Sequential Alkene Isomerization and Ring-Closing Metathesis in Production of Macrocyclic Musks from Biomass

Article abstract of DOI:10.1002/chem.201800728

We report successful utilization of sequential alkene isomerization and ring-closing metathesis of dec-9-enoic acid based dienes in synthesis of macrocyclic lactones that possess a strong scent of musk. This catalytic sequence was essential to trim the chain length of starting dienes to yield macrocycles of the right size. Dec-9-enoic acid is conveniently obtainable from oleic esters by Ru-catalysed ethenolysis.

Full text of DOI:10.1002/chem.201800728

DOI: 10.1002/chem.201800728
Full Paper
&
Alkene Metathesis
Sequential Alkene Isomerization and Ring-Closing Metathesis in
Production of Macrocyclic Musks from Biomass
Adrian Sytniczuk,[a] Gwꢀnaꢁl Forcher,[a] Douglas B. Grotjahn,*[b] and Karol Grela*[a, c]
Abstract: We report successful utilization of sequential
alkene isomerization and ring-closing metathesis of dec-9-
enoic acid based dienes in synthesis of macrocyclic lactones
that possess a strong scent of musk. This catalytic sequence
was essential to trim the chain length of starting dienes to
yield macrocycles of the right size. Dec-9-enoic acid is con-
veniently obtainable from oleic esters by Ru-catalysed ethe-
nolysis.
Introduction
leads to unsaturated macrocyclic musks, that are in general
more appreciated because they are more powerful as com-
pared to their saturated analogues.[15] It seemed favourable to
us to use ethenolysis-derived 9-DA (1) and eventually also dec-
9-enol (2) obtained from its reduction in the synthesis of mac-
rocyclic musks by RCM. Unfortunately, RCM of ester 3 formed
from renewable oleic acid derived 1 and 2 leads to a large, 19-
membered macrocycle 4 of rather weak[16,17] odour (Scheme 1).
Therefore, we opted to search for a procedure that allows for
formation of more pleasantly odoured 15 to 18-membered
musks from renewable 9-DA. Ring sizes could be tailored only
if selective alkene isomerization[17–19] followed by RCM could be
achieved. Because alkene isomerization and metathesis reac-
tions are both very important tools in organic chemistry, devel-
Fats and oils are very important renewable resources which
have many applications in modern synthesis and industrial
chemistry. They may be subjected to numerous transforma-
tions[1–3] into valuable products or synthetic intermediates.
Their industrial applications can include, inter alia: polymers,
oil based paints or printing inks,[4] surfactants[5] and lubri-
cants.[6] Among the many various reactions of oils and fats,
ethenolysis[7,8] has become a very promising transformation
which leads to terminal alkenes and shorter esters used in the
refining industry. Of the most commonly applied substrates
are oleic acid esters which, after ethenolysis and saponification,
lead to dec-9-enoic acid 1 (9-DA).[9]
A well-known and best-selling class of fragrance compounds
are macrocyclic lactones and ketones known for centuries as
musks. In the past, musks such as civetone or muscone were
obtained from animals (Civettictis civetta or Moschus moschife-
rus) leading to severe decrease in their population. Nowadays,
emphasis is placed on developing methods for obtaining syn-
thetic musks such as those originally obtained from animals.
From the chemical point of view many approaches are plau-
sible, including acyloin condensation,[10,11] acid-catalysed depo-
lymerization known as Carothers process,[12] methodologies
with the expansion of the macrocyclic ring,[13] and finally the
ring closing metathesis reaction (RCM).[14] Importantly, RCM
[a] A. Sytniczuk, Dr. G. Forcher, Prof. K. Grela
Biological and Chemical Research Centre, Faculty of Chemistry
˙
University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw (Poland)
E-mail: karol.grela@gmail.com
[b] Prof. D. B. Grotjahn
Department of Chemistry and Biochemistry, San Diego State University
5500 Campanile Drive, San Diego, California 92182-1030 (USA)
E-mail: dbgrotjahn@sdsu.edu
[c] Prof. K. Grela
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, P.O. Box 58, 01-224 Warsaw (Poland)
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
https://doi.org/10.1002/chem.201800728.
