On the importance of the relative stereochemistry of substituents in the formation of nine-membered lactones by ring-closing metathesis

Article abstract of DOI:10.1055/s-0034-1380130

The effects of isopropyl substituents and molar concentration of diastereomeric esters toward the formation of nine-membered unsaturated lactones, in the context of the synthesis of the intermediates of the antihypertensive drug aliskiren, have been studied

Full text of DOI:10.1055/s-0034-1380130

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1317–1324
paper
1317
J.-P. Cusson et al.
Paper
Synthesis
On the Importance of the Relative Stereochemistry of Substituents
in the Formation of Nine-Membered Lactones by Ring-Closing
Metathesis
Jean-Philippe Cusson
O
S
Etienne Chénard
O
O
O
Stephen Hanessian*
R
R
R
S
Department of Chemistry, Université de Montréal, CP6128
Succursale A, Centre-ville, Montréal, Québec, H3C 3J7, Canada
stephen.hanessian@umontreal.ca
MeO
MeO
7 steps
H2N
(S,R,S)
R = H or O(CH2)3OMe
MeO
OH
H
N
NH2
S,S,S analogues: no ring-closing metathesis
O
O
O
aliskiren
MeO
Received: 26.11.2014
Accepted after revision: 02.01.2015
Published online: 19.02.2015
DOI: 10.1055/s-0034-1380130; Art ID: ss-2014-m0721-op
O
S
S
G1 (5 mol%)
O
O
O
toluene (10 mM)
r.t.
R
Abstract The effects of isopropyl substituents and molar concentra-
tion of diastereomeric esters toward the formation of nine-membered
unsaturated lactones, in the context of the synthesis of the intermedi-
ates of the antihypertensive drug aliskiren, have been studied.
R
R
MeO
MeO
1a, R = O(CH2)3OMe
1b, R = H
2a, R = O(CH2)3OMe
2b, R = H
Key words lactone, metathesis, cyclization, macrocycle, dimerization
OH
The now-venerable Grubbs olefin metathesis reaction1
and its many recent variants2 is an exceedingly useful and
versatile method to construct internally unsaturated com-
pounds of varying ring sizes.3 Among these, the synthesis of
nine-membered unsaturated lactones4 and ethers5 is of
particular interest because of their limited occurrence in
nature and their interesting biological activity.6
H
N
7 steps
H2N
NH2
R
O
O
aliskiren
(TekturnaTM
)
MeO
R = O(CH2)3OMe
In a recent paper7 on the total synthesis of the marketed
antihypertensive drug aliskiren (TekturnaTM)8 we utilized a
ring-closing metathesis reaction with the ester 1a using
Grubbs’ 1st generation catalyst (G1)9 to obtain a critical
nine-membered unsaturated lactone intermediate 2a that
harbored two isopropyl groups in strategically pre-defined
positions on an 8-aryloctanoic acid core unit (Scheme 1).
The lactone 2a was further elaborated to provide aliskiren
in seven steps and 7% overall yield from readily available
starting materials.7 Compared to recent syntheses,10 and a
plethora of published patents,11 our synthesis proved to be
the shortest to date.
During the ring-closing metathesis reaction of a mixture
of esters 1a and diastereomeric 3a with G1 catalyst in re-
fluxing toluene at a concentration of 10 mM, we observed
that only the (S,R,S)-ester 1a was converted into the lactone
2a. The same observation was made with the (S,R,S)-ester
of the corresponding p-methoxyphenyl analogue 1b. The
O
S
O
O
O
G1 (5 mol%)
R
R
S
S
toluene (10 mM)
r.t.
MeO
MeO
4a, R = O(CH2)3OMe
4b, R = H
3a, R = O(CH2)3OMe
3b, R = H
Scheme 1 Synthetic route to aliskiren via a nine-membered lactone
diastereomeric ester 3b did not give the expected lactone
4b and remained unchanged. Further studies with Grubbs
second-generation (G2)12 and Hoveyda–Grubbs second-
generation (H-G2)2b catalysts with a 4:1 diastereomeric
mixture of p-methoxyphenyl analogue 1b led to the lactone
2b in excellent yield and in much shorter time. Under these
conditions, the diastereomeric (S,S,S)-ester 3b, obtained in-
dependently from a stereoselective reduction of the corre-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324

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J.-P. Cusson et al.
Paper
Synthesis
as their mono- and disubstituted diastereomeric esters in
the presence of a variety of catalysts, in order to determine
the influence of the isopropyl and vicinal aryl substituents
and their relative stereochemistry on the nature of the
products (Figure 1).
S
H-G2 (5 mol%)
O
O
toluene (10 mM)
reflux
S
S
In the absence of any substituents, a mixture of racemic
esters 7a led to an inseparable mixture of dilactones 8a and
9a in excellent yield in presence of the G1, G2, and H-G2
catalysts (Scheme 3, Table 1, entries 1–4). Compared to the
G1 catalyst, the dilactones were formed much faster with
the G2 catalyst. The reaction rate was slower in presence of
H-G2 catalyst in dichloromethane (entries 1–3). However,
complete conversion occurred in refluxing toluene within
30 minutes (entry 4). No reaction occurred with the G1 cat-
alyst even in the presence of titanium(IV) isopropoxide15 at
room temperature in toluene. Hydrogenation of the double
bonds was followed by treatment with triethylsilane/tri-
fluoroacetic acid to give 11a and 12a in a quasi 1:1 ratio,
which mirrored the amounts of the respective original di-
lactones 8a and 9a in the mixture (entries 1–4). The oc-
tanedioic acid was not isolated.
