Synthesis of 5-cyclodecenones via RCM and a three-pot sequence for bisannulation

Article abstract of DOI:10.1016/j.tetlet.2016.07.084

5-Cyclodecenones were made by RCM, using the first generation Grubbs catalyst and infinite dilution in refluxing dichloromethane. A convenient one-pot procedure for making 2,6-disubstituted cyclohexanones was developed, which allowed for the synthesis of

Full text of DOI:10.1016/j.tetlet.2016.07.084

Accepted Manuscript
Synthesis of 5-cyclodecenones via RCM and a three-pot sequence for bisannu-
lation
Nicholas Curton, Joel Ornelas, Abby Uhrinak, Brittney Rhem, Jess Coulter, Joe
Zhang, P. Matthew Joyner, James B. White
PII:
S0040-4039(16)30951-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.084
TETL 47946
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 June 2016
23 July 2016
27 July 2016
Please cite this article as: Curton, N., Ornelas, J., Uhrinak, A., Rhem, B., Coulter, J., Zhang, J., Matthew Joyner, P.,
White, J.B., Synthesis of 5-cyclodecenones via RCM and a three-pot sequence for bisannulation, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.084
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Synthesis of 5-cyclodecenones via RCM and a three-pot sequence for bisannulation
Nicholas Curton, Joel Ornelas, Abby Uhrinak, Brittney Rhem, Jess Coulter, Joe Zhang, P.
Matthew Joyner* and James B. White*
Division of Natural Science, Pepperdine University, 24255 Pacific Coast Highway, Malibu, CA
9
0263, United States
Corresponding author: james.white@pepperdine.edu
Abstract: 5-Cyclodecenones were made by RCM, using the first generation Grubbs catalyst and
infinite dilution in refluxing dichloromethane. A convenient one-pot procedure for making 2,6-
disubstituted cyclohexanones was developed, which allowed for the synthesis of a bridged bicyclo
compound, containing a 5-cyclodecenone. Transannular cyclization of this substrate led to a
tricyclic product. The overall three-pot sequence of dialkylation, RCM and transannular cyclization
results in bisannulation on a pre-existing ring.
Keywords: 2,6-Disubstituted cyclohexanones; Ring-closing metathesis; 5-Cyclodecenones;
Transannular cyclization; Bisannulation; Perhydrophenalene
Introduction
Our research group has prepared a number of 5-cyclodecenones via anionic oxy-Cope
rearrangements of 1,2-dialkenylcyclohexanols in which the two alkenyl groups are trans, as
1
-7
illustrated in equation 1.
respect to the cyclodecene ring both in our work and in the work of others.
In general the stereochemistry of the resulting alkene is trans with
1-23
In considering other routes to 5-cyclodecenones, we were inspired by the work of
2
4-25
Nevalainen and Koskinen
(
who prepared 4-cyclodecenones via ring-closing metathesis (RCM)
equation 2). Their optimized procedure involved adding 10 mol % of first-generation Grubbs
i
catalyst 2 to a 0.56 mM solution of dienone 1 pre-complexed with 10 mol% of Ti(OPr)
CH Cl , resulting in a mixture of 4-cyclodecenones 3a-c. When the RCM was done without
Ti(OPr) , the same mixture of products was obtained albeit it in a slightly altered ratio and slightly
lowered yield.
4
in refluxing
2
2
i
4
24