Scheme 1. Oleic acid as potential source of a musk macrocycle.
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oping ways of linking them in a sequence is of great impor-
tance.[20]
The catalytic activity of the five metal complexes was evalu-
ated in the model reaction (Table 1). Under the standard condi-
tions, complex A was identified as the most efficient catalyst.
Desired product (3a) was obtained with 82% yield after one
Results and Discussion
Table 1. Screening of catalysts A–E.[a]
Selectivity in CÀC double bond isomerisation
Entry
Catalyst
t
Conv. of terminal
3a
[%]
During the last decades several efficient catalysts were specifi-
cally developed for isomerizing double bonds.[21] Most alkene
isomerization methodologies are applicable for very specific
substrates in which ring strain, steric hindrance, or achieving
conjugation control the isomerization step. In contrast, we
needed movement over a single position on an alkene chain
that offered no unusual steric or electronic control.
[h]
C=C bond [%][b]
1
2
3
4
5
A
B
C
D
E
1
98
17
49
5
82
24
24
24
24
11[c]
n.d.[c]
n.d.
4
n.d.
[a] Reaction conditions (unless otherwise noted): 0.5m alkene
3 in
[D6]acetone, room temperature. [b] Determined by NMR analysis with
Me4Si as an internal standard. [c] Complex mixture of compounds was
observed by NMR analysis.
Complex A shows a remarkable ability to isomerize a large
range of alkene derivatives with high selectivity for the E
isomer products and usually with low loading (0.05–5 mol%).
Although this catalyst appears as the most adapted for our
study, we wished to compare its efficiency with other catalysts
(B–E).[22]
hour at room temperature (entry 1). During this time the start-
ing material was completely converted and 4 and 14% of un-
desired isomers 3b, 3b“ and 3c, 3c”, respectively, were
formed (Scheme 2). Compared to A, catalysts B–E presented
poor activity and the reactions were not completed after 1 day.
After 24 h, partial conversion of the terminal CÀC double
bonds were observed with the catalyst B and C (entry 2 and
3). For both cases, over-isomerized compounds were detected
at high levels compared to the conversion. Interestingly, ruthe-
nium hydrides D and E gave the lowest conversions after 24 h
(entry 4 and 5). When these catalysts were described in the lit-
erature, higher temperature (40 to 1208C) and higher loading
(0.5 to 10 mol%) were usually used which explain the lack of
reactivity observed during this study.[25,26] Among the catalysts
screened (entries 1–5), A was found to be the optimum for the
isomerization of 3a, giving the desired product in good yield
with high selectivity and short reaction time (entry 1). To im-
prove the process and find the optimal conditions, the reac-
tion solvent and the catalyst’s loading (Table 2) were varied.
Changing solvent from [D6]acetone to [D2]dichloromethane re-
sulted in lower conversion after 1 h at RT (Table 2, entry 2). In-
terestingly, this solvent which was previously described as an
alternative to acetone[27] appears inferior in this case and ace-
tone was kept as reference. Then we turned our attention to
The first objective of this research was to find the most suit-
able conditions for the migration of the double bond over pre-
cisely one position in unhindered long chains present in oleic
substrates. For this purpose, dec-9-enyl dec-9-enoate (3) was
chosen as challenging substrate and the initial conditions used
were based on a literature procedure.[23] Following this publica-
tion, standardized parameters were maintained; the reactions
were performed at room temperature in [D6]acetone (0.5m of
substrate) with 0.1 mol% of catalyst. In case of low reactivity,
the reactions were stopped after 24 h. Five isomers of the
1
starting material were considered (Scheme 2). Key H NMR sig-
nals distinguish alkene types: for terminal, CH2 =signals at
4.88–5.02 ppm, and for over-isomerized alkenes, the
CH3CH2CH=triplet upfield, near 0.94 ppm.[24] For mono-isomer-
ized alkene, the CH3CH=doublet near 1.8 ppm was obscured
by signals from other CH2 protons.
