Construction of enantioenriched cyclic compounds by asymmetric allylic alkylation and ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201300971

A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. Copyright

Full text of DOI:10.1002/ejoc.201300971

FULL PAPER
DOI: 10.1002/ejoc.201300971
Construction of Enantioenriched Cyclic Compounds by Asymmetric Allylic
Alkylation and Ring-Closing Metathesis
Francesca Giacomina[a] and Alexandre Alexakis*[a]
Keywords: Asymmetric synthesis / Allylic alkylation / Cyclization / Metathesis / Copper / Iridium
A new approach to highly enantioenriched cyclic compounds
(up to 98% ee) has been developed by using ω-ethylenic
allylic substrates in a one-pot asymmetric allylic alkylation
and ring-closing metathesis sequence. The starting com-
pounds are synthetic equivalents of cyclic allylic substrates.
The method is exemplified with both Cu and Ir catalysts, and
chiral phosphoramidite ligands.
circumvent this problem and elucidate the mechanistic
pathway.[7] In contrast, palladium has been widely em-
ployed for the formation of enantioenriched cyclic com-
pounds because the choice of an appropriate chiral ligand
allows the discrimination of the two enantiotopic termini
of the meso π-allyl species formed upon ionization.
A different situation arises when a linear monosubsti-
tuted (or non-symmetrical) allylic substrate is used in the
copper-catalyzed allylic alkylation. The leaving group
stands at an achiral center and thus the chiral ligand plays
the main role in controlling the selectivity during the oxi-
dative addition step.
Introduction
Asymmetric allylic alkylation is one of the most used and
versatile transformations for the generation of new C–C
bonds in asymmetric synthesis.[1] A wide range of metals
have been employed for this reaction and among them Pd,
Ir, Mo, Ni, Rh, and Ru are the most representative exam-
ples.[2] In particular, palladium has been extensively re-
viewed in recent years, and preferentially used in combina-
tion with symmetrical substrates and stabilized nucleo-
philes, such as malonate carbanions, showing excellent re-
sults.[3]
Copper can be considered complementary to palladium
because it is highly γ regioselective with unsymmetrical or
monosubstituted allylic substrates, and allows the introduc-
tion of alkyl groups in the form of organometallic species,
including organozinc, lithium, magnesium, and aluminium
reagents.[4] However, despite the diverse applications that
have been found in recent years, there are still some limita-
tions in the copper-catalyzed asymmetric allylic alkylation
of cyclic compounds. Notably, the main feature of the all-
ylic alkylation mechanism using copper as the metal source
is the SN2Ј anti displacement, which occurs in oxidative ad-
dition with excellent chirality transfer.[4,5] The SN2Ј anti dis-
placement can be over-ruled by using a syn-directing leaving
group.[6] However, when starting from a racemic mixture of
a cyclic allylic substrate, the stereogenic center of the sub-
strate, not the chiral catalyst, dictates the course of the reac-
tion, thus both possible diastereomeric σ-allyl intermediates
would be formed, generating both possible products in
equal amounts. Only recently have we been able to partly
Because of these observations, we envisaged creating en-
antioenriched cyclic compounds through a copper-cata-
lyzed allylic alkylation followed by ring-closing metathesis.
Our strategy relies on the use of an aliphatic allylic com-
pound containing a terminal double bond as synthetic
equivalent of a cyclic allylic substrate. This ω-ethylenic all-
ylic substrate can undergo copper-catalyzed asymmetric all-
ylic alkylation and bears a convenient functionality to be
cyclized through ring-closing metathesis (pathway a,
Scheme 1). This approach is not entirely new, but comple-
mentary to the one already developed in our laboratory in
[a] Département de Chimie Organique, Université de Genève,
30, quai Ernest Ansermet, CH-1211 Genève 4, Switzerland
E-mail: alexandre.alexakis@unige.ch
Homepage: http://www.unige.ch/sciences/chiorg/alexakis/
welcome_fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300971.
Scheme 1. Strategies for the enantioselective construction of cyclic
compounds.
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Construction of Enantioenriched Cyclic Compounds
which this functionality is introduced through the allylic achieved with phosphoramidite ligand L1. Similarly, ligand
alkylation step from the nucleophile (pathway b, L2, containing two naphthyl substituents on the amine
Scheme 1).[8]
moiety, gave a good ee of 78%. A matched/mismatched ef-
fect was observed when using ligand L5 as only 40% ee was
obtained, and, in addition, the opposite enantiomer was
formed, which suggests that the chiral binaphthol moiety
dictates the enantioselective outcome of the reaction. Sur-
prisingly, the orientation of the substituent is significant, as
only 30% ee was obtained when ligand L7 was used (entry 7
vs. 2). Biphenol-derived ligands L3 and L6 were not ef-
ficient as only moderate-to-low selectivities were observed
(entries 3 and 6). Bidentate ferrocenyl-based ligands L8 and
L9 were also tested and appeared to be ineffective for this
transformation, although the γ adduct was favored in the
process. Similarly to the ferrocenyl-based ligands, Sim-
plePhos ligand L11 behaved well, as excellent regioselec-
tivity was observed, but low enantioselectivity. Lower
enantiomeric excesses were generally observed when using
a secondary Grignard reagent. Ligand L3 was the most ef-
ficient for promoting the formation of adduct 4b, giving
80% ee, whereas only 67% ee was obtained with ligand L1.
These results suggest that the more hindered nucleophile
requires the more flexible biphenol-derived ligand. Better
enantioselectivities were not achieved with the other phos-
phoramidites tested. Indeed, almost racemic mixtures were
Results and Discussion
We started our investigation by considering the simple
unsubstituted allylic chloride 1a, which contains four meth-
ylene units in between the two double bonds, producing af-
ter the process a seven-membered ring product. Copper-cat-
alyzed asymmetric allylic alkylation was performed by using
3 mol-% of copper thiophenecarboxylate (CuTC), 3.3 mol-
% of a chiral ligand (Figure 1), and 1.3 equiv. of Grignard
reagent in dichloromethane at –78 °C. Grubbs I catalyst[9]
was used for the subsequent ring-closure step.
For this initial screening, phenethylmagnesium bromide
and cyclohexylmagnesium chloride were used as representa-
tive primary and secondary Grignard reagents, respectively.
A preliminary screening of different chiral ligands, includ-
ing phosphoramidite-type,[10] ferrocenyl-based,[11] and
SimplePhos ligands,[12] was performed to evaluate their effi-
ciency. The results are shown in Table 1.
High regioselectivity, up to 99%, was observed in all
cases. Concerning the enantioselectivity, in the case of
phenethyl addition, up to 85% enantiomeric excess was
Figure 1. Chiral ligands used in this work.
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Table 1. Screening of chiral ligands for the Cu-AAA/RCM of allylic chloride 1a.[a]
Entry
R
L*
γ/α[b]
Product
ee [%], config.[c]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L1
L2
L3
L5
L6
L7
L8
L9
L10
Ͼ99:1
98:2
90:10
95:5
98:2
87:13
91:9
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
85, R
78, R
58, S
50, S
40, S
18, R
30, R
2, R
98:2
93:7
9
16, R
0
10
11
12
13
14
15
16
17
18
19
20
89:11
Ͼ99:1
98:2
88:12
Ͼ99:1
91:9
90:10
Ͼ99:1
Ͼ99:1
97:3
27, R
67, R
48, R
80, S
53, S
36, R
46, R
2, R
6, S
2, R
90:10
1
[a] General reagents and conditions: 3 mol-% CuTC, 3.3 mol-% L*, 1.3 equiv. RMgX in CH2Cl2 at –78 °C. [b] Determined by H NMR
or GC–MS analysis. [c] Determined by chiral GC or SFC analysis.
obtained with ferrocenyl-based ligands L8 and L9, al- (entries 3 and 5). Up to 74% enantiomeric excess was ob-
though these ligands were highly regioselective (entries 18 served for the cyclohexyl-substituted adduct with ligand L1
and 19).
(entry 4), which was also the best ligand for the formation
We continued our study on the formation of enantio- of the five-membered ring with a phenethyl moiety (86%
enriched cyclic compounds by synthesizing two other allylic ee, entry 6). A good enantioselectivity of 82% was also
substrates to give access to six- and five-membered ring ad- achieved with ligand L3 for the introduction of the more
ducts. For the following screening we used a selection of sterically demanding cyclohexyl group (entry 7). In these
chiral phosphoramidite ligands and increased the scope of two latter instances, it was possible to determine the enan-
the reaction to show the versatility of our methodology by tiomeric excess after the alkylation process, thus showing
introducing other nucleophiles. As a key feature of our that no loss of enantioselectivity takes place during the ring
strategy, we performed the copper-catalyzed asymmetric all- closure. Finally, up to 73% ee was obtained with ligand L4
ylic alkylation and ring-closing metathesis in one pot, which in the case of the 4-tert-butoxybutyl-substituted five-mem-
means that the Grubbs catalyst was added to the reaction bered adduct.
mixture after the allylic alkylation step without quenching
the reaction. The results are summarized in Table 2.
