Asymmetric Synthesis of a Bicyclo[43.0]nonene Derivative Bearing a Quaternary Carbon Stereocenter: Desymmetrization of σ-Symmetrical Diketones through Intramolecular Addition of an Alkenyl Anion

Article abstract of DOI:10.1055/s-0040-1706421

The enantioselective synthesis of a bicyclo[4.3.0]nonene derivative bearing a quaternary carbon stereocenter is achieved by employing a desymmetrization strategy involving an intramolecular addition. The intramolecular nucleophilic addition of a highly reactive carbanion generated from an alkenyl iodide in the presence of a chiral ligand occurs with discrimination of two keto carbonyl groups to give the corresponding bicyclic compound in 81% yield and 39% ee. Asymmetric synthesis via an intramolecular desymmetrization strategy using a chiral ligand-carbanion complex represents a complementary approach to using chiral organocatalysts or chiral ligand-transition-metal complexes.

Full text of DOI:10.1055/s-0040-1706421

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
paper
A
en
T. Yoshimura et al.
Paper
Synthesis
Asymmetric Synthesis of a Bicyclo[4.3.0]nonene Derivative
Bearing a Quaternary Carbon Stereocenter: Desymmetrization of
-Symmetrical Diketones through Intramolecular Addition of an
Alkenyl Anion
Tomoyuki Yoshimura*
Yuki Enami
0
0
0
0-
0
0
0
2-6
9
3
1-1
0
4
8
n-BuLi
MeO
OMe
O
I
O
Jun-ichi Matsuo
0
0
0
0-
0
0
0
3-3
6
6
7-7
6
5
7
Me
Ph
Ph
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192,
Japan
toluene, –78 °C
30 min
O
OH
81% yield, 39% ee
yosimura@p.kanazawa-u.ac.jp
Received: 26.06.2020
Accepted after revision: 25.07.2020
Published online: 20.08.2020
This method is applied in the proline-catalyzed preparation
of Wieland–Miescher (1)3 and Hajos–Parrish (2)4 ketones,
which are useful compounds for the synthesis of cyclic mol-
ecules having a quaternary carbon stereocenter (Figure
1).5,6
DOI: 10.1055/s-0040-1706421; Art ID: ss-2020-f0352-op
Abstract The enantioselective synthesis of a bicyclo[4.3.0]nonene de-
rivative bearing a quaternary carbon stereocenter is achieved by em-
ploying a desymmetrization strategy involving an intramolecular addi-
tion. The intramolecular nucleophilic addition of a highly reactive
carbanion generated from an alkenyl iodide in the presence of a chiral
ligand occurs with discrimination of two keto carbonyl groups to give
the corresponding bicyclic compound in 81% yield and 39% ee. Asym-
metric synthesis via an intramolecular desymmetrization strategy using
a chiral ligand–carbanion complex represents a complementary ap-
proach to using chiral organocatalysts or chiral ligand–transition-metal
complexes.
O
O
O
OH Cl
O
R
O
Cl
O
O
Cl3C
HO
HO
1
2
4
OAc
sigillin A (3)
Figure 1 Structures of bicyclic compounds and sigillin A (3)
Key words desymmetrization, asymmetric synthesis, alkenyl lithium,
quaternary carbon stereocenter, bicyclo[4.3.0]nonene
The asymmetric synthesis of bicyclic compounds simi-
lar to 1 and 2 via desymmetrization strategies involving in-
tramolecular reactions has also been reported;7–9 such
compounds show valuable potential as synthons for the
synthesis of certain functional molecules. Our plan for the
total synthesis of sigillin A (3), isolated from Ceratophysella
sigillata,10 included the use of chiral bicyclo[4.3.0]nonene
derivative 4 (R = Me) as the starting material (Figure 1). The
synthesis of 4 (R = Me) in racemic form has been reported,9
while the synthesis of the chiral form is unknown. Herein,
we report a novel enantioselective synthesis of 4 by de-
symmetrization of 2,2-disubstituted cyclohexane-1,3-di-
one 5 through intramolecular nucleophilic addition of an
alkenyl anion to a carbonyl group (Scheme 1).
The synthetic plan involved treatment of 2-alkyl-2-(3′-
halo-2′-propenyl)-1,3-diketone 5 with an alkylmetal in the
presence of a chiral ligand to give intermediate A, which
would undergo intramolecular nucleophilic addition with
discrimination between the two carbonyl groups to afford
chiral bicyclic compound 4. Asymmetric syntheses using a
The stereoselective construction of a quaternary carbon
stereocenter, as commonly found in useful organic mole-
cules, is a key step in the synthesis of such molecules due to
challenges associated with steric hindrance. These challeng-
es also affect the transformation of functional groups and
the construction of other stereocenters close to the quater-
nary carbon stereocenter. Therefore, developing a new
method for the effective construction of a quaternary car-
bon stereocenter including the surrounding scaffold is an
important challenge in synthetic organic chemistry.1 De-
symmetrization of prochiral compounds is expected to be a
valuable method for the enantioselective construction of
quaternary carbon stereocenters because asymmetric in-
duction occurs by discrimination of identical residues re-
mote from the preexisting quaternary carbon stereocenter.2
With this approach, steric repulsion caused by a quaternary
carbon has minimal influence on asymmetric induction.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Yoshimura et al.