Table 2. Optimization of isomerization of 3 with catalyst A.[a]
Entry
Loading
[mol%]
Solvent
t
[h]
Conv. of terminal
C=C bond [%][b]
3a
[%][b]
1
2
3
4
5
0.1
0.1
0.075
0.05
0.025
acetone
CD2Cl2
acetone
acetone
acetone
1
1
1.33
5
14
98
28
98 (95)
98 (49)
97 (24)
82
26
82
82
82
[a] Reaction conditions (unless otherwise noted): 0.5m solution of 3 in
deuterated solvent, room temperature. [b] Determined by NMR analysis
with TMS as an internal standard. Numbers in parentheses correspond to
conversion after 1 h.
Scheme 2. Catalysts studied in isomerization of 3 and possible products.
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reducing catalyst loading. As summarized in Table 2 (entries 3–
5), the same conversions and yields as for entry 1 can be ob-
tained with 1:4 the catalyst, simply by increasing the reaction
time to 14 h.
Preparation of other starting materials by isomerization
Figure 1. Dienes obtained by esterification of acid 1 and 1a. (Reaction con-
ditions: [1] (COCl)2, DMF cat., CH2Cl2, RT, 1 h; [2] 8-decen-1-ol for 10, 9-
decen-1-ol for 11 or 7-octen-1-ol for 12, pyridine, CH2Cl2, À788C to RT, 1 h.)
Under the standard conditions isomerization of 5 was not
complete after 24 h of reaction. Increasing the loading of A to
500 ppm allowed in 5 h for formation of bis-isomerized 5a in
84% yield (Scheme 3). Compound 6a was obtained in 94%
yield in 2 h. In this case the terminal alkene of substrate 6 re-
acted much faster than the internal disubstituted Z-alkene,
RCM macrocyclisation of isomerized substrates
Having a small library of dienes obtained from renewable sour-
ces, we attempted to convert them into macrocyclic musks
through the RCM reaction. We started our investigation by es-
tablishing optimal reaction conditions. In our tests, the com-
mercially available metathesis catalyst F[29] was used (for the
structure see Scheme 1). Reactions were performed in toluene
in 508C for 5 h. It is well known fact that during the metathesis
reaction the catalyst undergoes a decomposition process lead-
ing to ruthenium species, which can lead to further isomeriza-
tion of double bonds in both substrates and products, there-
fore tetrafluorobenzoquinone was added as a RuÀH scaveng-
er.[30] Based on various examples of RCM macrocyclisations
available in literature,[31–33] we chose to keep the substrate con-
centration near 1.5 mm. According to the general optimized
procedure, we performed several RCM reactions obtaining
macrocyclic lactones with different ring sizes (Table 3), varying
from 15 to 19 atoms. We started with RCM of the non-isomer-
ized oleic substrate, dec-9-en-1-yl dec-9-enoate (3, entry 1)
leading to a macrocyclic lactone 4 with the 19 atoms in the
ring in 78% yield. Next, we conducted the RCM reactions of
unsaturated esters bearing isomerized double bonds to obtain
“trimmed” macrocycles (entries 2–6) characterized by stronger
smell. In most cases, we obtained very satisfactory results from
the RCM step. Notably, in entries 6 and 7 one can observe that
RCM with isomerized substrates leading to 15-membered
rings, is much more effective than the similar reaction with the
substrate with terminal double bonds leading to a macrocycle
of identical size (entry 8). Metathesis of terminal CÀC double
bonds involves formation of Ru-methylidene propagating spe-
cies, which are known to be less stable than the homologous
alkylidene ones and the easier decomposition of which limits
the productivity of the process.[34a–f] A very important fact in
favour of the RCM reaction of isomerized dienes is that much
lower levels of by-products (cyclic dimers and oligomers) were
formed during metathesis. This can be rationalized by the fact
that the internal double bonds are generally less reactive in
metathesis, so are less likely to create dimeric and oligomeric
side products.[35,36]
Scheme 3. Preparation of isomerized alkenes and dienes. (Reaction condi-
tions: [D6]acetone, RT, 2–5 h.)
thanks to the extremely high selectivity of catalyst A for termi-
nal or E-alkenes.[20a,23] Similarly, product 7a was synthesized in
92% yield starting from diene 7. For this substrate, only the
terminal alkene was isomerized, whereas the more hindered
trisubstituted alkenes stayed intact. These observations are in
agreement with the reaction mechanism proposed in the liter-
ature.[27,28] Next, the isomerization methodology was applied to
dec-9-enoic acid 1 and oct-7-en-1-ol 9, and the corresponding
isomerized compounds were obtained in the same 92% yield.