We then considered the reactivity of β-substituted allylic
substrates, which have been scarcely documented over the
Excellent SN2Ј selectivity was observed in all instances. years, although we have reported a few examples in which
Ligand L2 gave the best enantioselectivity for the construc- an inversion of the matched/mismatched effect was ob-
tion of a six-membered ring with a primary substituent as served.[13] In this study we prepared two β-methyl-substi-
up to 86 and 93% ee were obtained for the introduction tuted ω-ethylenic allylic chlorides, which were subjected to a
of a phenethyl and 4-tert-butoxybutyl moiety, respectively one-pot copper-catalyzed asymmetric allylic alkylation and
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Construction of Enantioenriched Cyclic Compounds
Table 2. Cu-AAA/RCM of allylic chlorides 1a–c.
Table 3. Cu-AAA/RCM of β-methyl-substituted allylic chlorides
5a,b.
Entry Substr.
R
L*
γ/α[a]
ee of
4
Yield[c] ee [%],
3[b] [%]
[%] config.[b]
Entry Substr.
R
L*
L5
γ/α[a]
7
Yield[b]
[%]
ee [%],
1[d]
2[d]
3
4
5
6
7
8
1a
1a
1b
1b
1b
1c
1c
1c
2a
2b
2a
2b
2c
2a
2b
2c
L1 Ͼ99:1
L3 Ͼ99:1
L2 Ͼ99:1
–
–
–
–
–
4a
4b
4c
4d
4e
4f
62[e]
55[e]
66
68
68
62
74
52
85, R
80, S
86, R
74, R
93, R
86, R
82, S
73, R
config.[c]
1
2
3
5a
5a
5a
5b
5b
2a
2b
2c
2a
2b
93:7
7a
7b
7c
7d
7e
62
–
65
–
82, S
40, (+)
82, (+)
66, S
ent-L1 83:17
L2
L5
L1
L2 Ͼ99:1
L1 92:8
94:6
91:9
95:5
4[d]
5[d]
87, R
82, S
–
ent-L1 90:10
–
30, (–)
L3 Ͼ99:1
L4 Ͼ99:1
4g
4h
1
[a] Determined by H NMR or GC–MS analysis. [b] Yield of the
isolated product after flash column chromatography on SiO2. [c]
Determined by chiral GC or SFC analysis. [d] Reaction performed
in a two-pot procedure.
1
[a] Determined by H NMR or GC–MS analysis. [b] Determined
by chiral GC or SFC analysis. [c] Yield of the isolated product after
flash column chromatography on SiO2. [d] Reaction performed in
a two-pot procedure. [e] Overall yield.
drance at this site. In palladium chemistry it is well known
that this catalyst is usually regioselective for the less hin-
dered position. However, the presence of a substituent in
the γ position generates a non-meso π-allyl intermediate,
preventing deracemization of the substrate and leading to
the formation of a mixture of enantiomers (Scheme 2).
ring-closing metathesis by using the same conditions as re-
ported previously and replacing the Grubbs I catalyst with
the more active Grubbs II catalyst[14] (Table 3).
Moderate-to-good regioselectivities were obtained. Mis-
matched ligand L5 was effective for the addition of the
phenethyl moiety in the synthesis of both the six- and five-
membered rings, however, lower enantioselectivity was ob-
tained in the latter case (82 and 66%, respectively, entries 1
and 4). Conversely, the more bulky phosphoramidite ligand
L2 was the most efficient in the case of the introduction of
the 4-tert-butoxybutyl moiety. The addition of a secondary
Grignard reagent was also explored, and in both cases low
enantiomeric excess was observed, up to 40% for the six-
membered adduct and 30% for the five-membered product
(entries 2 and 5).
We then turned our attention to a challenging class of
allylic substrates that contain a substituent in the γ posi-
tion. Direct asymmetric allylic alkylation of this type of cy-
clic system would not generate the alkylated cyclic product
in a highly selective manner. In fact, limitations in regio-
and enantiocontrol would arise from either a copper- or
palladium-catalyzed transformation. As discussed earlier
for the copper-catalyzed allylic alkylation, both possible
diastereomeric species would be formed with excellent chi-
Scheme 2. Allylic alkylation of γ-substituted cyclic systems.
To circumvent these problems we wished to apply our
rality transfer after oxidative addition when starting from a strategy, thereby forming enantioenriched cyclic com-
racemic mixture of the unsubstituted allylic cyclic substrate, pounds through an asymmetric allylic alkylation and ring-
thus eventually producing a homogeneous mixture of the closing metathesis. For this unprecedented reaction se-
possible products, that is, a racemate. Furthermore, in the quence leading to γ-substituted cycloalkenes, we decided to
presence of a substituent in the γ position, a mixture of use both nonstabilized and stabilized nucleophiles. We syn-
regioisomers would be expected because of the steric hin- thesized the corresponding substituted ethylenic allylic
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F. Giacomina, A. Alexakis
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chloride for the copper-catalyzed transformation and the
substituted allylic carbonate for the iridium-catalyzed pro-
cess. The choice of iridium as metal catalyst instead of pal-
ladium is a result of the recent and rapid growth of iridium-
mediated allylic substitution reactions, which have shown
high selectivities in favor of the branched product.[15]
Table 4 shows the results obtained for the one-pot cop-
per-catalyzed asymmetric allylic alkylation and ring-closing
metathesis reactions of allylic chlorides 8a and 8b. All reac-
tions proceeded in a highly regioselective manner. Ligand
L4 gave the best enantiomeric excess of 67% for the forma-
tion of a six-membered ring with a phenethyl group. Phos-
phoramidite ligand L3 was reasonably efficient with both
8a and 8b for the cyclohexyl alkylation with a maximum of
74% ee in the case of the five-membered adduct (entry 4),
whereas ligand L1 (or ent-L1) gave moderate enantio-
selectivity for the introduction of the 4-tert-butoxybutyl
group with a maximum of 70% ee in the case of the more
sterically demanding cyclohexyl substituent on the ethylenic
double bond in 8c (entry 6).
Scheme 3. Ir-AAA/RCM of allylic carbonates 11a,b.
In view of the results obtained with monosubstituted all-
ylic olefins, we studied the reactivity of a double allylic sub-
strate to generate enantioenriched disubstituted cycloalk-
enes. This class of electrophile contains two reactive sites
that can sequentially undergo allylic alkylation to produce
two terminal vinyl groups that can be subjected to intramo-
lecular metathesis. The advantage of this approach is that
essentially complete enantio- and diastereoselectivity can be
achieved as a result of double stereoselection or double
asymmetric induction. The double asymmetric synthesis
plays a decisive role in the stereochemical control of a vari-
ety of transformations,[17] and a few examples have already
been reported for the allylic substitution reaction.[18]
Table 4. Cu-AAA/RCM of allylic chlorides 8a,b.
We prepared the corresponding double allylic substrates
by using either a bromide or chloride as the leaving group.
Copper-catalyzed asymmetric allylic alkylation was carried
out by using our standard conditions employing chiral li-
gand L1, which was the best ligand for the alkylation of
Table 5. Double Cu-AAA/RCM of allylic chlorides 14a–c.
Entry Substr. RЈ
R
L*
γ/α[a]
10 Yield[b] ee [%],
[%]
config.[c]
1[d]
2
3
8a
8a
8a
8b
8b
8c
Me 2a
Me 2b
Me 2c ent-L1 Ͼ99:1 10c
Me 2b
Me 2c
cHex 2c ent-L1 96:4
L4
L3
92:8
Ͼ99:1 10b
10a
62[e]
70
78
55
60
–
67, S
64, S
62, S
74, S
68, S
70, (+)
4
L3
L1
Ͼ99:1 10d
Ͼ99:1 10e
5
6[d]
10f
1
[a] Determined by H NMR or GC–MS analysis. [b] Yield of the
isolated product after flash column chromatography on SiO2. [c]
Determined by chiral GC or SFC analysis. [d] Reaction performed
in a two-pot procedure. [e] Overall yield.
The iridium-catalyzed asymmetric allylic alkylation and
ring-closing metathesis were then studied, and the results
are reported in Scheme 3. The optimum conditions required
4 mol-% of [Ir(cod)Cl]2 and 8 mol-% of a chiral ligand.
Only π-accepting ligand L4 was employed because its effi-
ciency has already been described with similar substrates.[16]
Note that because of the incompatibility of the reaction
conditions (i.e., different reaction solvents), the whole pro-
cess was performed in a two-step procedure. Excellent re-
gioselectivity was observed with both substrates as well as
high enantioselectivities of up to 98% ee.
Entry Substr. 15
Yield[a]
[%]
γ,γ/γ,α
16 Yield[a] dr [c] ee[c]
(or α,α)[b]
[%]
[%]
[%]
1
14a 15a
14b 15a
14c 15b
88
82
Ͼ99:1
Ͼ99:1
88:12
16a
64
83:17
96
97
97
2
16a 100[e] 84:16
16b 100[e] 85:15
3[d]
100[e]
[a] Yield of the isolated product after flash column chromatography
on SiO2. [b] Determined by H NMR or GC–MS analysis. [c] De-
termined by chiral GC or SFC analysis. [d] Hoveyda–Grubbs II
catalyst was used in the RCM step. [e] Conversion.
1
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Construction of Enantioenriched Cyclic Compounds
allylic substrate 1c, and by using phenethylmagnesium
bromide as the alkylating agent. The results are shown in
Table 5.