Treatment of the benzylic (R)-ester of 7b with the G1
catalyst resulted in the formation of the lactone 10b in 33%
yield, but only in the presence of titanium(IV) isopropox-
ide15 and after repeated addition of catalyst (entry 5). In ad-
dition, dilactones 8b and 9b were formed in equal amounts
as an inseparable mixture. The reaction rate was accelerat-
ed in the presence of the G2 and H-G2 catalysts (entries 6
and 7), but the yields were not improved. After completion
of the reaction, lactone 10b was isolated by chromatogra-
phy and the mixture of the remaining dilactones was sub-
MeO
3b
OMe
ratio: 20:1
OMe
O
O
O
O
5
6
O
O
O
O
+
trans, trans isomer (X-ray)14
MeO
MeO
Scheme 2 Formation of dilactone dimers from ester 3b
sponding ketone13 led to an approximately 1:1 mixture of
head-to-head and head-to-tail 18-membered dilactone di-
mers 5 and 6 as an inseparable mixture of olefin isomers.
The structure of the C2-symmetrical dilactone 6 was ascer-
tained by X-ray crystallography (Scheme 2).14
In view of the continuing interest to develop viable syn-
thetic routes to aliskiren, we focused on the key ring-clos-
ing metathesis step in our original synthesis.7 In this paper,
we report our qualitative observations pertaining to the re-
action of the p-methoxyphenyl analogues 1b and 3b as well
N
N
N
N
P(Cy)3
Cl
Cl
Ru
O
Cl
Ph
Cl
Ru
Ru
Cl
Ph
Cl
P(Cy)3
P(Cy)3
Grubbs 1st generation (G1)
Grubbs 2nd generation (G2)
Hoveyda–Grubbs 2nd generation (H-G2)
N
N
N
N
N
N
Cl
Ru
O
Cl
Cl
Cl
Ru
O
Ru
O
Cl
Cl
F
F
F
F
NH
NH
N
CF3
F
O
O
O
O
Omega M71-SIPr
Omega M73-SIMes
Omega M853
16
Figure 1 Structures of catalysts used for the ring-closing metathesis (M71-SIPr, M73-SIMes, and M853
)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324

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J.-P. Cusson et al.
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Synthesis
mitted to hydrogenation then reductive cleavage of the
benzylic ester functions to give the corresponding products
11b and 12b (Scheme 3).
In contrast, reaction of the benzylic (S)-ester of 7b with
the G2 and H-G2 catalysts led only to a mixture of the dilac-
tones 8b and 9b which were converted into a 1:1 mixture of
11b and 12b as described above (entries 8 and 9). No reac-
tion was observed with the G1 catalyst.
Treatment of 7c (as a mixture of benzylic ester diaste-
reomers) with G1, G2, and H-G2 gave dilactones 8c and 9c
in a quasi 1:1 ratio with a distinct preference for the latter
catalyst with regard to time. Hydrogenation and reductive
cleavage led to 11c and 12c (entries 9–11). Trace amounts
of the corresponding lactone 10c were observed by MS.
We then returned to the original disubstituted model
(S,R,S)-ester 1b, and studied the reaction in the presence of
G2 and then H-G2 catalysts and the newer generation cata-
lysts (Figure 1).16 Using 5 mol% catalyst in refluxing toluene
led to the nine-membered lactone 2b in good yield, al-
though the reaction was 2–3 times slower with the new
generation catalysts (entries 13–17). Finally, the (S,S,S)-es-
ter 3b was subjected to the same reactions conditions, lead-
ing solely to the dilactones 5 and 6 as previously observed
with the G2 and H-G2 catalysts (entries 18–22).14 Hydroge-
nation of the double bonds and reductive cleavage in the
presence of triethylsilane/trifluoroacetic acid led to 11d
and 12d in a 1:1 ratio; 2,7-diisopropyloctanedioic acid was
not isolated.
Since the formation of dilactone dimers prevailed in the
case of the (S,S,S)-esters 3a and 3b (as well as other esters
shown in Table 1), we considered running the reaction at
higher dilution. Surprisingly, upon changing the concentra-
tion from 10 mM to 1 mM in refluxing toluene, ester 3b
gave the elusive lactone 4b in 53% isolated yield, accompa-
nied by 24% of the dimers 5 and 6 (Scheme 4, Table 2, entry
4). Extending the reaction time reduced the yield of lactone
4b while favoring dilactone formation (entry 3). In contrast,
dilution did not affect dilactone formation in the case of the
Table 1 Formation of Dilactones, Products from Cleavage Reactions, Reaction Parameters, and Ratio of Products with Different Catalyst (Scheme 3)
Entry
Ester
Ratio
Catalysta
Solventb
Temp (°C)
Time
Yield (%)
11
12
49
2/10
1
2
7a (R/S)
rac
G1
CH2Cl2
50
50
24 h
47
34
39
31
17
16
19
32
36
40
46
44
–
–
7a (R/S)
7a (R/S)
7a (R/S)
7b (R)
7b (R)
7b (R)
7b (S)
7b (S)
7c (R/S)
7c (R/S)
7c (R/S)
1b (R)
1b (R)
1b (R)
1b (R)
1b (R)
3b (S)
3b (S)
3b (S)
3b (S)
3b (S)
rac
G2
CH2Cl2
75 min
24 h
45
44
38
20
17
19
36
37
35
45
41
–
–
3
rac
H-G2
H-G2
G1c,d
G2e
CH2Cl2
50
–
4
rac
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
110
r.t.