Paper
Synthesis
material 6a (75%), respectively, instead of the desired prod-
uct (±)-4a (entries 1 and 2). It was assumed that carboxylic
acid 8 was produced through a retro-Claisen reaction after
aqueous work-up. These results suggested that effective
lithium–bromine exchange did not occur. Therefore, the re-
action with ketone 6b having an alkenyl iodide was at-
tempted because lithium–iodine exchange proceeds more
effectively than lithium–bromine exchange. Treatment of
6b with 1.5 equivalents of n-BuLi afforded (±)-4a in 37%
yield, while the reaction with 1.2 equivalents of t-BuLi af-
forded (±)-4a in 34% yield (entries 3 and 4). The reaction
with n-BuLi resulted in a more complex reaction mixture
than that with t-BuLi, although a similar yield was observed
for both cases in the production of (±)-4a. Therefore, opti-
mization of the reaction conditions using t-BuLi was inves-
tigated. Increasing the number of equivalents of t-BuLi re-
sulted in an improved yield of (±)-4a from 34% to 78% (en-
tries 4–6). No effect on the yield of (±)-4a was observed
when more than 3.0 equivalents of t-BuLi were used (en-
tries 6 vs 7). Because 3 equivalents of t-BuLi was required to
complete the reaction, it was assumed that an excess
amount of t-BuLi would work as a base. To investigate this
possibility, compound 6b was treated under conditions
identical to those indicated in Table 1 entry 6, except for the
reaction time, which was reduced from 5 hours to 20 min-
utes, and then quenched by the addition of methanol-d4
(Scheme 3). Deuterium incorporation of 90% was observed
at C(3) of (±)-4a-D. This indicates that 2 equivalents of
t-BuLi were consumed for lithium–iodine exchange to give
the intermediate B and that 1 equivalent of t-BuLi depro-
tonates at C(3) of intermediate B to generate the dianion C.
R1M
R*Z
O
O
R
R
(chiral ligand)
R*Z
M
X
Z = OR, NR2
O
O
R*Z
5a: X = Br
5b: X = I
intermediate A
discrimination
of ketones
O
R
HO
4
Scheme 1 Strategy for the asymmetric synthesis of 4
desymmetrization strategy with an intramolecular reaction
have been developed using functional-group-tolerant re-
agents such as organocatalysts or catalysts of chiral ligand–
transition-metal complexes. However, the use of highly re-
active carbanion intermediates in reactions involving de-
symmetrization with an intramolecular reaction have been
reported infrequently,11 likely due to the poor compatibility
of reactive carbanions with various functional groups. The
success of this strategy requires (1) the faster generation of
chiral intermediate A than deprotonation or nucleophilic
addition of an alkylmetal, and (2) effective discrimination
between carbonyl groups by a chiral ligand. While lithium–
halogen exchange is known to selectively occur in the pres-
ence of carbonyl groups, the selective addition of alkyllithi-
um nucleophiles to one of the carbonyl groups represents a
challenge.12
Table 1 Investigation of the Reaction Conditions in Racemic Forma
The reaction conditions were optimized using diketones
6a and 6b,9 which were prepared using reported proce-
dures (Scheme 2, eqs 1 and 2).13,14 Alkylation of 2-methyl-
cyclohexane-1,3-dione with the corresponding cis-1-halo-
3-bromopropene 7a or 7b gave products 6a and 6b in 56%
and 75% yields, respectively.
X
O
O
O
Br
THF
–78 °C
O
8
CO2H
OH
)-4a
6a: X = Br
6b: X = I
(
Br
Br
O
Br
O
7a
LiI, DBU
Entry
Precursor Reagent (equiv)
Time (h)
Product (% yield)b
(1)
1c
2
3
4
5
6
7
6a
6a
6b
6b
6b
6b
6b
n-BuLi (1.3)
t-BuLi (3.0)
n-BuLi (1.5)
t-BuLi (1.2)
t-BuLi (2.2)
t-BuLi (3.0)
t-BuLi (6.0)
22
6.5
8 (77)
THF, reflux
56%
O
O
6a
6a (75)
4a (37)
4a (34)d
4a (54)d
4a (78)
4a (73)
I
Br
3
7b
O
I
O
7
TBAOH
5.5
5
(2)
H2O/dioxane, rt
75%
O
6b
O
1
Scheme 2 Preparation of precursors 6a and 6b
a A stirring solution of 6 was treated with RLi.
b A small amount of an inseparable impurity was present.
c The reaction temperature was allowed to increase gradually from –78 °C to
rt over 12 h.
Cyclization of 6a was first attempted without a chiral li-
gand to confirm whether bicyclic ketone 4a would be ob-
tained (Table 1). Treatment of 6a with n-BuLi or t-BuLi in
THF afforded linear ketone 8 (77%) or recovered starting
d Starting material 6b was recovered (entry 4: 47%, entry 5: 26%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
T. Yoshimura et al.
Paper
Synthesis
(entries 9 and 10). The reaction with i-PrMgCl·LiCl resulted
in recovery of 4a (57%), probably due to the low efficiency
of iodine–magnesium exchange (entry 11). Treatment of 6b
with n-BuLi in the presence of ZnCl2 led to a slightly low-
ered yield and ee (entry 12). Although various chiral ligands
(L2–L6) were evaluated using similar conditions to those of
entry 6 (Table 2) in an attempt to improve the yield and ee
of 4a, these efforts were unsuccessful (entries 13–17). The
following observations on the chiral ligands are notewor-
thy: (1) chiral ligands containing oxygen atoms tended to
give better enantioselectivities than those possessing nitro-
gen atoms (entries 6 and 14 vs 16 and 17), (2) a methyl
group was a suitable substituent on the oxygen atom of the
chiral ligand (entries 6 and 14 vs 13), and (3) a phenolic ox-
ygen on the chiral ligand decreased both the yield and ee of
4a (entries 6 and 14 vs 15). An improvement in the yield
was achieved by prolonging the time allowed for formation
of the chiral ligand–lithium complex to give 4a in 81% yield
and 39% ee and by-product 11 in 15% yield (entry 18). The
yield of recovered L1 was not determined, however, the de-
gradants from L1 were thought to have little effect on the
enantioselectivity of 4a due to the same ee being obtained
irrespective of the time for formation of the chiral ligand–
lithium complex (entries 6 and 18). The addition of 1.0
equivalent of LiI, which it was hoped would influence the
aggregation state of A, proved fruitless (entry 19).16 It was
assumed that the lower ee with t-BuLi rather than with n-
BuLi should be attributed to the higher concentration of LiI
(entries 2 vs 19 and 3). The addition of triethylamine, which
modifies the aggregation state16 of intermediate A, resulted
in a low yield of 4a (entry 20).