We report herein our preliminary investigations into the preparation of 5-cyclodecenones
via RCM.
Dodeca-1,11-dien-6-one and its RCM
We began our work with the model compound dodeca-1,11-dien-6-one (4), which has been
2
6-28
made by several routes.
hept-6-enenitrile in one pot via addition of the Grignard reagent to the nitrile, followed by
We prepared 4 from commercially available 5-bromopent-1-ene and
29
hydrolysis of the intermediate imine (equation 3).
Attempted RCM of dienone 4, using the conditions of Nevalainen and Koskinen (0.35 mM
in refluxing CH Cl ), led to a less than 10% yield of the products from RCM. This led us to explore
a variety of conditions for promoting RCM. It turned out that the Ti(OPr)
2
2
i
4
was unnecessary for our
substrate, but infinite dilution conditions were. Addition of dienone 4 over a 24-hour period to a
refluxing solution of first-generation Grubbs catalyst 2 in refluxing dichloromethane containing 22
30-31
mol% of 2 followed by addition of activated carbon and filtration though Celite led to a 1.5:1
ratio of the two possible 5-cyclodecenones that slightly favored the trans isomer in a combined
yield of 46%.
32
33
The ratio of products is most likely a kinetic result, given the low reactivity of 2 towards
disubstituted alkenes. We observed that shortening the time for the addition did not alter the
product ratio, only the yield of products. Furthermore, when a mixture of 1.66 equivalents of allyl
ether (to insure conversion of the pre-catalyst 2 to its propagating form) and the trans isomer 5
was added over 24 hours to 0.21 equivalents of 2 under the otherwise identical conditions used to
make 5 and 6, 85% of 5 was recovered and no trace of either the cis isomer 6 or of oligomers was
detected by either TLC or NMR, indicating that 5 does not react with the active form of the
catalyst.
We examined the effect that temperature had on RCM of dienone 4. At room temperature
in dichloromethane we isolated less than 10% of the compounds 5 and 6, and substantially more
of the oligomeric products. Higher temperatures are known to aid RCM using second-generation
3
4-35
36
ruthenium catalysts,
benzene or 1,2-dichloroethane led to partial recovery of 4 and little or none of 5 and 6.
but reaction with first-generation Grubbs catalyst 2 at 75-80 °C in either
37
We also examined alternative ruthenium catalysts. Use of second-generation Grubbs
catalyst 7 in refluxing dichloromethane resulted in isolation of a mixture of 5 and 6 in a combined
38
39
yield of less than 10%. We prepared the first-generation Hoveyda-Grubbs catalyst 8 and the

4
0-41
second-generation Hoveyda-Grubbs catalyst 9,
significant amounts of the desired compounds 5 and 6.
but in refluxing dichloromethane neither led to
2
,6-Disubstituted Cyclohexanones and RCM
In reflecting on alternative substrates that would also lead to 5-cyclodecenones upon RCM,
we considered incorporating a ring into the 1,11-dodecadiene. A pre-existing ring might aid RCM
relative to oligomerization, and transannular cyclization of the product from RCM would lead to
tricyclic products. A few examples of RCM to add a cyclodecene ring to a pre-existing six-
4
2,43
membered ring are known.
compounds from 1,2-disubstituted benzene and cyclohexene rings.
In these examples, the products from RCM are fused bicyclo
We were interested in the RCM of cyclohexanone 10 whose RCM would lead to a bridged
bicyclo compound. In principal, the previously unknown 2,6-disubstitued cyclohexanone 10 could
44
45
be made by alkylation of either of the known monosubstituted cyclohexanones 11 or 12. In
practice, alkylation under standard conditions (LDA, THF/HMPA, -78 °C) with the appropriate alkyl
bromide or iodide lead to low yields of a mixture of the cis and trans isomers of 10 along with side
products such as the 2,2-disubstituted cyclohexanones.
46
In considering alternative methods for making 2,6-substituted cyclohexanones, we were
attracted to the alkylation of the metalloenamine from deprotonation of imine 13 with n-BuLi and
47
48
hydrolysis of the alkylated imine to prepare 11 in very high yield, as it allowed for possible
sequential alkylation and one-pot preparation of the desired cyclohexanone 10. In practice, this
worked as illustrated in equation 5, to prepare 10a and 10b in a 1:1.2 ratio in 70% yield that
49
favored the trans isomer 10b.
The assigned relative stereochemistry of 10a and 10b is consistent with an NMR sample of
trans isomer 10b in unfiltered CDCl slowly isomerizing to a slightly greater than 3:1 ratio in favor
of the more stable cis isomer 10a. The cis isomer is also the faster eluting diastereomer by flash
3
0
5
chromatography, as observed in the separation of diastereomeric pairs of other 2,6-disubstituted