Notably, the isomerization of alcohol 9 was relatively slow
(>24 h) and higher loading of A (250 ppm) had to be used
most likely because presence of some impurities in the sub-
strate used, such as allylic hydroperoxides or others. The isom-
erized acid 1a, derived from 9-DA, was used to obtain esters
with selected unsaturated alcohols (Figure 1).
All dienes with at least one isomerised double bond have
undergone ring closing metathesis with satisfactory yields of
84–86%. Only in the case of dienes with less reactive trisubsti-
tuted CÀC double bonds (7a and 8a) lower yields were ob-
served.
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Recently, reports from industry showed that under carefully
optimised conditions, RCM macrocyclisation of terminal dienes
can be made with much lower catalyst loadings.[37a,b] Such con-
ditions include inter alia aggressive ethylene removal, slow ad-
dition of the catalyst or in several doses,[38] and, last but not
least, stringently purifying reagents and solvents.[39] Recently, it
was elegantly shown, that optimising of the Ru metathesis cat-
alyst structure can give much improved results in macro-RCM
of musks.[36,37a,b] Although the present work was aimed mostly
to show that the isomerisation-RCM sequence can be used for
utilisation of renewable plant oils as the source of valuable
musks, and we are not going to provide an industry-ready pro-
cess now, in one experiment we decided to test if there is
space for further lowering of the catalysts loading in the RCM
step. For this purpose, we chose our model non-terminal diene
3a and tried the RCM reaction with the reduced amount of F
(0.1 instead of 2 mol%). This lead to still satisfactory isolated
yield (66%). One can expect that application of newly intro-
duced specialised catalysts will allow further lowering of Ru
loading, if there would be such need in the future (Sche-
me 4).[36,37a,b]
Table 3. Facile formation of 15- to 19-atom rings by RCM.[a]
Entry
Substrate
Product
Yield
[%]
E/Z
1
77
86
84
3.6:1
3
4
2
3
3.1:1
2.3:1
11
13
3a
10
12
14
15
16
4
5
84
85
1.3:1
4.5:1
6
7
8
84
84
72
6.5:1
6.2:1
1.1:1
Scheme 4. Synthesis of 17-membered macrocyclic lactone 14 (ambrettolid
analogue) using lower loading. TFBQ=tetrafluorobenzoquinone.
5a
6a
18
17
17
19
One-pot isomerization-RCM macrocyclisation
Finally, we showed the feasibility of a one pot synthesis of
macrocyclic musk. In this experiment, the reaction mixture
after isomerization of the double bonds in 3 was finished was
mixed with a toluene solution of nitro catalyst F and tetrafluo-
robenzoquinone (toluene was added to adjust the concentra-
tion optimal for RCM: 1.5 mm), and the standard ring closing
reaction was performed leading to 17-membered musky mac-
rocyclic lactone in 73% overall yield (Scheme 5). In this way,
substrate 3, obtained from biomass can be converted not to
19-membered lactone but to more valuable 17-membered
odorant compound. Significantly, the Ru metathesis catalyst
was found to be fully compatible with the isomerization condi-
tions and the traces of complex A present in the reaction mix-
ture do not prevent obtaining product 14 in excellent overall
yield.
9
36
37
6.7:1
3.3:1
8a
20
10
7a
21
[a] Reaction conditions: toluene, 508C, 5 h, 2 mol% F, 4 mol% tetrafluoro-
benzoquinone.
Low loading experiment and industrial perspective
To date, in case of the RCM based macrocyclic musks, catalysts
loadings of 3–5 mol% were required to obtain practically
useful yields. (For a related discussion and literature, see ref.