30 min
5 d
–
5
4:1
33
30
32
–
6
4:1
110
110
110
110
r.t.
40 min
20 min
45 min
45 min
5 d
7
4:1
H-G2
G2e
8
20:1
20:1
rac
9
H-G2
G1c,d
G2e
–
10
11
12
13
14
15
16
17
18
19
20
21
22
–
rac
110
110
110
110
110
110
110
110
110
110
110
110
40 min
20 min
40 min
20 min
1 h
–
rac
H-G2
G2e
–
4:1
67
64
66
63
61
–
4:1
H-G2
–
–
e
4:1
M71-SIPr
–
–
e
4:1
M73-SIMes
1 h
–
–
e
4:1
M853
1 h
–
–
20:1
20:1
20:1
20:1
20:1
G2e
40 min
40 min
1 h
39
40
37
39
38
40
43
38
36
38
H-G2
–
e
M71-SIPr
–
e
M73-SIMes
1 h
–
e
M853
1 h
–
a Unless otherwise stated, 0.05 equiv (5 mol%).
b 0.01 M.
c Ti(Oi-Pr)4 (1 equiv).
d Catalyst (5 mol%) was added every day.
e Catalyst (5 mol%) was added after 30 min.
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Synthesis
OMe
OMe
R2
R1
O
O
O
R2
O
R2
O
O
R2
R1
+
R2
R2
O
1. catalyst
O
O
O
O
+
O
*
solvent, temp
10 mM
R1
R1
R1
R1
MeO
MeO
MeO
10b, R1 = i-Pr R2 = H
10c, R1 = H R2 = i-Pr
*: (S) and (R)
MeO
9a, R1 = R2 = H
9b, R1 = i-Pr, R2 = H
9c, R1 = H, R2 = i-Pr
6, R1 = R2 = i-Pr
7a, R1 = R2 = H
8a, R1 = R2 = H
7b, R1 = i-Pr, R2 = H
8b, R1 = i-Pr, R2 = H
8c, R1 = H, R2 = i-Pr
5, R1 = R2 = i-Pr
7c, R1 = H, R2 = i-Pr
2b, R1 = R2 = i-Pr
1b, (S,R,S), R1 = R2 = i-Pr
3b, (S,S,S), R1 = R2 = i-Pr
OMe
R1
11a = 11c, R1 = H
11b = 11d, R1 = i-Pr
R1
R2
1. Pd/C, H2
MeOH–EtOAc
12a, R1 = R2 = H
MeO
O
R2
12b, R1 = i-Pr, R2 = H
12c, R1 = H, R2 = i-Pr
12d, R1 = R2 = i-Pr
OH
5, 6,
OH
8 and
9
2. Et3SiH, TFA
CH2Cl2
HO
R1
O
R2
O
MeO
(not isolated)
Scheme 3 Formation of dilactones and products from cleavage reactions (Table 1)
unsubstituted ester 7a, since no monolactone was ob-
served. The monosubstituted ester 7c afforded 42% of the
corresponding lactone 10c and 37% yield of dilactones (en-
try 2). This was an improvement compared to the traces ob-
served in 10 mM solution (Table 1, entries 10–12).
R2
R2
O
H-G2 (5 mol%)
O
O
O
+
toluene (1 mM)
reflux
R1
R1
Table 2 Ring-Closing Metathesis of Diastereomeric Esters at 1 mM
(Scheme 4)
MeO
MeO
3b, (S,S,S), R1 = R2 = i-Pr
7a, R1 = R2 = H
7c, R1 = H, R2 = i-Pr
4b, R1 = R2 = i-Pr (X-ray)14
10c, R1 = H, R2 = i-Pr
Entry
Ester
Ratio
Time
Yield (%)
OMe
OMe
Monomer Dimers
R1
O
R1
1
2
3
4
7a (R/S)
rac
overnight
–
81
37
32
24
7c (R/S)
3b (S)
rac
overnight
overnight
7 h
42
46
53
O
O
O
20:1
20:1
R2
R2
R2
R2
3b (S)
+
O
O
O
O
The somewhat diminished yield of nine-membered
(S,S,S)-lactone 4b when the reaction was run overnight as a
1 mM solution, led us to question whether once formed, it
could undergo cycloreversion via alkylidene–ruthenium in-
termediates to the dilactones 5 and 6. Indeed, submitting
lactone 4b to the reaction conditions at the original concen-
tration of 10 mM in presence of H-G2 catalyst yielded the
corresponding dilactones 5 and 6 (Scheme 5). When a 1:1
mixture of (S,S,S)-lactones 4b and 10c was subjected to the
ring-closing metathesis with the H-G2 catalyst in 10 mM
R1
R1
MeO
MeO
5, R1 = R2 = i-Pr
6, R1 = R2 = i-Pr
9a, R1 = R2 = H
9c, R1 = H, R2 = i-Pr
8a, R1 = R2 = H
8c, R1 = H, R2 = i-Pr
Scheme 4 Ring-closing metathesis of diastereomeric esters at 1 mM
(Table 2)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324

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Synthesis
OMe
OMe
+
O
O
O
O
O
H-G2 (5 mol%)
O
toluene (10 mM)
reflux
O
O
O
O
MeO
4b
MeO
MeO
Scheme 5 Cycloreversion via ring-opening metathesis and cross-coupling reactions
5
6
solution, a mixture of all possible dilactones, including
cross-over products was obtained, indicating that cyclo-
reversion was possible in each case.
