne 19 was obtained in
an acceptable yield of 56% with respect to the starting
Scheme 4. Synthesis of 7E-10 and isomerization towards triene 11.
The isomerization reaction of 10 was performed with the
previously described cobalt catalyst system comprising
CoBr2ACHTUNGTRENNUNG
(dpppMe2),[9] zinc powder, and zinc iodide in dichloro-
methane at ambient temperature to generate the triene 11.
After a reaction time of 14 h, complete conversion and the
formation of a single new product was detected through
GC/MS analysis. The desired product 11 was isolated after
column chromatography in 66% yield.
The configuration of the 2Z- and the 4E-double bond
1
could be unambiguously assigned by H NMR coupling con-
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G. Hilt and A. Schmidt
ural product (C6: 30.7 ppm; C9: 27.3 ppm).[12a] Therefore,
the main task for the synthesis of the skipped triene subunit
was accomplished.
The deprotection of the catechol moiety utilizing BBr3
was described by Miyakoshi and co-workers for the synthe-
sis of minor components of urushiol.[12b] However, the de-
protected urushiol 6 is reported to be an extremely hazard-
ous material and, therefore, the deprotection step was delib-
erately not performed. The O-protected derivative 22 did
not cause any health problems to the persons involved,
either directly or indirectly, with the synthesis of 22.
Caution: Urushioles are also components of the so-called
poison ivy plant (Toxicodendron radicans)[13] and cause der-
matitis by allergic reactions to many people. In some cases,
the contact with the plant even leads to anaphylaxis.[14]
In conclusion, we presented a very mild cobalt-catalyzed
method for the isomerization/migration of 1,3-dienes to the
corresponding 2Z,4E-dienes with an additional double bond
in position 7. The cobalt-catalyzed isomerization did not
proceed further to yield conjugated 3,5,7-trienes. Addition-
ally, the configuration of the isolated double bond at posi-
tion 7 was not altered as was deduced from comparison of
13C NMR data with reported values for such materials. Fi-
nally, the cobalt-catalyzed isomerization reaction was ap-
plied as the key step in the synthesis of the O-protected
main component of urushiol 6, with the challenging skipped
2Z,4E,7Z-subunit.
Scheme 6. Synthesis of the 1,3,7-triene 21.
alkyne 16. The internal Z-configured double bond at posi-
tion 7 of the side chain of the natural product was generated
via Lindlar hydrogenation, and acidic deprotection of the
acetal group afforded the aldehyde 20 in 88% yield over
two steps. The terminal 1,3-diene in 21 was then introduced
by a Julia-Kocienski olefination with 2-(allylsulfonyl)benzo-
thiazole, and the desired 1,3,7-triene 21 (E:Z=5:3) was ob-
tained in 90% yield. Accordingly, the precursor for the
cobalt-catalyzed isomerization/migration reaction, 1,3,7-
triene 21, was synthesized in 32% overall yield in only six
steps.
The disclosed cobalt-catalyzed isomerization/migration af-
forded the desired O-protected 2Z,4E,7Z-triene 22 in 46%
yield as a single product (Scheme 7).[11] The reduced yield of
the O-protected natural product can be explained with ac-
companied polymerization. The 13C NMR spectroscopic
data of 22 (C6: 30.8 ppm; C9: 27.3 ppm) are in very good
agreement with the reported data of the O-deprotected nat-
Experimental Section
Experimental Details for the Isomerization Reaction
Anhydrous zinc iodide (20 mol%), zinc powder (20 mol%), and
CoACHTNUGTRENUNG(dpppMe2)Br2 (10 mol%) were suspended in anhydrous dichlorome-
thane under an argon atmosphere in a flame dried Schlenk tube fitted
with a Teflon screw cap. Subsequently, the E/Z-mixture of the 1,3,7-
triene (final conc. 1.0m) was added and the reaction mixture was stirred
at room temperature until complete conversion of the starting material
was observed (GC/MS analysis). The reaction mixture was then filtered
over a short pad of silica gel with pentane as eluent. The solvent of the
eluate was then removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel with pentane as
eluent.
Keywords: 1,3-dienes
·
cobalt
·
isomerization
·
stereoselectivity · urushiol
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Received: April 3, 2014
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COMMUNICATION
Isomerization
Anastasia Schmidt,
Gerhard Hilt*
&&&& — &&&&
Unprecedented Cobalt-Catalyzed
Isomerization Reactions to Single
Skipped 2,4,7-Trienes Applied in the
Synthesis of Urushiol
My heart skipped, skipped a beat: The
skipped 2,4,7-triene subunit of urushiol
was generated from the 1,3,7-triene
through a cobalt-catalyzed isomeriza-
tion reaction in a stereoselective fash-
ion. The double bond configuration of
the double bond at position 7
remained unchanged whereas the
2Z,4E-configuration was controlled by
the cobalt catalyst.
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These are not the final page numbers! ÞÞ