[36].)
Scheme 5. One pot synthesis of 17-membered macrocyclic lactone 14 (am-
brettolid analogue). (Reaction conditions: 250 ppm A, [D6]acetone RT, 15 h,
then added 2 mol% F, 4 mol% tetrafluorobenzoquinone in toluene, 508C,
5 h.)
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corresponding to starting material and the product were not used
for the analysis.
Conclusions
In summary, the combined power of Ru-catalysed alkene iso-
merization and ring-closing metathesis allows one to turn bio-
mass-derived compounds into valuable 15- to 17-membered
unsaturated lactones of pleasant musky smell. Only two syn-
thetic steps are needed, and these can be performed easily
without purification of the intermediate diene as shown in
Scheme 5. Because the developed system operates under mild
conditions we believe that it holds great promise for future ap-
plications in synthesis of unsaturated macrocyclic musks. Fur-
ther research in this direction is in progress in our laboratories.
Isomerization of dec-9-enyl dec-9-enoate (3)
Following the general procedure dec-9-enyl dec-9-enoate (3)
(0.5 mmol, 150.3 mg), and catalyst A solution (125 nmol, 250 ppm,
24 mL) were used. For the dec-9-enyl dec-9-enoate in the mixture:
1H NMR (400 MHz, (CD3)2CO): d 5.80 (ddt, 2H, Jd=17.0 Hz, Jd=
10.2 Hz, Jt=6.7 Hz), 4.98 (ddt, 2H, Jd=17.1 Hz, Jd=2.2 Hz, Jt=
1.6 Hz), 4.91 (ddt, 2H, Jd=10.2 Hz, Jd=2.2 Hz, Jt=1.3 Hz), 4.02 (t,
2H, J=6.7 Hz), 2.27 (t, 2H, J=7.4 Hz), 2.08–2.00 (m, 4H), 1.65–1.54
(m, 4H), 1.43–1.32 ppm (m, 18H); 13C NMR (100 MHz, (CD3)2CO): d
173.3 (CO), 139.6 (CH), 139.6 (CH), 114.6 (CH2), 114.6 (CH2), 64.4
(CH2), 34.5 (CH2), 34.4 (CH2), 34.4 (CH2), 30.0 (CH2), 29.9 (CH2), 29.8
(CH2), 29.7 (CH2), 29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4
(CH2), 26.6 (CH2), 25.6 ppm (CH2).
Experimental Section
For the (E)-dec-8-enyl (E)-dec-8-enoate in the mixture: 1H NMR
General procedure for synthesis of dienes
(400 MHz, (CD3) CO): d 5.48–5.32 (m, 4H), 4.02 (t, 2H, J=6.7 Hz),
2
9-Decenoic (1) or (E)-dec-8-enoic acid (1a) (slight excess) was dis-
solved in dry DCM under inert gas atmosphere (Ar). Two drops of
DMF and oxalyl chloride (1.2 equiv) were added dropwise; gas
emission was observed. The solution changed from colourless to
light yellow. After 1 h, conversion of substrate was verified via
1H NMR spectroscopy. Volatiles were evaporated using a mem-
brane pump, and fresh dry DCM was added to dissolve the crude
acid chloride. The resulting solution was cooled to À788C (dry ice–
acetone bath) and dry pyridine (2 equiv) and alcohol were added
dropwise. The reaction was stirred for 5 min at À788C and then for
1 h at room temperature. TLC control (10% EtOAc in c-hex) sug-
gested completion. n-Hexane was added to precipitate pyridine
hydrochloride, the mixture was filtered and solvents were evapo-
rated from the filtrate. Column chromatography as a final step of
purification (1% EtOAc in c-hex).
2.27 (t, 2H, J=7.4 Hz), 2.01–1.91 (m, 4H), 1.71–1.54 (m, 10H), 1.38–
1.12 ppm (m, 14H); 13C NMR (100 MHz, (CD3)2CO): d 173.4 (CO),
132.1 (CH), 132.1 (CH), 125.2 (CH), 125.1 (CH), 64.4 (CH2), 34.5 (CH2),
33.2 (CH2), 33.1 (CH2), 30.2 (CH2), 30.1 (CH2), 29.8 (CH2), 29.7 (CH2),
29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 26.6 (CH2), 25.6 (CH2), 18.0 ppm
(2CH3).