O
I
O
D
t-BuLi (3.0 equiv)
3
H
THF, –78 °C
20 min, 63%
quenched with methanol-d4
HO
O
(
)-4a-D
6b
axial: 74%
equatorial: 16%
t-BuLi
(2 equiv)
CD3OD
O
OLi
H
t-BuLi (1 equiv)
LiO
LiO
C
B
Scheme 3 Deuteration experiment
Next, the enantioselective synthesis of 4a was investi-
gated using the optimized conditions identified for the ra-
cemic synthesis (Table 2). Treatment of 6b with 3.3 equiva-
lents of t-BuLi in the presence of 6.0 equivalents of chiral li-
gand L111a,b,15 in THF at –78 °C afforded the desired product
4a in 66% yield as an almost racemic product (–1% ee) (en-
try 1). The highly coordinating property of THF was thought
to be the cause of the failed asymmetric induction, presum-
ably due to THF preventing coordination of the chiral ligand
L1 to the lithium cation. When the reaction was carried out
in toluene as the solvent, which has a lower coordinating
ability than THF, the cyclization of 6b afforded 4a in 61%
yield and 5% ee (entry 2). Because the ee value was not im-
proved with a different solvent, the effect of the alkyllithi-
um was revisited. Reinvestigation of alkyllithium reagents
in the presence of L1 showed that n-BuLi was more appro-
priate for the enantioselective cyclization of 6b. Treatment
of 6b with 3.3 equivalents of n-BuLi in the presence of 6.6
equivalents of L1 in toluene gave 4a in 56% yield and 37% ee
(entry 3). When the equivalent ratio of n-BuLi to L1 was
kept at 1:2 and the number of equivalents of n-BuLi was re-
duced from 3.3 to 2.5, both the yield and ee were improved
(entries 3 vs 4), while reduction from 3.3 to 1.5 equivalents
of n-BuLi resulted in a low yield and ee (entries 3 vs 5). It is
well known that the aggregation state of intermediate A in-
fluences its reactivity and enantioselectivity.16 Therefore, it
was expected that the enantioselectivity would be im-
proved by modifying the aggregation state of intermediate
A. As the aggregation state of intermediate A can be modu-
lated by changing the amount of chiral ligand relative to the
concentration of the lithium cation,16 the effect of the num-
ber of equivalents of L1 versus the equivalents of n-BuLi
was investigated. Treatment of 6b with 2.5 equivalents each
of n-BuLi and L1 gave 4a in 70% yield and 39% ee (entry 6).
Reducing the number of equivalents of L1 from 2.5 to 0.5
lowered both the yield and ee of 4a (entries 6 vs 7 and 8).
The effects of other alkylmetals on the yield and ee of 4a
were then investigated. Treatment with sec-BuLi improved
the yield while that with PhLi reduced both the yield and ee
The optimized method described above was applied to
the synthesis of bicyclo[3.3.0]octene derivatives bearing a
quaternary carbon stereocenter (Scheme 4). Treatment of
diketone 12 with 2.5 equivalents of n-BuLi in the presence
of 2.5 equivalents of L1 afforded bicyclic ketone 13 in 73%
yield and 13% ee. The ee of 13 was determined after its con-
version into 14. The reaction of 15 was also carried out sim-
ilarly to give 16 in 60% yield and 14% ee. The enantioselec-
tivity for the formation of bicyclo[3.3.0]octene derivatives
I
O
N NHTs
O
L1 (2.5 equiv)
n-BuLi (2.5 equiv)
toluene, –78 °C
30 min
O
O
OH
13
OH
14
12
73% yield, 13% ee
I
O
O
Ph
Ph
L1 (2.5 equiv)
n-BuLi (2.5 equiv)
toluene, –78 °C
30 min
OH
15
16
60% yield, 14% ee
Scheme 4 Syntheses of bicyclo[3.3.0]octene derivatives. The relative
and absolute configurations of 13 and 16 were tentatively assigned.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
T. Yoshimura et al.
Paper
Synthesis
Table 2 Investigation of the Enantioselective Cyclization of 6ba
O
I
O
RLi (X equiv)
chiral ligand (Y equiv)
solvent, –78 °C
30 min
O
OH
4a
6b
Entry
RM
t-BuLi
X
Chiral ligand
Y
Solvent
Yield (%)b of 4a
ee (%)c of 4a
1
2
3.3
3.3
3.3
2.5
1.5
2.5
2.5
2.5
2.5
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
6.0
6.0
6.6
5.0
3.0
2.5
1.0
0.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
THF
66d
–1
5
t-BuLi
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
61d
3
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
s-BuLi
56d,e,f
64d,e
47d,e,f
70d,e,f
60d,e,f
66d,e,f
80d
37
42
35
39
29
25
23
19
–
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18h
19h
20h
PhLi
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
18
i-PrMgCl·LiCl
n-BuLig
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLii
n-BuLij
0f
67e
31
3
76e,f
68e,f
5d,f
22
0
40d,e,f
31d,e,f
81e
7
4
39
15
64
7k
–
l
OMe
OMe
Ph
Ph
NHTs
O
N
H
N
Ph
Ph
OH
Et2N
Ph
NEt2
Ph
N
H
EtO
Ph
OEt
Ph
MeO
Ph
OMe
Ph
OMe
OMe
n-Bu
O
O
L6
L3
L2
L5
L1
L4
O
OH
11
10
9
OH
a A solution of L1 and n-BuLi was stirred at –78 °C for 10 min before addition of 6b.
b The absolute configuration was determined after conversion of 4a into the known compound 17 (see Scheme 5) and its specific rotation was compared with
that reported (vide infra).
c The ee of 4a was determined by chiral stationary HPLC after conversion of 4a into tosyl hydrazone 9.
d Compound 10 was concomitantly produced (2–12%).
e Compound 11 was concomitantly produced (4–15%) as a single isomer.
f Diketone 6b was recovered (2–57%).
g ZnCl2 (2.5 equiv) was added.
h A solution of L1 and n-BuLi was stirred at –78 °C for 1 h before addition of 6b.
i LiI (1.0 equiv) was added.
j Et3N (2.5 equiv) was added.
k Diketone 6b was recovered in 79% yield.
l The ee was not determined because of the low yield of 4a.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

E
T. Yoshimura et al.
Paper
Synthesis
was found to be much lower than that of the bicyclo-
[4.3.0]nonene derivative.
reported, the following abbreviations are used: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. Mass spectra were ob-
tained on a JEOL JMS-T100TD mass spectrometer.