The double allylic alkylation reactions of substrates 14a
and 14b were highly regioselective in favor of the γ adduct,
whereas the regioselectivity was moderately good in the case
of double allylic chloride 14c, which has only one carbon
atom between the two reactive sites, which results in some
steric hindrance between the two substituents at the γ posi-
tions. Concerning the diastereoselectivity, up to 85:15 was
achieved with the latter substrate. The synergic effect of the
catalyst and the substrate in controlling the outcome of the
reaction could be responsible for this result. As expected,
Scheme 4. Possible derivatization of product 16a.
high enantioselectivities were achieved for this transforma- field with copper as catalyst.[22] On the other hand, to intro-
tion with ee values of up to 97%. duce a 4-tert-butoxybutyl moiety, for example, the first ap-
We envisaged a possible derivatization of the highly en- proach is maybe more desirable because of the easier prepa-
antioenriched dialkylated products by transformation of the ration of the starting materials. Scheme 5 shows two specific
double bond (Scheme 4). Cycloalkene 16a was converted examples of these complementary methodologies that can
into the corresponding epoxide under classical reaction be used to synthesize the same product. Similar selectivities
conditions.[19] No matter how the oxidation proceeds (from were achieved, slightly better in the case of method b, al-
the top or the bottom face), the same C2-symmetrical com- though the advantage of method a is the ease of prepara-
pound should be obtained. This compound should be able tion of the starting material and the availability of the Grig-
to undergo a desymmetrization reaction. Indeed, the open- nard reagent.
ing of the epoxide with a nucleophile, such as an amine, for
In view of the results obtained with the different ω-ethyl-
example, would generate a chiral 1,2-amino alcohol. This enic allylic substrates, we have gained more insight into
class of compound has largely been used in asymmetric syn- some mechanistic aspects of the process. First, we consid-
thesis either as chiral auxiliaries[20] or as chiral building ered the effect of the substituent in the β position of the
blocks for natural product synthesis.[21]
allylic olefin because the presence of this substituent could
The methodology presented herein represents an alterna- cause hindrance in the system and modify the chiral envi-
tive approach to the construction of enantioenriched cyclic ronment. From a direct comparison of the results obtained
compounds through an asymmetric allylic alkylation com- with the unsubstituted allylic chlorides 1b and 1c, and the
bined with ring-closing metathesis (Scheme 1). By this ap- β-methyl-substituted allylic chlorides 5a and 5b, a general
proach, different alkyl-substituted cycloalkenes were ob- decrease in the enantioselectivity was observed for the latter
tained because a broad range of alkyl Grignard reagents substrates, accentuated in the case of the addition of the
can be employed as alkylating partners for the chiral copper cyclohexyl group for the construction of both the six- and
complex in the allylic substitution reaction. When an aro- five-membered rings. This shows that, as mentioned above,
matic group is needed as a substituent in the cyclic unit the the methyl group is generally detrimental to the reaction.
complementary approach is perhaps more advantageous as
Then we questioned whether the terminal double bond
the asymmetric allylic arylation remains challenging for ali- of the ω-ethylenic allylic chlorides used in this study could
phatic allylic substrates, despite the progress achieved in this play a role in the allylic alkylation reaction, and at which
Scheme 5. Complementary strategy for the formation of a cyclohexyl-substituted ring.
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F. Giacomina, A. Alexakis
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stage, as this olefin could take part in the catalytic cycle as tuted substrates 8a,b and the unsubstituted analogues 1b,c,
a ligand coordinated to the copper(III) complex formed a decrease in enantioselectivity was again observed in the
upon the oxidative addition, or prior to this step. This intra- case of the substituted alkylated adducts in the phenethyl,
molecular coordination could eventually change the chiral cyclohexyl, or tert-butoxybutyl substitution. In particular,
environment around the reactive center, and therefore the in the case of the cyclohexyl-substituted five-membered sys-
terminal double bond could influence the outcome of the tem, we did not observe such a strong decrease in enantio-
reaction. To demonstrate this hypothesis we prepared the selectivity as was noted when using the saturated allylic sub-
saturated analogue 17 of allylic chloride 1c. This compound strate 17. Thus, we can speculate that in this instance, the
does not contain the terminal double bond, consequently it positive effect of the coordinated double bond is weaker.
should show a different reactivity in the copper-catalyzed On the contrary, especially for the formation of six-mem-
asymmetric allylic alkylation reaction. For a direct com- bered substituted rings, the substantial loss of enantiocon-
parison of the reactivity of the two allylic chlorides, we per- trol could result from the steric hindrance generated by the
formed the copper-catalyzed allylic alkylation with two nu- methyl group. We have also reported one example with the
cleophilic species employed before in our investigations, more sterically demanding cyclohexyl group as substituent
phenethylmagnesium bromide and cyclohexylmagnesium on the terminal olefin to gain more insight into the role
chloride (Table 6).
of this substituent. Surprisingly, the copper-catalyzed allylic
alkylation of substrate 8c proceeded with a selectivity of
70%, similar to the values observed with the other sub-
strates, which suggests that the cyclohexyl group exhibits
steric hindrance comparable to that of the methyl group.
Table 6. Asymmetric allylic alkylation of unsaturated and saturated
allylic substrates.
Conclusions
We have described an efficient enantioselective process
for the construction of enantioenriched cyclic compounds
by coupling the powerful asymmetric allylic alkylation and
ring-closing metathesis reactions. For this approach, ω-eth-
ylenic allylic substrates were employed as synthetic equiva-
lents of cyclic allylic compounds.[23]
Entry Substr.
R
L*
γ/α[a]
Product ee [%], config.[b]
1
2
3
4
1c
17
1c
17
2a
2a
2b
2b
L1
L1
L3
L3
92:8
98:2
Ͼ99:1
Ͼ99:1
3a
18a
3b
87, R
95, R
82, R
38, R
With simple unsubstituted ω-ethylenic allylic chlorides,
five-, six-, and seven-membered rings could be generated
with enantiomeric excesses of up to 86, 93 and 85%, respec-
tively. We also studied the reactivity of β-methyl-substituted
ω-ethylenic allylic chlorides to access five- and six-mem-
bered cycloalkenes with a methyl group in the β position,
achieving an enantioselectivity of up to 82%. Next, we illus-
trated the formation by this methodology of challenging en-
antioenriched rings not easily accessible by direct asymmet-
ric allylic alkylation of cyclic substrates. In this instance we
used both copper and iridium as metal sources for the
asymmetric allylic alkylation step, achieving the γ-methyl-
substituted cyclopentenes and -hexenes in up to 98% ee.
Finally, the insertion of a second allylic leaving group into
the allylic substrate allowed a highly enantioselective
double asymmetric allylic alkylation to obtain interesting
synthons that could be further elaborated for synthetic pur-
poses.
18b
1
[a] Determined by H NMR or GC–MS analysis. [b] Determined
by chiral GC or SFC analysis.
Divergent results were obtained for the primary and sec-
ondary Grignard reagents. Better regio- and enantio-
selectivities were obtained for the phenethyl alkylation of
the saturated analogue 17 than for the unsaturated substrate
1c, whereas only 38% ee was observed for the saturated
cyclohexyl-substituted adduct 18b instead of the 82% ee de-
termined for the unsaturated product 3b. This suggests that
in the latter instance (cyclohexyl alkylation), there is a posi-
tive effect of the terminal double bond coordinated to the
metal center, although we do not have any experimental
evidence of this coordination. In contrast, the presence of
this double bond has a slight negative impact on the out-
come of the reaction with the primary phenethylmagnesium
bromide reagent because the intramolecular coordination
of the double bond to copper modifies the chiral pocket.
We also investigated the reactivity of ω-ethylenic olefins
having a methyl substituent on the terminal double bond.
In this instance, the presence of the methyl group could
cause a decrease in the coordinating ability of the olefin
through steric hindrance such that maybe the reactivity of
this substrate becomes more similar to its saturated ana-
logue, or, alternatively, there could be a significant modifi-
cation of the chiral environment around the reactive center.
We also tried to elucidate the effect of the ethylenic
double bond during the allylic alkylation step. Even though
the role of this terminal olefin has not been totally clarified
in the catalytic cycle, proof of its intervention has been
documented with some extra experimental data, and fur-
ther investigations need to be carried out for a better under-
standing of the effect of this second double bond.
Experimental Section
General: All reactions were conducted under an inert atmosphere.
From a comparison of the results obtained with the substi- Unless otherwise stated, all reagents were purchased from commer-
6716 Eur. J. Org. Chem. 2013, 6710–6721
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Construction of Enantioenriched Cyclic Compounds
cial suppliers and used without further purification. All solvents
employed in the reactions were dried by passage through alumina
columns and degassed prior to use. Organic solutions were concen-
trated under reduced pressure on a Büchi rotary evaporator. 1H
(300 or 400 MHz) and 13C (75 or 101 MHz) NMR spectra were
recorded in CDCl3, and chemical shifts (δ) are given in ppm relative
to residual CHCl3. The reactions were monitored by GC–MS using
a Hewlett-Packard (EI mode) HP6890-5973 instrument. Optical ro-
tations were measured at 20 °C in a 1 cm cell in the stated solvent.