General procedure for RCM reactions
In a dried round bottom flask under inert gas atmosphere (Ar),
diene (1 equiv) and tetrafluorobenzoquinone (4 mol%) were dis-
solved in dry toluene to final diene concentration equal to 1.5 mm.
The reaction mixture was stirred at 508C. Catalyst F (2 mol%) was
placed in a dried Schlenk and dissolved in toluene (average 1 mg
of catalyst was dissolved in 1 mL of toluene). Catalyst was added
during 5 h in 15 min intervals. TLC control (5% EtOAc in c-hex) was
used to judge reaction completion. The reaction was cooled to
room temperature and quenched with 1 mL solution of 2m ethyl
vinyl ether in DCM. The mixture was stirred 15 min and next sol-
vents were evaporated. Purification was performed using column
chromatography (20% toluene in c-hex).
Synthesis of dec-9-en-1-yl dec-9-enoate (3)
Ester 3 was prepared according to a general procedure. 9-decenoic
acid (1) (1.51 g, 1.65 mL, 8 mmol) oxalyl chloride (1.24 g, 0.829 mL,
9.6 mmol), dec-9-en-1-ol (2) (1.19 g, 1.358 mL, 7.6 mmol), pyridine
(1.270 g, 1.293 mL, 16 mmol) were used to give final product as a
colourless oil. Yield 91%. 1H NMR (400 MHz, CDCl3): d 5.81 (ddtd,
J=10.1, 8.6, 6.7, 2.0 Hz, 2H), 5.07–4.87 (m, 4H), 4.05 (t, J=6.7 Hz,
2H), 2.29 (t, J=7.5 Hz, 2H), 2.11–1.97 (m, 4H), 1.69–1.57 (m, 4H),
1.42–1.24 ppm (m, 20H);13C NMR (100 MHz, CDCl3) : d 174.14 (CO),
139.30 (CH), 139.27 (CH), 114.33 (CH2), 114.31 (CH2), 64.54 (CH2),
34.54 (CH2), 33.92 (CH2), 29.50 (CH2), 29.34 (CH2), 29.26 (CH2), 29.24
(CH2), 29.18 (CH2), 29.08 (CH2), 29.03 (CH2), 28.99 (CH2), 28.79 (CH2),
26.06 (CH2), 25.15 ppm (CH2).
Synthesis of (9E/Z)-oxacycloheptadec-9-en-2-one (14) from
dec-8-en-1-yl dec-8-enoate (3a)
a) 2 mol% loading: Lactone 14 was prepared according to a gen-
eral procedure. Dec-8-en-1-yl dec-8-enoate (3a) (0.155 g,
0.502 mmol), catalyst F (0.00674 g, 0.01 mmol), tetrafluorobenzo-
quinone (0.00362 g, 0.00201 mmol) and 334 mL of dry toluene
were used to give final product as a colourless oil. Yield 84%.