This is evident from the results of reactions comprising the
diastereomeric ester pairs (S,R,S)-1b and (S,S,S)-3b, and
(S,R)-7b and (S,S)-7b (Scheme 3, Table 1, entries 13 and 18).
From our qualitative observations, it appears that the
(S,R,S)-ester 1b offers a less encumbered path to the ruthe-
nium metallocycle, and eventually to the observed lactone
2b (Scheme 6). A combination of stereochemical, conforma-
tional, and possibly stereoelectronic effects associated with
a transoid ester configuration combine to favor the cycliza-
tion to give 2a and 2b as thermodynamically favored prod-
ucts. Reports concerned with the formation of nine-mem-
bered lactones using ring-closing metathesis are scarce. For
example, cyclization of functionalized esters harboring ter-
minal olefinic appendages, led to nine-membered unsatu-
rated lactones with cis- and trans-geometries depending on
the substituents.18 However, no dimeric dilactones were re-
ported or discussed in this study. The key steps in the total
synthesis of the nine-membered unsaturated marine me-
The existence of multiple coordination sites within each
series of esters presents a major challenge with regard to
the identity of the actual reactive intermediates and a pre-
ferred pathway. The outcome of ring-closing metathesis re-
actions leading to medium-sized rings is difficult to predict
due to many intervening factors. For example, the nature of
the catalyst, the solvent, the molarity, combined with con-
formational pre-organization, steric factors, as well as sub-
stituent and polar effects can have dramatic influences on
the nature of the products (and byproducts) in a given reac-
tion.17 Nevertheless, it is clear that the ratio of nine-mem-
bered lactone formation compared to dilactones depends
on the relative stereochemistry of the C7 isopropyl group
and the adjacent C8 aryl moiety, and the concentration in
the case of 1b and 3b (Scheme 3, Table 1, entries 14 and 19).
S
Ru
O
G1, G2,
H-G2
O
O
O
Ru
2a, 2b
1a, 1b
R
R
R
10 mM
S
MeO
MeO
O
S
Ru
10 mM
O
Ru
10 mM
O
O
3a, 3b
R
4a, 4b
S
R
1 mM
S
1 mM
MeO
MeO
10 mM
10 mM
10 mM
dimers
5 and 6
Scheme 6 Ring-closing metathesis in 10 mM and 1 mM solutions; only one of the two possible alkylidene–ruthenium intermediates is shown
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324

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J.-P. Cusson et al.
Paper
Synthesis
tabolite helicolactone, involved a ring-closing metathesis
step achieved in the presence of G1 catalyst in excellent
yields.4 The effect of substituents in the cyclization of larger
rings has been reported.18,19
1-(4-Methoxyphenyl)pent-4-enyl Pent-4-enoate (7a); Typical Pro-
cedure
To a solution of the corresponding allylic acid (52 mg, 0.52 mmol, 1.0
equiv) in anhydrous toluene (4 mL) at 0 °C was added Et3N (0.09 mL,
0.62 mmol, 1.2 equiv), 2,4,6-trichlorobenzoyl chloride (0.1 mL, 0.62
mmol, 1.2 equiv), and DMAP (76 mg, 0.62 mmol, 1.2 equiv). The re-
sulting white slurry was stirred at 0 °C for 10 min. In a second dry
round-bottomed flask a solution of corresponding benzylic alcohol
(100 mg, 0.52 mmol, 1.0 equiv) in a minimum amount of anhydrous
toluene was transferred to the reaction vessel containing the slurry in
a dropwise manner at 0 °C then the reaction media was allowed to
warm to r.t. The reaction was stirred at r.t. until TLC monitoring indi-
cated no starting material remained. The solvent was removed and
the resulting crude was taken up in EtOAc (10 mL) and H2O (10 mL).
The aqueous layer was separated and extracted with EtOAc (3 × 10
mL). The combined organic layers were successively washed with 10%
aq citric acid (10 mL) and sat. aq NaHCO3 (10 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated to afford a yellow oil.
The residue was purified by flash chromatography (silica gel, 1.5 cm ×
20 cm; CH2Cl2–hexanes, 3:7) to yield 7a (134 mg, 94%) as a pale yel-
low oil; Rf = 0.55 (Et2O–hexanes, 1:9).
It can be presumed that the (S,S,S)-esters 3a and 3b ex-
perience substantial steric clash between the C7 isopropyl
and the C8 aryl moiety so as to interfere with the proper
alignment of the alkylidene–ruthenium intermediates en
route to the ruthenium metallocycles. Thus, competitive in-
termolecular cross-coupling reactions predominate to give
the corresponding dilactones irreversibly (Scheme 6). At
lower molar concentration, the steric effect is overcome by
the low rate of interactions of the alkylidene–ruthenium in-
termediates. This is reflected by the fact that the lactone 4b
may be kinetically formed at 10 mM concentrations, but
rapidly undergoes cycloreversion to form the stable dilac-
tones 5 and 6. Although there appears to be a cooperative
beneficial effect of having the two isopropyl groups present
in addition to a stereochemical preference for the (S,R,S)-es-
ters 1a and 1b, it is not clear why the monosubstituted or
the unsubstituted substrates such as 7a and 7c have a pref-
erence for macrocyclic dilactone formation.