[α]D values are given in 10–1 °Cm2 g–1 (concentration c given as g
per 100 mL). Enantiomeric excesses were determined by chiral GC
(capillary column, 10 psi H2). Temperature programs are described
as follows: initial temperature (°C)–initial time (min)–temperature
gradient (°Cmin–1)–final temperature (°C); retention times (tR) are
given in min. All Grignard reagents except for cyclohexylmagne-
sium chloride (Aldrich) were synthesized in diethyl ether by ad-
dition of the corresponding bromide to magnesium. Flash
chromatography was performed on silica gel (32–63 μm, 60 Å). The
synthesis of the starting substrates is described in the Supporting
Information.
or second generation, 5 mol-%) in a dried Schlenk tube and dis-
solved in dichloromethane (2 mL). The reaction mixture was left
at room temperature until complete conversion (by GC–MS analy-
sis) at which point the solvent was evaporated. The oily residue was
purified by flash column chromatography to yield the metathesis
product. GC or SFC analysis on a chiral stationary phase showed
the enantiomeric excess.
1
(R)-(3-Vinylnon-8-enyl)benzene (3a): H NMR (300 MHz, CDCl3):
δ = 7.31–7.21 (m, 5 H), 5.93–5.79 (m, 1 H), 5.70–5.57 (m, 1 H),
5.11–4.97 (m, 4 H), 2.76–2.66 (m, 1 H), 2.62–2.52, (m, 1 H), 2.11–
2.00 (m, 3 H), 1.81–1.68 (m, 1 H), 1.67–1.54 (m, 1 H), 1.49–1.24
(m, 6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 143.2, 143.0,
139.3, 128.6 (2 C), 128.4 (2 C), 125.7, 114.9, 114.3, 43.9, 37.0, 35.0,
33.9, 33.7, 29.2, 26.7 ppm. HRMS (EI): calcd. for C17H24 [M]+
228.1878; found 228.1882. Enantiomeric excess was measured on
the metathesis product 4a.
(–)-(R)-3-Phenethylcyclohept-1-ene (4a):[7a] 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.20 (m, 5 H), 5.90–5.81 (m, 1 H), 5.72–5.65 (m,
1 H), 2.77–2.16 (m, 2 H), 2.09–1.95 (m, 3 H), 1.81–1.55 (m, 4 H),
1.44–1.24 (m, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
143.0, 137.9, 131.6, 128.6 (2 C), 128.4 (2 C), 125.7, 39.3, 39.0, 33.8,
33.6, 30.7, 28.9, 27.1 ppm. [α]2D5 = –25.5 (c = 1.0, CHCl3) for 85%
ee {ref.:[7a] [α]2D5 = –18 (c = 1.0, CHCl3, 38% ee, (R) enantiomer}.
The enantiomeric excess was determined by SFC on a chiral sta-
tionary phase (Chiralcel OB column, method: MeOH 0%–2–1–15,
5 °C): tR = 4.26 (–), 4.72 (+) min.
(R)-Nona-1,8-dien-3-ylcyclohexane (3b): 1H NMR (300 MHz,
CDCl3): δ = 5.87–5.74 (m, 1 H), 5.61–5.47 (m, 1 H), 5.02–4.85 (m,
4 H), 2.08–1.96 (m, 2 H), 1.90–0.88 (m, 18 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 141.8, 139.4, 114.9, 114.2, 50.2, 41.9, 33.9,
31.7, 31.3, 29.8, 29.2, 27.2, 27.0, 26.9, 26.8 ppm. HRMS (EI): calcd.
for C15H26 [M]+ 206.2035; found 206.2034. Enantiomeric excess
was measured on the metathesis product 4b.
(+)-(S)-3-Cyclohexylcyclohept-1-ene (4b): 1H NMR (400 MHz,
CDCl3): δ = 5.81–5.72 (m, 1 H), 5.69–5.61 (m, 1 H), 2.16–1.90 (m,
3 H), 1.80–0.95 (m, 17 H) ppm. 13C{1H} NMR (75 MHz, CDCl3):
δ = 136.9, 131.1, 45.3, 43.7, 31.0, 30.4, 30.2, 29.8, 28.7, 27.2, 27.0,
26.9, 26.8 ppm. HRMS (EI): calcd. for C13H22 [M]+ 178.1722;
found 178.1723. [α]2D5 = +11.4 (c = 0.4, CHCl3) for 80% ee. The
enantiomeric excess was determined by GC on a chiral stationary
phase (HYDRODEX B-6-TBDM column, method: 70–80–1–170–
0, 50 cms–1): tR = 28.65 (+), 28.95 (–) min.
(R)-(3-Vinyloct-7-enyl)benzene (3c): 1H NMR (300 MHz, CDCl3):
δ = 7.40–7.18 (m, 5 H), 5.95–5.76 (m, 1 H), 5.71–5.55 (m, 1 H),
5.14–4.93 (m, 4 H), 2.77–2.50 (m, 2 H), 2.17–1.96 (m, 3 H), 1.82–
1.20 (m, 6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 142.9,
142.8, 139.0, 128.4 (2 C), 128.3 (2 C), 125.6, 114.8, 114.3, 43.7,
36.8, 34.5, 33.9, 33.5, 26.6, 26.5 ppm. HRMS (EI): calcd. for
C16H22 [M]+ 214.1722; found 214.1719. Enantiomeric excess was
measured on the metathesis product 4c.
(–)-(R)-[2-(Cyclohex-2-enyl)ethyl]benzene (4c):[23] 1H NMR
(300 MHz, CDCl3): δ = 7.50–7.27 (m, 5 H), 5.82–5.63 (m, 2 H),
2.72 (t, J = 8.3 Hz, 2 H), 2.25–1.42 (m, 9 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 143.0, 131.9, 128.5 (2 C), 128.4 (2 C), 127.3,
125.8, 38.4, 34.9, 33.4, 29.1, 25.5, 21.6 ppm. [α]2D5 = –65.2 (c = 1.0,
CHCl3) for 86% ee {ref.:[23] [α]2D5 = –104.4 (c = 1.2, CHCl3, 92%
ee) (R) enantiomer}. The enantiomeric excess was determined by
GC on a chiral stationary phase (HYDRODEX B-3P column,
method: 60–30–1–170–0, 50 cms–1): tR = 104.2 (+), 104.7 (–) min.
Typical Procedure for the One-Pot Copper-Catalyzed Enantioselec-
tive Allylic Alkylation/Ring-Closing Metathesis: A flame-dried
Schlenk tube was charged with the copper salt (3 mol-%) and the
chiral ligand (3.3 mol-%). Dichloromethane (2 mL) was added and
the mixture was stirred at room temperature for 20 min. The allylic
chloride (0.5 mmol) dissolved in dichloromethane (1 mL) was in-
troduced dropwise and the reaction mixture was stirred for a fur-
ther 5 min before being cooled to –78 °C. The Grignard reagent
(1–2 m in diethyl ether, 1.3 equiv.) in dichloromethane (up to 1 mL)
was added over 60 min through a syringe pump. Once the addition
was complete, the reaction mixture was left at –78 °C for a further
60 min until GC–MS analysis of an aliquot showed that all the
starting material had been converted. At this point the reaction
mixture was warmed to room temperature and Grubbs catalyst
(first or second generation, 5 mol-%) was added. The reaction mix-
ture was stirred at room temperature until GC–MS analysis of an
aliquot showed that all of the SN2Ј product had been converted.
The reaction was then quenched by the addition of aqueous hydro-
chloride acid (1 n, 2 mL). Diethyl ether (5 mL) was added and the
aqueous phase was separated and extracted with diethyl ether (3ϫ
3 mL). The combined organic fractions were washed with brine
(5 mL), dried with anhydrous sodium sulfate, filtered, and reduced
in vacuo. The oily residue was purified by flash column chromatog-
raphy to yield the metathesis product. Analysis by GC or SFC on
a chiral stationary phase showed the enantiomeric excess.
Typical Procedure for the Enantioselective Iridium-Catalyzed Allylic
Alkylation: A flame-dried Schlenk tube was charged with [Ir(cod)-
Cl]2 (4 mol-%), the chiral ligand (8 mol-%), and lithium chloride
(1 equiv.). Tetrahydrofuran (0.5 mL) was added and the mixture
was stirred at room temperature for 20 min. The allylic carbonate
(0.5 mmol) and a solution of freshly prepared sodium malonate
were added, and the reaction mixture was stirred at 60 °C for 16 h.
The reaction mixture was hydrolyzed with water, extracted with
diethyl ether, and dried with magnesium sulfate. The oily residue
was purified by flash column chromatography to yield the product
as a mixture of SN2Ј and SN2 regioisomers. Sodium malonate was
prepared as follows: A flame-dried flask was charged with sodium
hydride (1 mmol), which was washed with pentane (3ϫ 5 mL) and
tetrahydrofuran (5 mL). Tetrahydrofuran (1.5 mL) was then added
followed by dimethyl malonate (1 mmol).
Typical Procedure for the Intramolecular Ring-Closing Metathesis: (S)-Octa-1,7-dien-3-ylcyclohexane (3d): 1H NMR (300 MHz,
The substrate was placed together with the Grubbs catalyst (first CDCl3): δ = 5.87–5.72 (m, 1 H), 5.62–5.47 (m, 1 H), 5.04–4.85 (m,
Eur. J. Org. Chem. 2013, 6710–6721
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6717

F. Giacomina, A. Alexakis
FULL PAPER
4 H), 2.12–1.92 (m, 3 H), 1.82–1.58 (m, 5 H), 1.52–0.81 (m, 10
H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 141.6, 139.2, 114.9,
114.2, 50.1, 41.8, 33.9, 31.2, 29.7, 26.9, 26.8 (2 C), 26.7 (2 C) ppm.