b) 0.1 mol% loading: Lactone 14 was prepared according to a
general procedure. Dec-8-en-1-yl dec-8-enoate (3a) (0.078 g,
0.253 mmol), catalyst F (0.00017 g, 0.000253 mmol[40]), tetrafluoro-
benzoquinone (0.000094 g, 0.000506 mmol[41]) and 168 mL of dry
toluene were used to give final product as a colourless oil. Yield
66%. 1H NMR (400 MHz, CDCl3): d=5.44–5.23 (m, 2H), 4.18–4.03
(m, 2H), 2.36–2.26 (m, 2H), 2.08–1.94 (m, 4H), 1.70–1.53 (m, 4H),
1.46–1.21 ppm (m, 14H); 13C NMR (100 MHz, CDCl3): d=174.28
(CO), 173.98 (CO), 131.44 (CH), 130.83 (CH), 130.33 (CH), 130.22
(CH), 64.47 (CH2), 64.40 (CH2), 34.72 (CH2), 33.45 (CH2), 31.49 (CH2),
31.36 (CH2), 29.03 (CH2), 28.99 (CH2), 28.86 (CH2), 28.85 (CH2), 28.81
(CH2), 28.33 (CH2), 27.91 (CH2), 27.77 (CH2), 27.58 (CH2), 27.51 (CH2),
26.89 (CH2), 26.35 (CH2), 26.32 (CH2), 26.20 (CH2), 25.92 (CH2), 25.74
(CH2), 25.16 (CH2), 24.66 ppm (CH2); IR: n˜ =2926, 2855, 1731, 1460,
Experimental procedures for isomerisation
In a glovebox, internal standard tetramethylsilane (ꢀ15 mg) and
substrate were dissolved in [D6]acetone (800–900 mL) and then the
NMR spectrum of this solution was acquired. Back in the glovebox,
the catalyst was added followed by enough solvent to reach a final
volume of 1 mL. The resulting mixture was kept at room tempera-
ture until the completion of the reaction. Spectra were acquired at
room temperature (temperature monitored at 22Æ18C). The value
of the integral for the singlet corresponding to the internal stan-
dard (tetramethylsilane) was set to 10.00 integral units in each
case. Data were acquired at 400 MHz using sixteen 308 pulses and
1
10 second delays between pulses. The overlapped H resonances
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D. B. Grotjahn, J. Am. Chem. Soc. 2014, 136, 1226–1229, but the
ꢁ2 mol% loadings and longer reaction times needed, persuaded us to
try A instead. A catalyst system for selective mono-isomerization ap-
peared after our work was nearly completed (Y. Wang, C. Qin, X. Jia, X.
Leng, Z. Huang, Angew. Chem. Int. Ed. 2017, 56, 1614–1618; Angew.
Chem. 2017, 129, 1636–1640).
1386, 1345, 1248, 969, 722; HRMS (ESI): calculated for C17H31O2
[M+H]+ : 253.2162, found: 253.2154.
Acknowledgements
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[24] It is possible that the triplet near 0.94 ppm contains contributions from
CH3CH2CH2CH= as well, but our conclusions about the yield of desired
3a would remain unchanged, see the Supporting Information. Based
on experience of the Grotjahn group, if mono-isomerized product is
still major as it is here (>82%), most of the over-isomerized material
would consist of 3-alkene and little would be 4-alkene.
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The authors would like to thank Dr. Christian Chapuis from Fir-
menich SA for useful discussions. For A.S., G.F., and K.G. the re-
search was in part supported by the Polish–Singapore Grant
(3/3/POL-SIN/2012) “Green and Sustainable Catalysts for Chemi-
cal, Agrochemical and Pharmaceutical Industry” 2012–2015
NCBR, and for D.B.G. by US NSF (grant CHE-14164781).
Conflict of interest
The authors declare no conflict of interest.
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Keywords: biomass
metathesis · musk
· isomerization · macrocyclization ·
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Manuscript received: February 21, 2018
Revised manuscript received: April 16, 2018
Version of record online: && &&, 0000
[22] See references cited in: D. B. Grotjahn, C. R. Larsen, G. Erdogan, Top.
Catal. 2014, 57, 1483–1489. We considered using the Cp* analogue of
A, described in the reference just cited and in: C. R. Larsen, G. Erdogan,
&
&
Chem. Eur. J. 2018, 24, 1 – 7
www.chemeurj.org
6
ꢂ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Isomerize and close: A new method for
the preparation of macrocyclic lactones
with musk scent is investigated. Our
study clearly shows that selective isom-
erisation of double bonds in combina-
tion with a metathesis reaction allows
us to obtain valuable compounds using
biomass.
&
Alkene Metathesis
A. Sytniczuk, G. Forcher, D. B. Grotjahn,*
K. Grela*
&& – &&
Sequential Alkene Isomerization and
Ring-Closing Metathesis in Production
of Macrocyclic Musks from Biomass
Chem. Eur. J. 2018, 24, 1 – 7
www.chemeurj.org
7
ꢂ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