The absolute configuration of 4a was determined after
its conversion into the known compound 17 (Scheme 5).
Oxidation of 4a (40% ee) with PDC in CH2Cl2 gave diketone
17 in 57% yield, which was identified by comparison with
the reported proton NMR spectrum.17 The reported specific
rotation of (R)-17 is +47.3 while the specific rotation of
synthetic 17 was found to be –18.0 (40% ee). Therefore, the
absolute configuration of the quaternary carbon in 17 was
determined to be S. From these results, the absolute config-
urations of the newly formed contiguous tetrasubstituted
carbons in 4a were determined to be 1S,6S due to the
known cis-fused structure. Mechanistic investigations of
the stereochemical course of the reaction are in progress.
2-(2′Z,3′-Bromopropenyl)-2-methylcyclohexane-1,3-dione (6a)
To a mixture of 2-methylcyclohexane-1,3-dione (1.19 g, 9.45 mmol)
and LiI (1.65 g, 12.3 mmol) in THF (75 mL) was added dropwise DBU
(1.84 mL, 12.3 mmol) at rt. After being stirred for 30 min, a solution of
1,3-dibromopropene (7a)19 (3.78 g, 18.9 mmol) in THF (30 mL) was
added to the mixture at rt. The resulting mixture was stirred for 20 h
under reflux. The reaction mixture was poured into ice water at 0 °C
and the resulting mixture extracted with EtOAc. The organic layers
were washed with sat. aq Na2S2O3 solution, water, and brine and dried
over Na2SO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (hexane/EtOAc, 5:1) to afford 6a
(1.30 g, 56%) as a yellow oil.
IR (neat): 1726, 1695, 1624 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.28 (dt, J = 7.1, 1.6 Hz, 1 H), 5.94 (q,
J = 7.1 Hz, 1 H), 2.79–2.64 (m, 6 H), 2.06–1.87 (m, 2 H), 1.31 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 209.0, 129.0, 110.9, 64.6, 37.6, 36.0,
O
O
S
S
PDC
4 Å MS
1
6
O
CH2Cl2, rt, 5.5 h
57%
Z
19.1, 17.6.
17
OH
S
[α]D28 = –18 (c 0.58, CHCl3, 40% ee)
HRMS-DART: m/z [M + H]+ calcd for C10H14BrO2: 245.01772; found:
245.01871.
Lit.17 [α]D20 = +47.3 for the R-enantiomer (c 0.42, CHCl3)
4a (40% ee)
Scheme 5 Determination of the absolute configuration of 4a
2-(2′Z,3′-Iodopropenyl)-2-methylcyclohexane-1,3-dione (6b)9
To a solution of 2-methylcyclohexane-1,3-dione (210.7 mg, 1.67
mmol) in 1,4-dioxane (5 mL) were added tetrabutylammonium hy-
droxide (TBAOH) (1.1 mL, 2.51 mmol, 40% in water) and a solution of
3-bromo-1-iodopropene (7b)19 (800 mg, 2.51 mmol) in 1,4-dioxane
(5 mL) at rt. After being stirred for 23 h at the same temperature, the
reaction was quenched with 1 N HCl at rt. The resulting mixture was
extracted with EtOAc. The extracts were washed with water and
brine, and dried over Na2SO4, filtered, and concentrated. The residue
was purified by silica gel column chromatography (hexane/EtOAc,
2:1) to give a colorless oil that was further purified by silica gel col-
umn chromatography (toluene/EtOAc, 9:1) to afford 6b (365.7 mg,
75%) as a colorless oil.
In conclusion, we have developed an asymmetric syn-
thesis of bicyclo[4.3.0]nonene derivative 4a through an in-
tramolecular nucleophilic addition of an alkenyl anion with
discrimination of two carbonyl groups. Highly reactive car-
banion intermediates were compatible with this desymme-
trization strategy undergoing intramolecular reactions un-
der optimized conditions. Although further improvement
of the enantioselectivity is needed for this reaction, the po-
tency of carbanions in asymmetric synthesis through a de-
symmetrization strategy involving an intramolecular reac-
tion has been demonstrated. These results are expected to
provide opportunities for developing new methods in
asymmetric synthesis using highly reactive carbanions.
IR (neat): 1726, 1691, 1608 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.37 (d, J = 7.6 Hz, 1 H), 6.00 (q, J = 7.6
Hz, 1 H), 2.79–2.63 (m, 6 H), 2.07–1.87 (m, 2 H), 1.32 (s, 3 H).
MS (DART): m/z = 293 [M + H]+.
Solutions of n-BuLi in hexane and t-BuLi in pentane were purchased
from Kanto Chemical Co., Inc. and were titrated with diphenylacetic
acid, which is a standard material and an indicator, when they were
newly opened. Chiral ligands L1–L411b and L618 were prepared ac-
cording to reported procedures. Flash column chromatography was
performed with SilicaFlash® F60 silica gel (40~50 micrometer). Thin-
layer chromatography was performed on precoated plates (0.25 mm,
silica gel, Merck Kieselgel 60F245), and compounds were visualized
with UV light and p-anisaldehyde stain or phosphomolybdic acid
stain. IR spectra were recorded on a Horiba IR-710 spectrophotome-
ter. 1H NMR spectra were measured in CDCl3 solution and referenced
to TMS (0.00 ppm) using JEOL JNM ECA-600 (600 MHz) or JEOL JNM
ECA-400 (400 MHz) spectrophotometers, unless otherwise noted.