Enantiomeric excess was measured on the metathesis product 4d.
(R)-9-tert-Butoxy-5-vinylnon-1-ene (3h): 1H NMR (300 MHz,
CDCl3): δ = 5.88–5.71 (m, 1 H), 5.58–5.43 (m, 1 H), 5.04–4.88 (m,
4 H), 3.31 (t, J = 6.8 Hz, 2 H), 2.18–1.90 (m, 3 H), 1.56–1.21 (m,
8 H), 1.18 (s, 9 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ =
143.0, 139.1, 114.4, 114.2, 72.4, 61.6, 43.5, 34.8, 34.1, 31.4, 30.8,
27.6 (3 C), 23.8 ppm. HRMS (EI): calcd. for C15H28ONa [M +
Na]+ 247.2032; found 247.2030. The enantiomeric excess was
measured on the metathesis product 4h.
(–)-(R)-3-Cyclohexylcyclohex-1-ene (4d):[23] 1H NMR (400 MHz,
CDCl3): δ = 5.74–5.51 (m, 2 H), 2.07–1.82 (m, 3 H), 1.80–1.42 (m,
8 H), 1.40–0.91 (m, 7 H) ppm. 13C{1H} NMR (75 MHz, CDCl3):
δ = 131.1, 127.2, 42.7, 40.9, 30.3, 29.9, 26.8 (2 C), 25.8 (2 C), 25.5,
22.3 ppm. [α]2D5 = –38.6 (c = 1.1, CHCl3) for 74% ee {ref.[23] [α]2D5
= –42 (c = 1.0, CHCl3, 70% ee) (R) enantiomer}. The enantiomeric
excess was determined by GC on a chiral stationary phase
(CHIRALDEX B-TA column, method: 70–120–15–170–5,
50 cms–1): tR = 90.27 (+), 92.31(–) min.
(+)-(R)-3-(4-tert-Butoxybutyl)cyclopent-1-ene (4h): 1H NMR
(300 MHz, CDCl3): δ = 5.79–5.70 (m, 2 H), 3.38 (t, J = 6.7 Hz, 2
H), 2.75–2.61 (m, 1 H), 2.43–2.22 (m, 2 H), 2.18–1.98 (m, 2 H),
1.65–1.29 (m, 6 H), 1.23 (s, 9 H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ = 135.4, 130.1, 72.4, 61.6, 45.6, 36.0, 32.0, 31.0, 29.9,
27.6 (3 C), 24.7 ppm. HRMS (ESI): calcd. for C13H24ONa [M +
Na]+ 219.1719; found 219.1719. [α]2D5 = +1.7 (c = 1.0, CHCl3) for
73% ee. The enantiomeric excess was determined by GC on a chiral
stationary phase (HYDRODEX B-3P column, method: 60–0–1–
170–0, 45 cms–1): tR = 45.09 (+), 45.44 (–) min.
(R)-10-tert-Butoxy-6-vinyldec-1-ene (3e): 1H NMR (300 MHz,
CDCl3): δ = 5.88–5.70 (m, 1 H), 5.60–5.41 (m, 1 H), 5.07–4.87 (m,
4 H), 3.31 (t, J = 6.8 Hz, 2 H), 2.11–1.87 (m, 3 H), 1.56–1.20 (m,
10 H), 1.18 (s, 9 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ =
143.3, 139.1, 114.2, 114.1, 72.4, 61.6, 43.9, 34.9, 34.4, 33.9, 30.8,
27.6 (3 C), 26.5, 23.7 ppm. HRMS (EI): calcd. for C16H30ONa [M
+ Na]+ 261.2189; found 261.2187. The enantiomeric excess was
measured on the metathesis product 4e.
(S)-[3-(Prop-1-en-2-yl)oct-7-enyl]benzene (6a): 1H NMR (300 MHz,
CDCl3): δ = 7.36–7.14 (m, 5 H), 5.90–5.73 (m, 1 H), 5.07–4.91 (m,
2 H), 4.82 (s, 1 H), 4.74 (s, 1 H), 2.86–2.42 (m, 2 H), 2.15–1.98 (m,
3 H), 1.72–1.60 (m, 2 H), 1.65 (s, 3 H), 1.42–1.27 (m, 4 H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ = 147.2, 142.9, 139.1, 128.4 (2
C), 128.3 (2 C), 125.6, 114.4, 112.1, 46.9, 35.4, 33.9, 33.8, 32.9,
26.8, 17.9 ppm. HRMS (EI): calcd. for C17H24 [M]+ 228.1878;
found 228.1877. The enantiomeric excess was determined on the
metathesis product 7a.
(–)-(R)-3-(4-tert-Butoxybutyl)cyclohex-1-ene (4e):[23] 1H NMR
(300 MHz, CDCl3): δ = 5.74–5.58 (m, 2 H), 3.38 (t, J = 6.6 Hz, 2
H), 2.14–1.97 (m, 3 H), 1.90–1.88 (m, 2 H), 1.86–1.12 (m, 8 H),
1.20 (s, 9 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 132.3,
126.7, 72.5, 61.6, 36.3, 35.2, 30.9, 29.1, 27.6 (3C), 25.4, 23.7,
21.6 ppm. [α]2D5 = –40.7 (c = 1.0, CHCl3) for 93% ee {ref.[23] [α]2D5
= –145.8 (c = 1.8, CHCl3, 90% ee) (R) enantiomer}. The enantio-
meric excess was determined by GC on a chiral stationary phase
(HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
45 cms–1): tR = 68.44 (–), 68.90 (+) min.
(–)-(S)-[2-(2-Methylcyclohex-2-enyl)ethyl]benzene (7a):[23] 1H NMR
(300 MHz, CDCl3): δ = 7.36–7.14 (m, 5 H), 5.44 (br. s, 1 H), 2.66
(m, 1 H), 2.64–2.48 (m, 1 H), 2.12–1.83 (m, 3 H), 1.68 (s, 3 H),
1.82–1.44 (m, 6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ =
143.0, 136.9, 128.4 (2 C), 128.3 (2 C), 125.6, 122.7, 38.3, 34.6, 33.6,
27.4, 25.6, 22.2, 19.8 ppm. HRMS (EI): calcd. for C15H20 [M]+
200.1565; found 200.1567. [α]2D5 = –37.3 (c = 1.05, CHCl3) for 82%
ee {ref.[23] [α]2D5 = –7.5 (c = 1.25, CHCl3, 18% ee) (S) enantiomer}.
The enantiomeric excess was determined by GC on a chiral station-
ary phase (HYDRODEX B-6-TBDM column, method: 60–0–1–
170–5, 45 cms–1): tR = 84.51 (–), 86.75 (+) min.
(–)-(R)-[2-(Cyclopent-2-enyl)ethyl]benzene (4f):[23] 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.14 (m 5 H), 5.84–5.69 (m, 2 H),
2.82–2.60 (m, 2 H), 2.50–2.25 (m, 2 H), 2.21–2.03 (m, 1 H), 1.88–
1.42 (m, 4 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 142.9,
135.0, 130.6, 128.5 (2 C), 128.4 (2 C), 125.7, 45.3, 38.1, 34.4, 32.1,
29.9 ppm. [α]2D5 = –36.7 (c = 0.4, CHCl3) for 86% ee {ref.[23] [α]2D5
= –117 (c = 1.5, CHCl3, 44% ee) (R) enantiomer}. The enantio-
meric excess was determined by SFC on a chiral stationary phase
1
(2-Methylocta-1,7-dien-3-yl)cyclohexane (6b): H NMR (400 MHz,
(Chiralcel OJ column, method: MeOH 0%–2–1–15, 5 °C): tR
11.21 (–), 11.53 (+) min.
=
CDCl3): δ = 5.88–5.73 (m, 1 H), 5.03–4.89 (m, 2 H), 4.75 (s, 1 H),
4.61 (s, 1 H), 2.12–1.31 (m, 2 H), 1.90–1.80 (m, 1 H), 1.78–1.48 (m,
5 H), 1.56 (s, 3 H), 1.28–1.07 (m, 6 H), 0.91–0.74 (m, 4 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 146.8, 139.3, 114.2, 112.2,
53.4, 39.7, 33.9, 33.3, 31.8, 31.1, 28.9, 27.1, 26.8, 26.6, 18.7 ppm.
HRMS (EI): calcd. for C15H26 [M]+ 206.2035; found 206.2033. The
enantiomeric excess was determined on the metathesis product 7b.