IR (neat): 3077, 2979, 2935, 2837, 1735, 1641, 1613, 1515, 1253,
1169, 1035 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.23 (m, 2 H), 6.89–6.84 (m, 2 H),
5.85–5.69 (m, 3 H), 5.06–4.95 (m, 4 H), 3.80 (s, 3 H), 2.45–2.31 (m, 4
H), 2.11–1.96 (m, 3 H), 1.89–1.79 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 172.5, 159.4, 137.6, 136.8, 132.8,
128.1, 115.6, 115.3, 114.0, 75.4, 55.4, 35.4, 34.0, 29.9, 29.0.
In earlier reports, Smith and co-workers20 have dis-
cussed the potentially reversible nature of the metathesis
reaction, while Fürstner and co-workers21 exploited the re-
versibility of olefin metathesis in the formation of macrocy-
clic dilactones related to (–)-(R,R)-pyrenophorin.22
HRMS (ESI): m/z [M + Na]+ calcd for C17H22NaO3: 297.1461; found:
297.1468.
In conclusion, we have reported our observations re-
garding the effect of vicinal isopropyl and aryl substituents
in diastereomeric esters with regard to their preference to
give nine-membered unsaturated lactones. These have
been recently utilized in the total synthesis of the antihy-
pertensive drug aliskiren.7
(S)-2-Isopropyl-1-(4-methoxyphenyl)pent-4-enyl Pent-4-enoate
(7b)
Following the typical procedure for 7a; chromatography (silica gel,
2.5 cm × 20 cm; EtOAc–hexanes, 1:9) gave 7b (236 mg, 75%) as a pale
yellow oil; Rf = 0.57 (EtOAc–hexanes, 1:9); [α]D20 +37 (c 0.5, CDCl3).
Unfortunately, the involvement of multiple ruthenium-
coordinated species and the dynamic nature of the ring-
closing metathesis process do not allow a more detailed
analysis beyond the qualitative observations reported in
this paper. Further studies in this area are in progress.
IR (neat): 3077, 2958, 2874, 2837, 1736, 1640, 1612, 1514, 1464,
1369, 1250, 1171, 1036 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.20 (m, 2 H), 6.87–6.82 (m, 2 H),
5.84–5.73 (m, 1 H), 5.69–5.66 (m, 1 H), 5.57–5.46 (m, 1 H), 5.05–4.94
(m, 2 H), 4.85 (s, 1 H), 4.81 (dd, J = 6.5, 1.8 Hz, 1 H), 3.79 (s, 3 H), 2.44–
2.31 (m, 4 H), 2.04–1.93 (m, 2 H), 1.90–1.79 (m, 2 H), 0.93 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 172.2, 159.2, 138.1, 136.8, 132.4, 128.6,
128.2, 115.6, 115.6, 113.7, 55.4, 48.8, 34.0, 31.1, 29.0, 27.3, 21.2, 18.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28NaO3: 339.1919; found:
339.1931.
All reactions were performed in oven-dried glassware under an argon
atmosphere using anhydrous, deoxygenated solvents. CH2Cl2 and tol-
uene were dried by passage through an activated alumina column un-
der argon [Solvent Drying System (SDS)]. Reagents were purchased
and used without further purification. Reactions were monitored by
analytical TLC carried out on 0.25-mm silica plates that were visual-
ized under a UV lamp (254 nm) and developed by staining with ceric
ammonium molybdate, p-anisaldehyde, and/or potassium permanga-
nate solution. Flash column chromatography was performed using
silica (particle size 40–63 μm, 230–400 mesh) at increased pressure.
NMR spectra (1H, 13C) were recorded at either 300, 400, or 500 MHz
relative to TMS (δ = 0.00) with the solvent resonance as the internal
standard (CHCl3, δ = 7.26); 13C NMR spectra are recorded using the
central peak of CDCl3 (δ = 77.16) as the internal standard. Optical ro-
tations were determined with a polarimeter at 589 nm, using a 1-dm
1-(4-Methoxyphenyl)pent-4-enyl (S)-2-Isopropylpent-4-enoate
(7c)
Following the typical procedure for 7a; chromatography (silica gel,
2.5 cm × 20 cm; EtOAc–hexanes, 1:9) gave 7c (771 mg, 94%) as a pale
yellow oil; Rf = 0.57 (EtOAc–hexanes, 1:9).
IR (neat): 3077, 2960, 2926, 2875, 1735, 1640, 1613, 1514, 1465,
1248, 1167, 1107, 1035 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.28–7.23 (m, 2 H), 6.87–6.83 (m, 2 H),
5.83–5.56 (m, 3 H), 5.03–4.95 (m, 3 H), 4.90 (ddd, J = 11.9, 8.7, 1.7 Hz,
1 H), 3.80 (s, 3 H), 2.35–2.17 (m, 3 H), 2.10–1.96 (m, 3 H), 1.91–1.78
(m, 2 H), 0.94 (d, J = 6.8 Hz, 1.5 H), 0.87 (d, J = 6.7 Hz, 1.5 H), 0.87 (d, J =
6.8 Hz, 1.5 H), 0.80 (d, J = 6.7 Hz, 1.5 H).
cell at r.t. and are reported in units of deg·cm3·g–1·dm–1
.
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1323
J.-P. Cusson et al.
Paper
Synthesis
13C NMR (126 MHz, CDCl3): δ = 174.5, 174.5, 159.3, 137.7, 137.7,
136.1, 135.9, 132.9, 132.8, 128.3, 116.56, 116.47, 115.31, 115.28,
113.79, 75.17, 75.13, 55.38, 52.72, 52.63, 35.40, 35.37, 34.12, 33.99,
30.54, 30.31, 29.92, 20.50, 20.33, 20.23.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28NaO3: 339.1918; found:
339.1935.