13C NMR spectra were measured in CDCl3 solution and referenced to
CDCl3 (77.0 ppm) using JEOL JNM ECA-600 (150 MHz) or JEOL JNM
ECX-400 (100 MHz) spectrophotometers, unless otherwise noted.
Chemical shifts are reported in ppm. When peak multiplicities are
Cyclization Reactions in Table 1; General Procedure 1
To a solution of 6a or 6b (1 equiv) in THF (the volume was determined
by the concentration of substrate being adjusted to 0.06 M) was add-
ed dropwise n-BuLi or t-BuLi (the equivalents are given in Table 1) at
–78 °C. After being stirred for the time indicated in Table 1, the reac-
tion was quenched by the addition of sat. aq NH4Cl solution and the
resulting mixture was extracted with EtOAc. The extracts were
washed with brine, dried over Na2SO4, filtered and concentrated. The
residual oil was purified by silica gel column chromatography
(hexane/EtOAc, 2:1 to 1:1) to give the products indicated in Table 1.
Cyclization Reactions in Table 2; General Procedure 2
To a solution of the chiral ligand (see Table 2) in THF or toluene was
added the base (the indicated equivalents in Table 2) at –78 °C. The
mixture was stirred for 10 min (entries 1–17) or 1 h (entries 18–20)
at –78 °C. Next, a solution of 6b (1 equiv) in THF or toluene (the total
volume of THF or toluene was determined by the concentration of 6b
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

F
T. Yoshimura et al.
Paper
Synthesis
being adjusted to 0.06 M) was added dropwise to the mixture at
–78 °C. After being stirred at –78 °C for 30 min, the resulting mixture
was quenched by the addition of a solution of AcOH (10 equiv) in tol-
uene (1 mL) and then poured into sat. aq NaHCO3 solution at 0 °C. The
resulting mixture was extracted with EtOAc and the extracts were
washed with brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by silica gel column chromatography (hexane/
EtOAc = 9:1 to 4:1) to afford the products indicated in Table 2. The ee
of 4a was determined by chiral stationary after its conversion into the
corresponding tosyl hydrazone.
2-Butyl-2,6-dihydroxy-1-methylbicyclo[4.3.0]non-7-ene (11)
Single isomer (the relative configuration was not determined); color-
less oil.
IR (neat): 3423, 1637 cm–1
.
1H NMR (600 MHz, CDCl3):  = 5.72 (dd, J = 6.0, 3.0 Hz, 1 H), 5.65–5.64
(m, 1 H), 2.28 (s, 1 H), 2.24 (d, J = 15.0 Hz, 1 H), 1.98 (dd, J = 15.6, 3.6
Hz, 1 H), 1.96–1.93 (m, 1 H), 1.85–1.82 (m, 1 H), 1.72–1.66 (m, 1 H),
1.50–1.45 (m, 1 H), 1.42–1.26 (m, 8 H), 1.15 (s, 3 H), 0.92 (t, J = 7.2 Hz,
3 H).
13C NMR (150 MHz, CDCl3):  = 139.7, 128.0, 85.1, 75.3, 52.5, 41.5,
37.4, 32.0, 24.8, 23.5, 16.6, 15.6, 14.2.
Deuteration Experiment
To a solution of 6b (60 mg, 0.21 mmol) in THF (3 mL) was added drop-
wise t-BuLi (0.41 mL, 1.53 M in pentane, 0.63 mmol) at –78 °C. After
being stirred for 20 min at –78 °C, the reaction was quenched by the
addition of methanol-d4 (1 mL) at –78 °C and the resulting mixture
was poured into sat. aq NH4Cl solution. The mixture was extracted
with EtOAc and the extracts were washed with brine and dried over
Na2SO4, filtered, and concentrated. The residual oil was purified by sil-
ica gel column chromatography (hexane/EtOAc = 1:10) to give (±)-4a-D
(22.1 mg, 63%) as a colorless oil.
HRMS-DART: m/z [M – H2O + H]+ calcd for C14H23O: 207.17489;
found: 207.17494.
N'-[(3aR,7aS)-7a-Hydroxy-3a-methyl-3,3a,5,6,7,7a-hexahydro-4H-
inden-4-ylidene]-4-methylbenzenesulfonohydrazide (9)
To a solution of (1S,6S)-4a (20.5 mg, 0.12 mmol) in THF (2 mL) were
added p-TsNHNH2 (24.2 mg, 0.13 mmol) and PPTS (1.3 mg, 0.04
mmol) at rt. After being stirred at rt for 5 h, the resulting mixture was
concentrated. The residual oil was dissolved in CH2Cl2 and washed
with water. The aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were washed with water, and brine, dried over
Na2SO4, filtered and concentrated. The residue was purified through
silica gel column chromatography (CH2Cl2/EtOAc, 9:1) to give product
9 (32.3 mg, 80%) as a colorless oil. HPLC conditions: DAICEL Chiralpak
AD-H, hexane/2-propanol = 9:1, flow = 1 mL/min, max = 254 nm, t1 =
27.4 min for (1S,6S)-4a, t2 = 33.1 min for (1R,6R)-4a.
(6RS,8Z)-9-Bromo-6-methyl-5-oxo-8-nonenoic Acid (8)
Yellow oil.
IR (neat): 3751, 1709, 1624 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.24 (d, J = 6.8 Hz, 1 H), 6.06 (dt, J = 6.8,
7.2 Hz, 1 H), 2.71–2.45 (m, 4 H), 2.42–2.29 (m, 3 H), 1.91 (quin, J = 7.2
Hz, 2 H), 1.14 (d, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 212.4, 179.3, 131.8, 109.8, 45.2, 39.5,
32.9, 32.6, 19.4, 16.1.
[]D26 = +8.0 (c 1.04, CHCl3, 41% ee).