5
1,52
cyclohexanones.
with NaBH and converting the mixture of alcohols to their acetate derivatives (equation 6). The
approximately 4:1 ratio of diastereomers could be partially separated. In the minor diastereomer
The stereochemistry was further confirmed by reducing the cis isomer 10a
4
3
1
5 the hydrogen alpha to the acetoxy group was a triplet with a Jax-ax = 10.1 Hz, indicating that all
three substituents on the cyclohexane ring are equatorial, as in 15, which is only possible if the
,6-disbutstitued cyclohexanone it was derived from has the cis stereochemistry of 10a. By
2
inference, 10b must be the trans diastereomer. The trans stereochemistry of 10b is also
consistent with the relative stereochemistry of the products derived from 10b (vide infra).
With the cyclohexanones 10a and 10b in hand we investigated their RCM. The cis isomer
0a when treated with 2 under infinite dilution conditions gave only compounds that appeared to
1
be oligomers. However, the trans isomer led to clean conversion to the bridged bicyclo compound
1
6 in 55% yield (equation 7) along with small amounts of oligomeric products.
The chemical shifts of the vinylic hydrogens of 16 were observed to be 5.49 ppm (td, J =
1.3, 11.3, 3.0 Hz) and 5.36 ppm (tdd, J = 11.3, 11.3, 5.7, 1.8 Hz). The coupling constant of J =
1.3 Hz between the vinylic hydrogens suggested a probable configuration of cis for the alkene,
1
1
but due to the nearness of this coupling value to the limit of the characteristic coupling of a cis
alkene further NMR experiments were used to confirm this assignment. The chemical shifts of the
allylic hydrogens adjacent to each vinyl hydrogen were assigned using selective 1D TOCSY
experiments with increasing mixing times. Only the resonance signals of the hydrogens nearest
each vinyl hydrogen were apparent in the 1D TOCSY spectra with the shortest mixing times
(
Figures S9 and S10 in the Supporting Information), while the remaining hydrogens in the spin
system were observed with longer mixing times. The resonances at 5.49 ppm and 2.23 ppm were
observed to correspond to one set of vinylic-allylic vicinal hydrogens and the resonances at 5.36
ppm and 2.45 ppm were observed to correspond to the other pair of vinylic-allylic vicinal
hydrogens (Figure 1). A 2D NOESY experiment was then used to identify NOEs between
hydrogens in relatively close proximity to each other. Unfortunately, the NOE between the two
vinylic hydrogens was obscured by the diagonal cross-peaks in the 2D NOESY spectrum and
could not be observed. Due to this absence of direct evidence, indirect evidence from the NOESY
spectrum was used to confirm the configuration of the alkene. The absence of NOEs between
each vinylic hydrogen and the allylic hydrogens on the opposite side of the alkene suggested that
the configuration was cis. Observation of NOEs between the vinylic hydrogens and their adjacent
allylic hydrogens indicated that the absence of observed NOEs was not due to weak signals.

Additionally, a signal corresponding to the NOE between the allylic hydrogens on opposite sides
of the alkene at 2.23 and 2.45 ppm provided further evidence for the cis configuration.
NOESY
H
H
TOCSY
O
H
H
Figure 1. Correlations from TOCSY and NOESY experiments used to assign the geometric configuration of the
geometry of the alkene group in 16.
Transannular cyclization and determination of relative stereochemistry
1-7
Given our interest in transannular cyclizations of 5-cyclodecenones, we treated the 5-
cyclodecenone 16 with trifluoroacetic acid, which led to the tricyclic alcohol 17 in 70% yield
(equation 8). A small amount (less than 3% by mass) of another product was isolated, but its
structure was not determined.
Based on the downfield shift of the chemical shifts of the hydrogens on C4 (+0.42 ppm) and
53
C5 (+0.26) in pyridine-d
C5 are syn to the hydroxyl group on C13, which is the same relative stereochemistry observed in
the analogous transannular cyclization of cis-5-cyclodecenone (6) with CF CO H in which a cis
5 3
compared to their chemical shifts in CDCl , the hydrogens on C4 and
3
2
alkene leads to a cis ring fusion between C13 and C5, and the cis relationship between the alkene
hydrogens that correspond to the hydrogens on C4 and C5 of the product is maintained. It could
further be determined that one of the other methine hydrogens on either C1 or C9 was syn and
one was anti to the hydroxyl group on C13 based on a downfield (+0.15 ppm) and an upfield shift
(
5 3
-0.25 ppm) in their chemical shifts in pyridine-d compared to their chemical shifts in CDCl , which
is consistent with the trans stereochemistry of 10b. This left two possible structures, 17 and 18,
for the product from transannular cyclization of 16.