Pd/C (cat.) was added to a solution of dilactones 8a and 9a in MeOH
(3 mL) and EtOAc (3 mL). The mixture was purged with H2 and the
mixture was stirred under a H2 atmosphere (H2 balloon). The reaction
was monitored by LR-MS. When the reaction was complete, the mix-
ture was filtered through Celite and concentrated to afford the crude
dilactones.
TFA (3 drops) was added to a solution of the crude dilactones and
Et3SiH (0.1 mL) in CH2Cl2 (1 mL). The solution was stirred at r.t. for 10
min. Volatiles were removed under vacuum with a rotary evaporator
and the residue was purified by flash chromatography [silica gel, 1.5
cm diameter × 20 cm height, hexanes (150 mL) then EtOAc–hexanes,
1:19] to yield alkane 11a (6 mg, 31%) and acid 12a (11 mg, 38%), both
as clear oils.
(8S,9R)-8-Isopropyl-9-(4-methoxyphenyl)-4,7,8,9-tetrahydro-
oxonin-2(3H)-one (10b)
Hoveyda–Grubbs 2nd generation catalyst (5 mg, 0.008 mmol, 0.05
equiv) was added to a solution of 7b (50 mg, 0.16 mmol, 1.0 equiv) in
anhydrous toluene (16 mL) and the mixture was stirred at reflux for
20 min. The mixture was cooled to r.t. then excess of ethyl vinyl ether
was added and gently evaporated. The residue was purified by flash
chromatography (silica gel, 1.5 cm diameter × 20.0 cm height, EtOAc–
hexanes, 1:50) to yield 10b (17 mg, 38%) as a clear oil; Rf = 0.55
(EtOAc–hexanes, 1:9); [α]D20 +37 (c 0.5, CDCl3).
Alkane 11a
Rf = 0.68 (EtOAc–hexanes, 1:4).
IR (neat): 2921, 2849, 1512, 1464, 1245, 1177, 1033 cm–1
.
IR (neat): 2955, 2925, 2872, 1722, 1612, 1514, 1460, 1245, 1173,
1H NMR (400 MHz, CDCl3): δ = 7.09 (d, J = 8.3 Hz, 4 H), 6.82 (d, J = 8.5
Hz, 4 H), 3.79 (s, 6 H), 2.59–2.48 (m, 4 H), 1.61–1.52 (m, 4 H), 1.36–
1.28 (m, 8 H).
13C NMR (75 MHz, CDCl3): δ = 157.7, 135.2, 129.4, 113.8, 55.4, 35.2,
31.9, 29.6, 29.4.
1138, 1035 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.30 (m, 2 H), 6.91–6.85 (m, 2 H),
5.84 (d, J = 10.6 Hz, 1 H), 5.72–5.63 (m, 1 H), 5.63–5.54 (m, 1 H), 3.80
(s, 3 H), 2.48 (dd, J = 20.3, 10.7 Hz, 1 H), 2.40–2.27 (m, 2 H), 2.17–2.08
(m, 1 H), 2.07–1.89 (m, 3 H), 1.47 (dtd, J = 13.7, 6.9, 2.4 Hz, 1 H), 0.86
(d, J = 6.9 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H31O2: 327.2319; found:
327.2328.
13C NMR (75 MHz, CDCl3): δ = 174.9, 159.6, 135.7, 132.1, 129.3, 125.5,
114.0, 79.8, 55.4, 52.6, 33.9, 27.8, 25.1, 24.8, 22.0, 16.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H24NaO3: 311.3765; found:
311.2605.
Acid 12a
Rf = 0.17 (EtOAc–hexanes, 1:4).
IR (neat): 2923, 2853, 1709, 1512, 1465, 1245, 1177, 1054, 1033 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.12–7.05 (m, 2 H), 6.85–6.79 (m, 2 H),
3.79 (s, 3 H), 2.61–2.48 (m, 2 H), 2.34 (t, J = 7.5 Hz, 2 H), 1.71–1.51 (m,
4 H), 1.35–1.29 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 179.9, 157.7, 135.0, 129.4, 113.8, 55.4,
35.1, 34.1, 31.8, 29.2, 29.1, 29.1, 24.8.
(3S,9R)-3-Isopropyl-9-(4-methoxyphenyl)-4,7,8,9-tetrahydro-
oxonin-2(3H)-one (10c)
Hoveyda–Grubbs 2nd generation catalyst (3 mg, 0.005 mmol, 0.05
equiv) was added to a solution of 7c (30 mg, 0.095 mmol, 1.0 equiv) in
anhydrous toluene (95 mL) and the mixture was stirred at reflux
overnight. The mixture was cooled to r.t. then excess of ethyl vinyl
ether was added and gently evaporated. The residue was purified by
flash chromatography (silica gel, 1.5 cm diameter × 20.0 cm height,
EtOAc–hexanes, 1:50) to yield 10c (12 mg, 42%) as a clear oil; Rf = 0.55
(EtOAc–hexanes, 1:9); [α]D20 –32 (c 0.5, CDCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NaO3: 273.1461; found:
273.1472.