(+)-(S)-Hepta-1,6-dien-3-ylcyclohexane
(3g):[24]
1H
NMR
(400 MHz, CDCl3): δ = 5.87–5.64 (m, 1 H), 5.60–5.41 (m, 1 H),
5.40–4.78 (m, 4 H), 2.12–1.97 (m, 1 H), 2.11–1.41 (m, 8 H), 1.38–
0.74 (m, 7 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 141.4,
139.4, 115.4, 114.3, 49.7, 41.9, 31.9, 31.3, 31.0, 29.8, 26.9, 26.8 (2
C) ppm. [α]2D5 = +3.4 (c = 0.76, CHCl3) for 82% ee {ref.[24] [α]2D5
=
(+)-6-Cyclohexyl-1-methylcyclohex-1-ene (7b): 1H NMR (300 MHz,
CDCl3): δ = 5.49 (br. s, 1 H), 2.03–1.58 (m, 3 H), 1.68 (s, 3 H),
1.85–1.55 (m, 7 H), 1.51–0.80 (m, 8 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 136.2, 124.1, 44.0, 39.4, 31.6, 27.4, 27.2,
27.0, 26.9, 25.6, 23.9, 22.2, 22.1 ppm. HRMS (EI): calcd. for
C13H22 [M]+ 178.1722; found 178.1720. [α]2D5 = +8.7 (c = 1.04,
CHCl3) for 40% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (HYDRODEX B-6-TBDM col-
umn, method: 60–0–1–170–5, 45 cms–1): tR = 56.74 (+), 58.27
(–) min.
+3.4 (c = 0.98, CHCl3, 73% ee) (S) enantiomer}. The enantiomeric
excess was determined by GC on a chiral stationary phase (Chirasil
DEX-CB column, method: 70–90–0.5–75–20–0.5–80–2–15–170–0,
30 cms–1): tR = 108.24 (–), 110.49 (+) min.
(+)-(S)-Cyclopent-2-enylcyclohexane (4g):[24] 1H NMR (400 MHz,
CDCl3): δ = 5.76–5.70 (m, 2 H), 2.49–2.40 (m, 1 H), 2.33–2.18 (m,
2 H), 1.99–1.88 (m, 1 H), 1.78–1.59 (m, 5 H), 1.53–1.43 (m, 1 H),
1.28–1.09 (m, 4 H), 1.02–0.87 (m, 2 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 133.6, 130.7, 51.9, 43.1, 32.4, 31.3, 31.2,
29.9, 27.5, 26.9, 26.7 ppm. [α]2D5 = +38.5 (c = 0.4, CHCl3) for 82%
ee {ref.[24] [α]2D5 = –88.2 (c = 1.03, CHCl3, 73% ee) (R) enantiomer}.
The enantiomeric excess was determined by GC on a chiral station-
ary phase (HYDRODEX B-3P column, method: 60–0–1–170–0,
50 cms–1): tR = 32.27 (+), 32.92 (–) min.
10-tert-Butoxy-6-(prop-1-en-2-yl)dec-1-ene
(6c):
1H
NMR
(400 MHz, CDCl3): δ = 5.86–5.72 (m, 1 H), 5.04–4.89 (m, 2 H),
4.75 (s, 1 H), 4.64 (s, 1 H), 3.30 (t, J = 6.8 Hz, 2 H), 2.10–1.94 (m,
3 H), 1.57 (s, 3 H), 1.55–1.46 (m, 4 H), 1.35–1.22 (m, 6 H), 1.18 (s, 9
H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 147.7, 139.1, 114.2,
6718
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6710–6721

Construction of Enantioenriched Cyclic Compounds
111.4, 72.4, 61.6, 47.2, 33.9, 33.4, 32.9, 30.8, 27.6 (3 C), 26.8, 24.1,
17.9 ppm. HRMS (EI): calcd. for C17H32O [M]+ 252.2453; found
252.2457. The enantiomeric excess was determined on the meta-
thesis product 7c.
C), 128.3 (2 C), 125.6, 114.8, 109.8, 43.7, 37.9, 36.9, 34.6, 33.6,
25.1, 22.4 ppm. HRMS (EI): calcd. for C17H24 [M]+ 228.1878;
found 228.1881. The enantiomeric excess was determined on the
metathesis product 10a.
(10a):[25]
1H
(+)-6-(4-tert-Butoxybutyl)-1-methylcyclohex-1-ene (7c): 1H NMR
(400 MHz, CDCl3): δ = 5.40 (br. s, 1 H), 3.33 (t, J = 6.8 Hz, 2 H),
2.03–1.85 (m, 3 H), 1.68 (s, 3 H), 1.66–1.38 (m, 6 H), 1.35–1.20 (m,
4 H), 1.19 (m, 9 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
137.5, 122.2, 72.5, 61.6, 38.5, 32.5, 30.9, 27.6 (3 C), 27.3, 25.6, 23.9,
22.3, 19.7 ppm. HRMS (ESI): calcd. for C15H28NaO [M + Na]+
247.20324; found 247.20350. [α]2D5 = +16.2 (c = 1.08, CHCl3) for
82% ee. The enantiomeric excess was determined by GC on a chiral
stationary phase (Chirasil DEX-CB column, method: 60–0–1–170–
5, 45 cms–1): tR = 75.04 (–), 77.04 (+) min.
(–)-(S)-[2-(3-Methylcyclohex-2-enyl)ethyl]benzene
NMR (300 MHz, CDCl3): δ = 7.32–7.11 (m, 5 H), 5.34 (br. s, 1
H), 2.65 (t, J = 8.2 Hz, 2 H), 2.12–1.90 (m, 2 H), 1.94–1.85 (m, 3
H), 1.67 (s, 3 H), 1.83–1.68 (m, 2 H), 1.66–1.42 (m, 2 H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ = 143.0, 134.2, 128.4 (2 C),
128.3 (2 C), 125.9, 125.6, 38.5, 35.0, 33.4, 30.3, 28.9, 24.9,
21.9 ppm. HRMS (EI): calcd. for C15H20 [M]+ 200.1565; found
200.1564. [α]2D5 = –24.7 (c = 1.0, CHCl3) for 49% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase
(HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
50 cms–1): tR = 87.56 (–), 88.50 (+) min.
(+)-(S)-[3-(Prop-1-en-2-yl)hept-6-enyl]benzene (6d): 1H NMR
(400 MHz, CDCl3): δ = 7.45–7.10 (m, 5 H), 5.96–5.77 (m, 1 H),
5.08–4.96 (m, 2 H), 4.91–4.87 (m, 1 H), 4.79 (d, J = 2.3 Hz, 1 H),
2.66–2.48 (m, 2 H), 2.22–1.93 (m, 3 H), 1.83–1.58 (m, 2 H), 1.70
(s, 3 H), 1.53–1.45 (m, 2 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ = 146.9, 142.9, 139.1, 128.6, 128.5, 128.4, 125.7, 114.6,
114.4, 112.5, 46.7, 35.4, 33.9, 32.7, 31.8, 19.4 ppm. HRMS (EI):
calcd. for C16H22 [M]+ 214.1722; found 214.1725. [α]2D5 = +0.8 (c =
1.04, CHCl3) for 65% ee. The enantiomeric excess was determined
by SFC on a chiral stationary phase (Chiralcel OJ column, method:
MeOH 2%–2–1–15): tR = 3.90 (+), 4.13 (–) min.
(R)-(7-Methylocta-1,7-dien-3-yl)cyclohexane (9b): 1H NMR
(400 MHz, CDCl3): δ = 5.62–5.49 (m, 1 H), 5.03–4.86 (m, 2 H),
4.70 (s, 1 H), 4.68 (s, 1 H), 2.07–1.90 (m, 2 H), 1.83–1.59 (m, 6 H),
1.70 (s, 3 H), 1.52–1.37 (m, 2 H), 1.35–0.83 (m, 8 H) ppm. 13C{1H}
NMR (101 MHz, CDCl3): δ = 146.2, 141.7, 114.9, 109.7, 50.1, 41.9,
37.9, 34.7, 31.3, 31.2, 29.7, 26.8, 26.7, 25.5, 22.4 ppm. HRMS (EI):
calcd. for C15H26 [M]+ 206.2035; found 206.2036. The enantiomeric
excess was determined on the metathesis product 10b.
(+)-(S)-3-Cyclohexyl-1-methylcyclohex-1-ene (10b): 1H NMR
(300 MHz, CDCl3): δ = 5.31 (br. s, 1 H), 2.10–1.86 (m, 3 H), 1.85–
1.42 (m, 8 H), 1.70 (s, 3 H), 1.40–0.80 (m, 7 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ = 134.2, 125.3, 43.0, 41.3, 30.5 (2 C),
30.4, 30.1, 26.9 (2 C), 25.7, 24.2, 22.7 ppm. HRMS (EI): calcd. for
C13H22 [M]+ 178.1722; found 178.1719. [α]2D5 = +2.4 (c = 0.5,
CHCl3) for 64% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (Chirasil DEX-CB column,
method: 60–0–1–170–5, 50 cms–1): tR = 57.29 (–), 57.73 (+) min.
(–)-(S)-[2-(2-Methylcyclopent-2-enyl)ethyl]benzene (7d): 1H NMR
(400 MHz, CDCl3): δ = 7.42–7.20 (m, 5 H), 5.46–5.38 (m, 1 H),
2.82–2.69 (m, 1 H), 2.68–2.50 (m, 2 H), 2.42–2.08 (m, 3 H), 2.06–
1.94 (m, 1 H), 1.71 (s, 3 H), 1.70–1.57 (m, 1 H), 1.56–1.42 (m, 1
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 143.1, 143.0, 128.4
(2 C), 128.3 (2 C), 125.7, 124.8, 47.8, 35.6, 33.9, 30.9, 30.2,
14.9 ppm. HRMS (EI): calcd. for C14H18 [M]+ 186.1409; found
186.1407. [α]2D5 = –17.1 (c = 1.08, CHCl3) for 66% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase
(HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
45 cms–1): tR = 70.61 (–), 71.74 (+) min.