In order to distinguish between these two diastereomers, 2D COSY, HSQC and HMBC
experiments were used to assign the chemical shift of the resonances of C1, C3, C4, C5, C6, C9
and C13 (Figure 2). The chemical shift in DMSO-d of the hydrogen on C4 was assigned as 5.52
6
ppm, with its downfield resonance caused by deshielding from the trifluoroacetoxy group. Cross-
peak signals with this hydrogen in the COSY spectrum allowed the assignment of the chemical
shifts of the hydrogens at C3 as 1.71 ppm and 1.66 ppm and at C5 as 1.87 ppm. Further
examination of the COSY spectrum led to the assignment of the chemical shifts of the hydrogens
1
13
on C6 (Figure 2). A H- C HSQC experiment enabled the assignment of the chemical shifts of
1
13
C3-C6 (Table S1 in the Supporting Information). With these assignments made, a H- C HMBC
experiment was used to assign the chemical shift of C1 and C9. Specifically, correlations in the
HMBC experiment were observed from 1.66 ppm (C3-Hb) to 155.8, 78.7, 47.0, and 32.0 ppm,
corresponding to the carbonyl carbon of the trifluoroacetate, C4, C5 and C1, respectively. Based
on these assignments, a 2D NOESY experiment was then used to identify hydrogens that were
syn to the C13 hydroxyl group. NOE signals between the hydrogens on C4 and C5 and the C13
hydroxyl group indicated that these hydrogens were syn to each other, while the absence of a
NOE signal between the hydrogen on C1 and those on C4, C5 and the C13 hydroxyl group
indicated that the hydrogen on C1 was anti to the other hydrogens. Additionally, an NOE signal
between the C13 hydroxyl group and the hydrogen on C9 indicated that these two hydrogens
were also syn to each other (Figure 3). These results supported the conclusion that the
configuration of the product of the transannular cyclization was that of 17.
HMBC
H4
COSY
F3CCO2
H5
H
3a
H3b
OH
H
9
H
1
Figure 2. Selected correlations from COSY and HMBC experiments used to assign the chemical
shift of the resonances of C1, C4, C5 and C13 and their attached hydrogens in 17. Assignments
of the chemical shifts of hydrogens to their respective carbons were made based on the results of
an HSQC experiment.
NOESY
H4
F3CCO2
H5
H3a
H3b
OH
H9
H1

Figure 3. Correlations from a 2D NOESY experiment used to assign the relative configuration of
7.
1
Conclusion
For the first time 5-cyclodecenones have been made by RCM, using Grubbs first
generation catalyst and infinite dilution in refluxing dichloromethane. To enable the synthesis of
more complex substrates, a convenient one-pot procedure was used to make 2,6-disubstituted
cyclohexanones 10, which allowed for the synthesis of a bridged bicyclo compound, containing a
5
-cyclodecenone (16). The success of the RCM reaction to prepare the bridged bicyclo
compound was dependent on the stereochemistry of substrate 10. Whereas the model substrate
for the RCM led to a mixture of cis and trans isomers of the resultant alkene, the more
4
substituted compound 10b underwent RCM to give only the product with the cis alkene (16). As
such, this compliments the use of the oxy-Cope rearrangement to make 5-cyclodecenones from
1
,2-dialkenylcyclohexanols, which generally lead to a trans alkene in the product.
Transannular cyclization of 16 led to the tricyclic product 17. The overall three-pot
sequence of 13 ꢀ 10b ꢀ 16 ꢀ 17 results in bisannulation to a pre-existing ring and the
generation of five chiral centers. This methodology rapidly increases molecular complexity and
has the potential to make a variety of tricyclic structures by altering the size of the starting ring and
the length of the two tethers by which the two alkenyl groups are attached to the cycloalkanone,
as illustrated in equation 9. Such studies are in progress and will be reported in due course.
Acknowledgments
This work was supported by Pepperdine University’s undergraduate research programs.
We thank the Ahmanson Foundation for purchasing a Bruker Ascend 400MHz NMR spectrometer.
JBW thanks Professor Bruce Lipshutz for a sabbatical stay in the Department of Chemistry &
Biochemistry at UC Santa Barbara.
Supplementary data
Supplementary data (characterization data and procedures) associated with this article can
be found, in the online version, at
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4
3
2.In preparing this manuscript, we discovered that the NMR data we previously reported for cis-
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1
-cyclodecenone (6) was incorrect. The corrected data for 6: H NMR (CDCl
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3
, 200 MHz) δ
(

1
3
C NMR (CDCl
1.3.
3
, 50 MHz) δ (ppm) 215.2, 132.3, 129.1, 46.3, 35.1, 28.9, 24.8, 23.7, 23.6,
2
3
3
3.Small amounts of oligomers were also obtained in this reaction. For an excellent review that
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3
3
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1
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1
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4
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4
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4
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/

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7
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Synthesis of 5-cyclodecenones via ring-closing metathesis.
Synthesis of bridged bicyclic compound via ring-closing metathesis
A convenient, one-pot synthesis of 2,6-disubstituted cyclohexanones.
Transannular cyclization to prepare a perhydrophenalene tricyclic compound.