(3R,8R)-3,8-Bis(4-methoxybenzyl)-2,9-dimethyldecane (11b) and
(R)-7-(4-Methoxybenzyl)-8-methylnonanoic Acid (12b)
IR (neat): 2954, 2928, 2865, 1702, 1513, 1459, 1247, 1173, 1159, 1037
Following the typical procedure for 11a and 12a gave 11b (7 mg, 36%)
and 12b (10 mg, 37%), both as clear oils.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.24 (m, 2 H), 6.90–6.85 (m, 2 H),
5.84–5.73 (m, 1 H), 5.71–5.61 (m, 1 H), 5.61–5.51 (m, 1 H), 3.80 (s, 3
H), 2.62–2.50 (m, 2 H), 2.33–2.24 (m, 1 H), 2.21–2.09 (m, 2 H), 2.06–
1.92 (m, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 164.8, 159.3, 137.5, 135.9,
135.1, 133.1, 131.0, 128.6, 127.9, 126.0, 114.0, 55.4, 51.5, 36.9, 29.9,
28.4, 23.8, 21.5, 19.8.
Alkane 11b
Rf = 0.64 (EtOAc–hexanes, 1:9); [α]D20 +21 (c 1.0, CHCl3).
IR (neat): 2924, 2861, 1512, 1246, 1055, 1464, 1033 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.08–7.01 (m, 4 H), 6.84–6.78 (m, 4 H),
3.79 (s, 6 H), 2.49 (dd, J = 13.7, 6.8 Hz, 2 H), 2.35 (dd, J = 13.8, 7.6 Hz, 2
H), 1.67 (dtd, J = 13.7, 6.9, 3.5 Hz, 2 H), 1.44–1.33 (m, 2 H), 1.23–1.02
(m, 8 H), 0.86 (d, J = 13.9 Hz, 6 H), 0.83 (d, J = 13.9 Hz, 6 H).
.
HRMS (ESI): m/z [M + Na]+ calcd for C18H24NaO3: 311.3766; found:
311.3772.
13C NMR (75 MHz, CDCl3): δ = 157.6, 134.5, 130.1, 113.6, 55.4, 46.1,
36.3, 29.7, 28.4, 28.0, 19.3, 18.8.
HRMS (ESI): m/z [M + H]+ calcd for C28H43O2: 411.3258; found:
411.3277.
1,8-Bis(4-methoxyphenyl)octane (11a) and 8-(4-Methoxyphe-
nyl)octanoic Acid (12a); Typical Procedure
Hoveyda–Grubbs 2nd generation catalyst (4 mg, 0.006 mmol, 0.05
equiv) was added to a solution of 7a (30 mg, 0.11 mmol, 1.0 equiv) in
anhydrous toluene (11 mL) and the mixture was stirred at reflux for
30 min. The mixture was cooled to r.t. then excess of ethyl vinyl ether
was added and gently evaporated and the mixture was filtered
through Celite to yield a crude mixture of dilactones 8a and 9a.
Acid 12b
Rf = 0.12 (EtOAc–hexanes, 1:9); [α]D20 +11 (c 1.0, CHCl3).
IR (neat): 2938, 2866, 1709, 1512, 1455, 1346, 1321, 1059, 1016 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324

1324
J.-P. Cusson et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.05 (d, J = 8.6 Hz, 2 H), 6.84–6.78 (m, 2
H), 3.79 (s, 3 H), 2.53 (dt, J = 12.0, 5.6 Hz, 1 H), 2.38–2.34 (m, 1 H),
2.34–2.28 (m, 2 H), 1.74–1.65 (m, 1 H), 1.62–1.53 (m, 2 H), 1.46–1.38
(m, 1 H), 1.31–1.22 (m, 6 H), 1.14 (dd, J = 18.5, 11.4 Hz, 1 H), 0.89 (d,
J = 6.9 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H).
(2) (a) Romero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem. Int.
Ed. 2004, 43, 6161. (b) Ung, T.; Hejl, A.; Grubbs, R. H.; Schrodi, Y.
Organometallics 2004, 23, 5399. (c) Kingsbury, J. S.; Harrity, J. P.
A.; Bonitatebus, P. J. Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 791.
(3) (a) Shiina, I. Chem. Rev. 2007, 107, 239. (b) Deiters, A.; Martin, S.
F. Chem. Rev. 2004, 104, 2199.
13C NMR (75 MHz, CDCl3): δ = 179.2, 157.7, 134.4, 130.0, 113.7, 55.4,
46.1, 36.3, 34.0, 29.6, 29.5, 28.6, 27.4, 24.8, 19.3, 18.9.
(4) (a) Takahashi, T.; Wataqnabe, H.; Kitahara, T. Heterocycles 2002,
58, 99. (b) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.;
Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81.
(c) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989,
30, 4543.
HRMS (ESI): m/z [M + Na]+ calcd for C18H28NaO3: 411.3258; found:
411.3277.
2-Isopropyl-8-(4-methoxybenzyl)octanoic Acid (12c)
Following the typical procedure for 11a and 12a gave 12c (19 mg,
41%) as a clear oil; Rf = 0.11 (EtOAc–hexanes, 1:9); [α]D –5 (c 1.0,
CHCl3).
(5) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
10264. (b) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahe-
dron 2002, 58, 1817. (c) Crimmins, M. T.; Emmitte, K. A. J. Am.
Chem. Soc. 2001, 123, 1533. (d) Crimmins, M. T.; Emmitte, K. A.
Synthesis 2000, 899.
(6) For an overview, see: Rousseau, G. Tetrahedron 1995, 51, 2777.
(7) Hanessian, S.; Guesné, S.; Chénard, E. Org. Lett. 2010, 12, 1816.