(R)-10-tert-Butoxy-2-methyl-6-vinyldec-1-ene (9c): 1H NMR
(300 MHz, CDCl3): δ = 5.59–5.44 (m, 1 H), 5.00–4.89 (m, 2 H),
4.69 (s, 1 H), 4.64 (s, 1 H), 3.31 (t, J = 6.6 Hz, 2 H), 2.08–1.90 (m,
2 H), 1.69 (s, 3 H), 1.55–1.12 (m, 11 H), 1.18 (s, 9 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ = 146.2, 143.4, 114.1, 109.7, 72.5, 61.6,
44.0, 37.9, 34.9, 34.6, 30.8, 27.6 (3 C), 25.2, 23.8, 22.9 ppm. HRMS
(+)-(2-Methylhepta-1,6-dien-3-yl)cyclohexane (6e): 1H NMR
(400 MHz, CDCl3): δ = 5.87–5.74 (m, 1 H), 5.10–4.88 (m, 2 H),
4.77–4.75 (m, 1 H), 4.73 (d, J = 2.3 Hz, 1 H), 2.10–2.05 (m, 1 H),
2.04–1.94 (m, 2 H), 1.90–1.55 (m, 7 H), 1.56 (s, 3 H), 1.30–1.10 (m,
6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 146.6, 139.5,
114.2, 112.6, 39.7, 32.1, 31.9, 31.2, 30.3, 28.9, 27.0, 26.9, 26.7,
18.8 ppm. HRMS (EI): calcd. for C14H24 [M]+ 192.1878; found
192.1881. [α]2D5 = +7.9 (c = 1.05, CHCl3) for 30% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase
(HYDRODEX B-3P column, method: 60–0–1–170–0, 45 cms–1):
tR = 40.35 (+), 40.96 (–) min.
(EI): calcd. for C17H32NaO [M
+
Na]+ 275.23454; found
275.23462. The enantiomeric excess was determined on the metath-
esis product 10c.
(–)-(S)-3-(4-tert-Butoxybutyl)-1-methylcyclohex-1-ene (10c): 1H
NMR (300 MHz, CDCl3): δ = 5.36–5.31 (br. s, 1 H), 3.38 (t, J =
6.7 Hz, 2 H), 2.11–1.85 (m, 3 H), 1.82–1.71 (m, 2 H), 1.68 (s, 3 H),
1.60–1.25 (m, 8 H), 1.24 (s, 9 H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ = 132.1, 126.5, 72.5, 61.6, 36.6, 35.5, 31.0, 30.3, 28.9,
27.6 (3 C), 24.0, 23.7, 22.0 ppm. HRMS (EI): calcd. for C15H28O
[M – C4H9]+ 167.1436; found 167.1433. [α]2D5 = –9.4 (c = 1.0,
CHCl3) for 61% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (HYDRODEX B-6-TBDM col-
umn, method: 60–0–1–170–5, 50 cms–1): tR = 76.94 (–), 77.44
(+) min.
(R)-(6-Methylhepta-1,6-dien-3-yl)cyclohexane (9d): 1H NMR
(300 MHz, CDCl3): δ = 5.63–5.47 (m, 1 H), 5.06–4.86 (m, 2 H),
4.73 (s, 1 H), 4.71 (s, 1 H), 2.10–1.52 (m, 8 H), 1.76 (s, 3 H), 1.42–
0.81 (m, 8 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 146.6,
141.5, 115.4, 109.6, 49.9, 42.0, 35.8, 31.3, 29.9, 29.7, 26.9, 26.9,
26.8, 22.8 ppm. HRMS (EI): calcd. for C14H24 [M]+ 192.1878;
found 192.1876. The enantiomeric excess was measured on the
metathesis product 10d.
(–)-(2-Methylcyclopent-2-enyl)cyclohexane
(7e):
1H
NMR
(400 MHz, CDCl3): δ = 5.38 (br. s, 1 H), 2.53–2.45 (m, 1 H), 2.27–
2.19 (m, 2 H), 1.92–1.53 (m, 7 H), 1.65 (s, 3 H), 1.38–0.80 (m, 6
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 141.8, 125.2, 53.7,
39.3, 32.2, 31.6, 27.1, 26.9, 26.7, 26.4, 25.0, 15.2 ppm. HRMS (EI):
calcd. for C12H20 [M]+ 164.1565; found 164.1563. [α]2D5 = –5.8 (c =
0.61, CHCl3) for 30% ee. The enantiomeric excess was determined
by GC on a chiral stationary phase (Chirasil DEX-CB column,
method: 60–0–1–170–5, 45 cms–1): tR = 35.94 (–), 36.24 (+) min.
1
(R)-(7-Methyl-3-vinyloct-7-enyl)benzene (9a): H NMR (300 MHz,
CDCl3): δ = 7.40–7.19 (m, 5 H), 5.71–5.58 (m, 1 H), 5.17–5.01 (m,
2 H), 4.74 (s, 1 H), 4.70 (s, 1 H), 2.78–2.65 (m, 1 H), 2.63–2.52 (m,
1 H), 2.18–1.97 (m, 3 H), 1.75 (s, 3 H), 1.68–1.27 (m, 6 H) ppm. (+)-(S)-(3-Methylcyclopent-2-enyl)cyclohexane (10d): 1H NMR
13C{1H} NMR (75 MHz, CDCl3): δ = 146.1, 142.9, 142.9, 128.4 (2
(400 MHz, CDCl3): δ = 5.34–5.30 (m, 1 H), 2.45–2.36 (m, 1 H),
Eur. J. Org. Chem. 2013, 6710–6721
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6719

F. Giacomina, A. Alexakis
FULL PAPER
2.21–2.13 (m, 2 H), 2.02–1.91 (m, 1 H), 1.71 (s, 3 H), 1.77–1.58 (m,
1 H), 1.57–1.47 (m, 5 H), 1.26–1.04 (m, 4 H), 0.91–0.83 (m, 2
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 140.4, 127.2, 52.0,
43.4, 36.6, 31.2, 31.1, 28.4, 26.8, 26.6, 26.5, 16.8 ppm. HRMS (EI):
calcd. for C12H20 [M]+ 164.1565; found 164.1564. [α]2D5 = +64.3 (c
= 1.0, CHCl3) for 74% ee. The enantiomeric excess was determined
by GC on a chiral stationary phase (HYDRODEX B-6-TBDM
column, method: 60–0–1–170–5, 45 cms–1): tR = 40.21 (+), 41.03
(–) min.
57.3, 52.4 (2 C), 35.8, 29.9, 26.5, 24.1, 21.3 ppm. HRMS (ESI):
calcd. for C12H18O4 [M]+ 226.1205; found 226.1208. [α]2D5 = +15.3
(c = 0.9, CHCl3) for 97% ee. The enantiomeric excess was deter-
mined by GC on a chiral stationary phase (HYDRODEX B-6-
TBDM column, method: 60–0–1–170–5, 45 cms–1): tR = 72.91 (–),
75.02 (+) min.
Dimethyl (R)-2-(6-Methylhepta-1,6-dien-3-yl)malonate (12b): 1H
NMR (300 MHz, CDCl3): δ = 5.70–5.54 (m, 1 H), 5.17–5.05 (m, 2
H), 4.71 (s, 1 H), 4.65 (s, 1 H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.40 (d,
J = 8.9 Hz, 1 H), 2.84–2.70 (m, 1 H), 2.20–1.88 (m, 4 H), 1.69 (s, 3
H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 168.7, 168.7, 145.1,
137.9, 118.1, 110.5, 57.0, 52.6, 52.4, 43.8, 35.1, 30.2, 22.6 ppm.
HRMS (ESI): calcd. for C13H20O4 [M]+ 240.1362; found 240.1364.
The enantiomeric excess was measured on the metathesis product
13b.
Dimethyl (+)-(R)-2-(3-Methylcyclopent-2-enyl)malonate (13b): 1H
NMR (300 MHz, CDCl3): δ = 5.22 (br. s, 1 H), 3.72 (s, 3 H), 3.71
(s, 3 H), 3.40–3.28 (m, 1 H), 3.24 (d, J = 9.8 Hz, 1 H), 2.28–2.05
(m, 2 H), 1.70 (s, 3 H), 1.65–1.52 (m, 2 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 169.3 (2 C), 143.2, 125.1, 57.2, 52.3 (2 C),
45.7, 36.0, 28.7, 16.7 ppm. HRMS (ESI): calcd. for C11H16O4
[M]+ 212.1049; found 212.1051. [α]2D5 = +59.1 (c = 1.0, CHCl3) for
98% ee. The enantiomeric excess was determined by GC on a chiral
stationary phase (HYDRODEX B-6-TBDM column, method: 60–
0–1–170–5, 45 cms–1): tR = 56.07 (–), 56.46 (+) min.