IR (neat): 3508, 1626, 1599, 1335, 1169 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.83 (d, J = 7.8 Hz, 2 H), 7.68 (br s, 1 H),
7.30 (d, J = 7.8 Hz, 2 H), 5.82–5.81 (m, 1 H), 5.50 (d, J = 5.4 Hz, 1 H),
2.78 (d, J = 16.8 Hz, 1 H), 2.43 (s, 3 H), 2.33 (d, J = 16.8 Hz, 1 H), 2.17–
2.11 (m, 2 H), 1.79–1.70 (m, 3 H), 1.54–1.51 (m, 1 H), 1.43–1.26 (m, 1
H), 1.14 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 163.8, 143.8, 136.2, 135.2, 133.0,
129.3, 128.1, 86.0, 52.6, 44.6, 34.4, 24.3, 21.6, 20.3, 17.8.
HRMS-DART: m/z [M + H]+ calcd for C10H16BrO3: 263.02828; found:
263.02607.
(1S,6S)-6-Hydroxy-1-methylbicyclo[4.3.0]non-7-en-2-one (4a)9
Colorless oil; []D28 = +9.3 (c 0.65, CHCl3, 40% ee).
IR (neat): 3453, 1704, 1639 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.02 (dt, J = 6.0, 2.7 Hz, 1 H), 5.69 (dt,
J = 6.0, 2.2 Hz, 1 H), 3.14 (ddd, J = 16.8, 3.0, 1.4 Hz, 1 H), 2.43 (ddd,
J = 15.2, 12.4, 6.0 Hz, 1 H), 2.35–2.28 (m, 1 H), 2.17 (dt, J = 16.8, 2.3 Hz,
1 H), 2.07–2.01 (m, 1 H), 1.96–1.85 (m, 2 H), 1.50–1.43 (m, 2 H), 1.25
(s, 3 H).
13C NMR (150 MHz, CDCl3):  = 214.6, 136.6, 136.0, 85.7, 59.7, 40.3,
37.3, 32.7, 19.2, 17.8.
HRMS-DART: m/z [M + H]+ calcd for C17H23N2O3S: 335.14294; found:
335.13969.
2-(3′-Iodoallyl)-2-methylcyclopentane-1,3-dione (12)9
Compound 12 was synthesized from 2-methylcyclopentane-1,3-di-
one (250 mg, 2.22 mmol) by following a similar method to that used
for the synthesis of 6b. Compound 12 (268.8 mg, 44%) was obtained
as a pale yellow oil.
MS (DART): m/z = 166 [M]+.
IR (neat): 1724, 1610 cm–1
.
The proton NMR spectrum of chiral 4a is compared with that of the
reported racemic example.
1H NMR (400 MHz, CDCl3):  = 6.44 (dt, J = 7.6, 1.2 Hz, 1 H), 6.11 (q,
J = 7.2 Hz, 1 H), 2.86–2.76 (m, 4 H), 2.46 (dd, J = 6.8, 1.2 Hz, 2 H), 1.18
(s, 3 H).
2-Methyl-2-(2′-propenyl)cyclohexane-1,3-dione (10)7l
Colorless oil.
IR (neat): 1726, 1695 cm–1
13C NMR (150 MHz, CDCl3):  = 215.0, 134.3, 86.9, 55.5 39.5, 35.0,
17.9.
.
1H NMR (400 MHz, CDCl3):  = 5.63–5.53 (m, 1 H), 5.06–5.05 (m, 2 H),
2.71–2.61 (m, 4 H), 2.53 (d, J = 7.2 Hz, 2 H), 2.05–1.85 (m, 2 H), 1.25 (s,
3 H).
MS (DART): m/z = 278 [M + H]+.
(3aS,6aS)-3a-Hydroxy-6a-methyl-3,3a,6,6a-tetrahydropentalen-
1(2H)-one (13)
13C NMR (150 MHz, CDCl3):  = 209.9, 132.2, 119.2, 65.2, 41.3, 38.2,
19.5, 17.5.
MS (DART): m/z = 167 [M + H]+.
Following general procedure 2, compound 12 (60 mg, 0.22 mmol) was
converted into 139a (24.6 mg, 73%, 13% ee) as a colorless oil.
[]D26 = +41.2 (c 0.96, CHCl3, 13% ee).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

G
T. Yoshimura et al.
Paper
Synthesis
IR (neat): 3439, 1738, 1612 cm–1
.
HRMS-DART: m/z [M + H]+ calcd for C18H15O2: 263.10720; found:
263.10561.
1H NMR (600 MHz, CDCl3):  = 5.96–5.95 (m, 1 H), 5.73–5.72 (m, 1 H),
2.66 (d, J = 17.4 Hz, 1 H), 2.35–2.30 (m, 2 H), 2.18–2.01 (m, 2 H), 1.64
(br s, 1 H), 1.11 (s, 3 H).
(S)-3a-Methyl-3,3a,6,7-tetrahydro-2H-indene-2,4(5H)-dione (17)
MS (DART): m/z = 153 [M + H]+.
To a solution of chiral 4a (20 mg, 0.12 mmol) and 4 Å MS (105 mg) in
CH2Cl2 (1.0 mL) was added PDC (135.4 mg, 0.36 mmol) at 0 °C. After
being stirred at rt for 5.5 h, the mixture was diluted with Et2O and
filtered through a pad of Celite. The filtrate was concentrated to give a
residue that was purified by preparative TLC (hexane/EtOAc = 1:1) to
afford 17 (11.3 mg, 57%) as a colorless oil.
The ee of 13 was determined after its conversion into the correspond-
ing tosyl hydrazone 14.
N'-[(3aS,6aR)-3a-Hydroxy-6a-methyl-3,3a,6,6a-tetrahydropental-
en-1(2H)-ylidene]-4-methylbenzenesulfonohydrazide (14)
[]D28 = –18 (c 0.58, CHCl3, 40% ee) {(R)-1717: Lit. []D20 = +47.3 (c 0.42,
CHCl3)}.