(8) (a) Maibaum, J.; Feldman, D. L. Annu. Rep. Med. Chem. 2009, 44,
105. (b) Jensen, C.; Herold, P.; Brunner, H. R. Nat. Rev. Drug Dis-
covery 2008, 7, 399. (c) Siragy, H. M.; Kar, S.; Kirkpatrick, P. Nat.
Rev. Drug Discovery 2007, 6, 779.
20
IR (neat): 2926, 2854, 1700, 1511, 1464, 1298, 1176, 1116, 1037 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.13–7.06 (m, 2 H), 6.86–6.79 (m, 2 H),
3.79 (s, 3 H), 2.58–2.50 (m, 2 H), 2.17–2.07 (m, 1 H), 1.88 (dq, J = 13.7,
6.7 Hz, 1 H), 1.67–1.45 (m, 4 H), 1.44–1.19 (m, 7 H), 0.97 (d, J = 6.7 Hz,
6 H).
13C NMR (75 MHz, CDCl3): δ = 182.4, 157.7, 135.0, 129.4, 113.8, 55.4,
52.7, 35.1, 31.8, 30.6, 29.6, 29.4, 29.2, 27.9, 20.6, 20.2.
HRMS (ESI): m/z [M + Na]+ calcd for C18H28NaO3: 411.3258; found:
411.3113.
(9) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(10) (a) Nam, G.; Ko, S. Y. Helv. Chim. Acta 2012, 95, 1937. (b) Slade,
J.; Liu, H.; Prashad, M.; Prasad, K. Tetrahedron Lett. 2011, 52,
4349. (c) Dong, H.; Zhang, Z.-L.; Huang, J.-H.; Ma, R.; Chen, S.-
H.; Li, G. Tetrahedron Lett. 2005, 46, 6337.
(11) For a summary, see: Yokokawa, F.; Maibaum, J. Expert Opin.
Ther. Pat. 2008, 18, 581; and references cited therein.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(13) Hanessian, S.; Chénard, E. Org. Lett. 2012, 14, 3222.
(14) Hanessian, S.; Chénard, E.; Guesné, S.; Cusson, J.-P. J. Org. Chem.
2014, 79, 9531.
(15) For examples of the use of Ti(Oi-Pr)4 in metathesis reactions see
ref. 4b and: Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130.
2-Isopropyl-7-(4-methoxybenzyl)-8-methylnonanoic Acid (12d)
Following the typical procedure for 11a and 12a gave 12d (11 mg,
20
40%). Rf = 0.12 (EtOAc–hexanes, 1:9) as a clear oil; [α]D +16 (c 0.3,
CDCl3).
IR (neat): 2925, 2860, 1704, 1511, 1461, 1375, 1245, 1178, 1038 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.59 (s, 1 H), 7.05 (d, J = 8.4 Hz, 2 H),
6.81 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 2.51 (dd, J = 13.7, 6.6 Hz, 1 H),
2.36 (dd, J = 13.7, 7.8 Hz, 1 H), 2.13–2.05 (m, 1 H), 1.85 (dq, J = 13.7,
6.9 Hz, 1 H), 1.74–1.63 (m, 1 H), 1.60–1.49 (m, 1 H), 1.48–1.36 (m, 2
H), 1.29–1.14 (m, 6 H), 0.96–0.92 (m, 6 H), 0.88 (d, J = 6.8 Hz, 3 H),
0.84 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 181.5, 157.7, 134.4, 130.1, 113.7, 55.4,
52.6, 46.1, 36.3, 30.6, 29.5, 29.4, 28.6, 28.2, 27.7, 20.6, 20.2, 19.3, 18.8.
HRMS (ESI–): m/z [M – H]– calcd for C21H33O3: 333.2435; found:
333.2440.
(16) See the Supporting Information.
(17) For a concise review, see: Monfette, S.; Fogg, D. E. In Green
Metathesis Chemistry: Great Challenges in Synthesis, Catalysis
and Nanotechnology; Dragutan, I.; Finkelstein, E. S., Eds.;
Springer Science: New York, 2010.
(18) Ramírez-Fernández, J.; Collado, I. G.; Hernández-Galán, R.
Synlett 2008, 339.
Acknowledgment
(19) See for example: (a) Dai, W.-M.; Sun, L.; Feng, G.; Guan, Y.; Liu,
Y.; Wu, J. Synlett 2009, 2361. (b) Vassilikogiannakis, G.;
Margaros, I.; Tofi, M. Org. Lett. 2004, 6, 205. (c) Lee, C. W.;
Grubbs, R. H. J. Org. Chem. 2001, 66, 7155. (d) Fürstner, A.; Thiel,
O. R.; Blanda, G. Org. Lett. 2000, 2, 3731.
We are grateful for financial support from NSERC and FQRNT. We
thank Professor Marc Mauduit for the new generation catalysts.
Supporting Information
(20) Smith, A. B.; Kozmin, S. A.; Adams, C. M.; Paone, D. V. J. Am.
Chem. Soc. 2000, 122, 4984.
Supporting information for this article is available online at
(21) Fürstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449.
(22) For selected reviews on using ring-closing metathesis in the
synthesis of macrolactone natural products, see (a) Gradillas,
A.; Pérez-Castells, J. Angew. Chem. Int. Ed. 2006, 45, 6086.
(b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4490. (c) Prunet, J. Angew. Chem. Int. Ed. 2003, 42,
2826.
http://dx.doi.org/10.1055/s-0034-1380130.
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References
(1) (a) Handbook of Metathesis; Vols. 1–3; Grubbs, R. H., Ed.; Wiley-
VCH: Weinheim, 2003. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1317–1324