(3,6-Divinyloctane-1,8-diyl)dibenzene (15a): 1H NMR (400 MHz,
CDCl3): δ = 7.47–7.16 (m, 10 H), 5.69–5.58 (m, 2 H), 5.14–4.95
(m, 4 H), 2.77–2.67 (m, 4 H), 2.66–2.48 (m, 2 H), 2.18–1.92 (m, 4
H), 1.80–1.67 (m, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ
= 143.1, 143.0, 142.9 (2 C), 128.5 (4 C), 128.4 (4 C), 125.7 (2 C),
115.0, 114.9, 44.1, 43.8, 37.0, 36.8, 33.6 (2 C), 32.6, 32.5 ppm.
HRMS (EI): calcd. for C24H30 [M]+ 318.2348; found 318.2343. The
enantiomeric excess was determined on the metathesis product 16a.
(S)-9-tert-Butoxy-2-methyl-5-vinylnon-1-ene (9e): 1H NMR
(300 MHz, CDCl3): δ = 5.61–5.45 (m, 1 H), 5.30–4.90 (m, 2 H),
4.73 (s, 1 H), 4.70 (s, 1 H), 3.31 (t, J = 6.7 Hz, 2 H), 2.10–1.86 (m,
3 H), 1.70 (s, 3 H), 1.57–1.22 (m, 8 H), 1.18 (s, 9 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ = 146.4, 143.2, 114.6, 109.7, 72.6, 61.7,
43.9, 35.5, 35.0, 33.0, 30.9, 27.6 (3 C), 23.9, 22.7 ppm. HRMS (EI):
calcd. for C16H30ONa [M + Na]+ 261.2189; found 261.2187. The
enantiomeric excess was measured on the metathesis product 10e.
(–)-(S)-3-(4-tert-Butoxybutyl)-1-methylcyclopent-1-ene (10e): 1H
NMR (300 MHz, CDCl3): δ = 5.35–5.28 (m, 1 H), 3.37 (t, J =
6.8 Hz, 2 H), 2.71–2.58 (m, 1 H), 2.30–1.98 (m, 4 H), 1.75 (s, 3 H),
1.60–1.27 (m, 6 H), 1.23 (m, 9 H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ = 139.9, 129.1, 72.4, 61.7, 45.9, 36.4, 36.3, 30.9, 30.8,
27.6 (3 C), 24.6, 16.7 ppm. HRMS (EI): calcd. for C14H26O [M]+
210.1984; found 210.1981. [α]2D5 = –32.4 (c = 0.6, CHCl3) for 68%
ee. The enantiomeric excess was determined by GC on a chiral
stationary phase (HYDRODEX B-6-TBDM column, method: 60–
0–1–170–5, 45 cms–1): tR = 58.75 (+), 59.13 (–) min.
(9-tert-Butoxy-5-vinylnon-1-en-2-yl)cyclohexane (9f): 1H NMR
(400 MHz, CDCl3): δ = 5.58–5.47 (m, 1 H), 5.03–4.90 (m, 2 H),
4.65 (s, 1 H), 4.69 (s, 1 H), 3.31 (t, J = 6.8 Hz, 2 H), 2.10–1.85 (m,
3 H), 1.83–1.62 (m, 6 H), 1.56–1.43 (m, 3 H), 1.41–1.03 (m, 10 H),
1.18 (s, 9 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 153.7,
143.3, 114.4, 106.5, 72.5, 61.6, 44.4, 44.0, 34.9, 33.5, 32.6, 32.5 (2
C), 30.8, 27.6 (3 C), 26.9, 26.8, 26.5, 23.8 ppm. HRMS (EI): calcd.
for C21H38NaO [M + Na]+ 329.28149; found 329.28181. The
enantiomeric excess was determined on the metathesis product 10f.
(–)-3,6-Diphenethylcyclohex-1-ene (16a): 1H NMR (400 MHz,
CDCl3): δ = 7.48–7.18 (m, 10 H), 5.72 (s, 2 H), 2.68 (t, J = 7.9 Hz,
4 H), 2.90–2.19 (m, 2 H), 1.80–1.48 (m, 8 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ = 142.8, 131.8 (2 C), 131.5 (2 C), 128.4 (4 C),
128.3 (4 C), 125.7, 38.4, 37.9, 35.4, 34.6, 33.6, 33.2, 29.1, 26.1 ppm.
HRMS (EI): calcd. for C22H26 [M]+ 290.2035; found 290.2033.
[α]2D5 = –92.8 (c = 1.0, CHCl3) for 96% ee. The enantiomeric excess
was determined by SFC on a chiral stationary phase (Chiralcel
OB column, method: MeOH 2%–2–1–15): tR = 12.31 (+), 13.35
(–) min.
(+)-[3-(4-tert-Butoxybutyl)cyclopent-1-enyl]cyclohexane (10f): 1H
NMR (400 MHz, CDCl3): δ = 5.25 (br. s, 1 H), 3.32 (t, J = 6.5 Hz,
2 H), 2.65–2.50 (m, 1 H), 2.31–2.12 (m, 2 H), 2.09–1.87 (m, 2 H),
1.80–1.65 (m, 7 H), 1.55–1.02 (m, 10 H), 1.18 (s, 9 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 149.6, 125.8, 72.4, 61.7,
45.4, 39.8, 36.4, 32.8, 32.1, 32.0 (2 C), 31.0, 30.3, 27.6 (3 C), 26.5
(2 C), 24.6 ppm. HRMS (EI): calcd. for C15H25O [M – C4H9]+
221.1905; found 221.1905. [α]2D5 = +30.2 (c = 1.0, CHCl3) for 70%
ee. The enantiomeric excess was determined by GC on a chiral
stationary phase (HYDRODEX B-3P column, method: 60–30–1–
170–0, 50 cms–1): tR = 102.50 (–), 102.71 (+) min.
(+)-(3,5-Divinylheptane-1,7-diyl)dibenzene
(15b):
1H
NMR
(300 MHz, CDCl3): δ = 7.42–7.10 (m, 10 H), 5.80–5.37 (m, 2 H),
5.23–4.95 (m, 4 H), 2.82–2.45 (m, 4 H), 2.30–2.02 (m, 2 H), 1.90–
1.23 (m, 6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 143.0,
142.9, 142.8, 142.7, 128.5 (2 C), 128.4 (2 C), 128.3 (4 C), 125.6 (2
C), 115.4, 114.6, 41.5, 40.8, 40.5, 37.7, 36.2, 33.6, 33.4 ppm. HRMS
(EI): calcd. for C23H28 [M]+ 304.2191; found 304.2194. [α]2D5 = +0.6
(c = 1.03, CHCl3) for 95% ee. The enantiomeric excess was deter-
mined by SFC on a chiral stationary phase (Chiralcel OJ column,
method: MeOH 2%–2–1–15). tR = 9.09 (+), 11.03 (–) min.
(–)-3,5-Diphenethylcyclopent-1-ene (16b): 1H NMR (300 MHz,
CDCl3): δ = 7.37–7.13 (m, 10 H), 5.76 (s, 2 H), 2.83–2.58 (m, 6 H),
1.82–1.53 (m, 6 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ =
142.8 (2 C), 134.6 (2 C), 128.4 (4 C), 128.3 (4 C), 125.6 (2 C), 44.4,
Dimethyl (R)-2-(7-Methylocta-1,7-dien-3-yl)malonate (12a): 1H
NMR (400 MHz, CDCl3): δ = 5.68–5.56 (m, 1 H), 5.13–5.04 (m, 2
H), 4.69 (s, 1 H), 4.65 (s, 1 H), 3.73 (s, 3 H), 3. 68 (s, 3 H), 3.38
(d, J = 8.9 Hz, 1 H), 2.82–2.72 (m, 1 H), 2.07–1.89 (m, 2 H), 1.68
(s, 3 H), 1.54–1.23 (m, 4 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ = 168.8 (2 C), 137.9, 125.4, 117.7, 110.0, 56.9, 52.4, 52.3,
44.2, 37.4, 31.9, 24.9, 22.4 ppm. HRMS (ESI): calcd. for C14H22O4
[M]+ 254.1518; found 254.1522. The enantiomeric excess was mea-
sured on the metathesis product 13a.
Dimethyl (+)-(R)-2-(3-Methylcyclohex-2-enyl)malonate (13a):[26] 1H 37.9 (2 C), 36.5 (2 C), 34.3 (2 C) ppm. HRMS (EI): calcd. for
NMR (300 MHz, CDCl3): δ = 5.27 (br. s, 1 H), 3.79 (s, 3 H), 3.77
(s, 3 H), 3.29 (d, J = 10.5 Hz, 1 H), 3.00–2.85 (m, 1 H), 1.98–1.90
(m, 2 H), 1.82–1.58 (m, 2 H), 1.68 (s, 3 H), 1.41–1.24 (m, 2 H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ = 169.1 (2 C), 137.1, 121.5,
C21H24 [M]+ 276.1878; found 276.1874. [α]2D5 = –85.9 (c = 1.07,
CHCl3) for 97% ee. The enantiomeric excess was determined by
SFC on a chiral stationary phase (Chiralcel OD column, method:
MeOH 2%–2–1–15): tR = 7.29 (–), 8.64 (+) min.
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Eur. J. Org. Chem. 2013, 6710–6721

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Received: July 1, 2013
Published Online: August 23, 2013
Eur. J. Org. Chem. 2013, 6710–6721
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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