Treatment of 13 (24.6 mg, 0.16 mmol) with TsNHNH2 (33.5 mg, 0.18
mmol) and PPTS (1.5 mg, 0.006 mmol) in THF (3 mL) gave tosyl hy-
drazone 14 (27.3 mg, 53%) as a colorless oil. HPLC conditions: DAICEL
Chiralpak AD-H, hexane/2-propanol = 9:1, flow = 1 mL/min, max
254 nm, t1 = 34.0 min, t2 = 40.9 min.
[]D24 = +13.9 (c 1.17, CHCl3, 13% ee).
IR (neat): 3473, 1653, 1598 cm–1
IR (neat): 1712, 1622 cm–1
.
=
1H NMR (400 MHz, CDCl3):  = 5.82 (d, J = 1.6 Hz, 1 H), 2.21 (d, J = 19.0
Hz, 1 H), 2.90–2.69 (m, 3 H), 2.49–2.43 (m, 1 H), 2.32–2.24 (m, 1 H),
2.14 (d, J = 19.0 Hz, 1 H), 1.80–1.67 (m, 1 H), 1.54 (s, 3 H).
MS (DART): m/z = 165 [M + H]+.
.
1H NMR (600 MHz, CDCl3):  = 7.82 (d, J = 7.8 Hz, 2 H), 7.44 (br s, 1 H),
7.30 (d, J = 7.8 Hz, 2 H), 5.81 (dt, J = 5.4, 2.6 Hz, 1 H), 5.58 (dt, J = 6.0,
2.0 Hz, 1 H), 2.61 (dt, J = 16.8, 2.1 Hz, 1 H), 2.43 (s, 3 H), 2.41–2.33 (m,
2 H), 2.16–2.12 (m, 1 H), 1.96–1.86 (m, 2 H), 1.65 (br s, 1 H), 1.07 (s, 3
H).
13C NMR (150 MHz, CDCl3):  = 171.8, 143.9, 136.2, 135.3, 134.4,
129.4, 127.9, 90.9, 53.6, 45.6, 32.2, 25.6, 21.6, 18.6.
Funding Information
This research was supported by the Japan Society for the Promotion
of Science (JSPS), Grants-in-Aid for Scientific Research (KAKENHI)
(Grant No. JP17K08208).
J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
7
K
0
8
2
0
8)
HRMS-DART: m/z [M + H]+ calcd for C16H21N2O3S: 321.12729; found:
321.12807.
Supporting Information
Supporting information for this article is available online at
2-(3-Iodoallyl)-2-phenyl-1H-indene-1,3(2H)-dione (15)
https://doi.org/10.1055/s-0040-1706421.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Compound 15 was synthesized from 2-phenylindane-1,3-dione (400
mg, 1.80 mmol) by following a similar method to that used for the
synthesis of 6b. Compound 15 (490.9 mg, 80%) was obtained as an or-
ange oil.
References
(1) (a) Li, C.; Ragab, S.; Liu, G.; Tang, W. Nat. Prod. Rep. 2020, 37,
276. (b) Xu, P.-W.; Yu, J.-S.; Chen, C.; Cao, Z.-Y.; Zhou, F.; Zhou, J.
ACS Catal. 2019, 8, 1820. (c) Feng, J.; Holmes, M.; Krische, M. J.
Chem. Rev. 2017, 117, 12564. (d) Overman, L. E.; Quasdorf, K. W.
Nature 2014, 516, 181.
(2) (a) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Chem.
Rev. 2016, 116, 7330. (b) Petersen, K. S. Tetrahedron Lett. 2015,
56, 6523. (c) Studer, A.; Schleth, F. Synlett 2005, 3033.
(3) Buchschacher, P.; Fürst, A.; Gutzwiller, J. Org. Synth. 1985, 63,
37.
IR (neat): 1706 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.06–8.02 (m, 2 H), 7.90–7.85 (m, 2 H),
7.44–7.41 (m, 2 H), 7.35–7.26 (m, 3 H), 6.29 (dt, J = 7.2, 1.6 Hz, 1 H),
6.10 (q, J = 7.1 Hz, 1 H), 3.08 (dd, J = 6.9, 1.4 Hz, 2 H).
13C NMR (150 MHz, CDCl3):  = 200.4, 141.5, 136.1, 135.7, 135.1,
128.9, 127.9, 127.1, 123.8, 86.4, 60.7, 40.4.
HRMS-DART: m/z [M + H]+ calcd for C18H14IO2: 389.00385; found:
389.00434.
(4) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, 26.
(5) Nakazaki, K.; Hayashi, K.; Hosoe, S.; Tashiro, T.; Kuse, M.;
Takikawa, H. Tetrahedron 2012, 68, 9029.
(6) Tang, Y.; Liu, J.; Chen, P.; Ly, M.; Wang, Z.; Huang, Y. J. Org. Chem.
2014, 79, 11729.
(3aR,8aR)-3a-Hydroxy-8a-phenyl-3a,8a-dihydrocyclopenta[a]in-
den-8(1H)-one (16)
Following general procedure 2, compound 15 (81.5 mg, 0.21 mmol)
was converted into 16 (38.4 mg, 60%, 14% ee) as a colorless oil. HPLC
conditions: DAICEL Chiralpak AD-H, hexane/2-propanol = 9:1, flow =
1 mL/min, max = 254 nm, t1 = 8.1 min, t2 = 12.0 min.
(7) (a) Wei, Q.; Cai, J.; Hu, X.-D.; Zhao, J.; Cong, H.; Zheng, C.; Liu,
W.-B. ACS Catal. 2020, 10, 216. (b) Selmani, A.; Darses, S. Org.
Lett. 2020, 22, 2681. (c) Yuan, Z.; Feng, Z.; Zeng, Y.; Zhao, X.; Lin,
A.; Yao, H. Angew. Chem. Int. Ed. 2019, 58, 2884. (d) Zanghi, J. M.;
Liu, S.; Meek, S. J. Org. Lett. 2019, 21, 5172. (e) Zhu, T.; Lui, Y.;
Smetankova, M.; Zhuo, S.; Mou, C.; Chai, H.; Jin, Z.; Chi, Y. R.
Angew. Chem. Int. Ed. 2019, 58, 15778. (f) You, C.; Li, X.; Gong,
Q.; Wen, J.; Zhang, X. J. Am. Chem. Soc. 2019, 141, 14560.
(g) Knowe, M. T.; Danneman, M. W.; Sun, S.; Pink, M.; Johnston,
J. N. J. Am. Chem. Soc. 2018, 140, 1998. (h) Cai, J.; Wei, Q.; Hu, X.-
D.; Zhang, Y.; Li, W.; Cong, H.; Liu, W.; Liu, W.-B. Synthesis 2018,
50, 1661. (i) Wu, X.; Chen, Z.; Bai, Y.-B.; Dong, V. M. J. Am. Chem.
Soc. 2016, 138, 12013. (j) Li, Y.; Yang, S.; Wen, G.; Lin, Q.; Zhang,
[]D25 = –9.2 (c 1.71, CHCl3, 14% ee).
IR (neat): 3423, 1709, 1603 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.83 (d, J = 7.8 Hz, 1 H), 7.78 (d, J = 7.2
Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.32 (t, J = 7.5
Hz, 2 H), 7.25–7.22 (m, 3 H), 5.97–5.93 (m, 2 H), 3.28–3.21 (m, 2 H),
1.85 (s, 1 H).
13C NMR (150 MHz, CDCl3):  = 205.8, 156.1, 137.9, 135.8, 135.4,
135.2, 132.6, 129.2, 128.6, 128.1, 127.3, 124.3, 124.2, 91.2, 68.5, 41.8.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
T. Yoshimura et al.
Paper
Synthesis
G.; Qiu, L.; Zhang, X.; Du, G.; Fang, X. J. Org. Chem. 2016, 81,
2763. (k) Ema, T.; Akihara, K.; Obayashi, R.; Sakai, T. Adv. Synth.
Catal. 2012, 354, 3283. (l) Deschamp, J.; Riant, O. Org. Lett. 2009,
11, 1217. (m) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T.
Org. Lett. 2009, 11, 4866.
M.; Paruch, E. Tetrahedron 2004, 60, 5185. (e) Shintani, R.; Fu, G.
C. Angew. Chem. Int. Ed. 2002, 41, 1057. (f) Hodgson, D. M.;
Cameron, I. D. Org. Lett. 2001, 3, 441. (g) Hodgson, D. M.; Lee, G.
P. Tetrahedron: Asymmetry 1997, 8, 2303.
(12) Martínez-Estíbalez, U.; Sotomayor, N.; Lete, E. Org. Lett. 2009,
11, 1237; and references cited therein.
(13) Bedekar, A. V.; Watanabe, T.; Tanaka, K.; Fuji, K. Synthesis 1995,
1069.
(14) Byrne, S. J.; Fletcher, A. J.; Hebeisen, P.; Willis, M. C. Org. Biomol.
Chem. 2010, 8, 758.
(15) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111,
8266.
(16) (a) Carl, E.; Stalke, D. In Lithium Compounds in Organic Synthesis;
Luisi, R.; Capriati, V., Ed.; Wiley-VCH: Weinheim, 2014, 3.
(b) Clayden, J. Organolithiums: Selectivity for Synthesis; Elsevier
Science: Oxford, 2002. (c) Reich, H. J. Chem. Rev. 2013, 113,
7130.
(17) Wei, Z.-L.; Li, A.-Y.; Lin, G.-Q. Synthesis 2000, 1673.
(18) Yearick, K.; Wolf, C. Org. Lett. 2008, 10, 3915.
(19) (a) Alkenyl halides 7a,b were synthesized from ethyl propiolate
by the following 3 steps: cis-addition of a hydrogen halide on
the triple bond, reduction of the ester, and bromination of the
alcohol. For cis-addition of a hydrogen halide on a triple bond,
see: Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709. (b) For con-
version of an ester into allylic bromide, see: Shen, Z.; Ni, Z.; Mo,
S.; Wang, J.; Zhu, Y. Chem. Eur. J. 2012, 18, 4859.
(8) (a) Zhao, Y.-S.; Tang, X.-Q.; Tao, J.-C.; Tian, P.; Lin, G.-Q. Org.
Biomol. Chem. 2016, 14, 4400. (b) Molander, G. A.; Huérou, Y. L.;
Brown, G. A. J. Org. Chem. 2001, 66, 4511. (c) Balog, A.; Geib, J.;
Curran, D. P. J. Org. Chem. 1995, 60, 345. (d) Villagómez-Ibarra,
R.; Alvarez-Cisneros, C.; Joseph-Nathan, P. Tetrahedron 1995, 51,
9285. (e) Kinoshita, A.; Mori, M. Chem. Lett. 1994, 23, 1475.
(f) Mori, M.; Kaneta, N.; Shibasaki, M. J. Organomet. Chem. 1994,
464, 35.
(9) (a) Mori, M.; Isono, N.; Kaneta, N.; Shibasaki, M. J. Org. Chem.
1993, 58, 2972. (b) Mori, M.; Isono, N.; Kaneta, N.; Shibasaki, M.
Tetrahedron Lett. 1991, 32, 6139.
(10) Schmidt, W.; Schulze, T. M.; Brasse, G.; Nagrodzka, E.; Maczka,
M.; Zettel, J.; Jones, P. G.; Grunenberg, J.; Hilker, M.; Trauer-
Kizilelma, U.; Braun, U.; Schulz, S. Angew. Chem. Int. Ed. 2015,
54, 7698.
(11) Enantioselective syntheses through desymmetrization via
intermolecular reactions of carbanion species are reported, see:
(a) Graff, J.; Debande, T.; Praz, J.; Guénée, L.; Alexakis, A. Org.
Lett. 2013, 15, 4270. (b) Perron, Q.; Alexakis, A. Adv. Synth. Catal.
2010, 352, 2611. (c) Hodgson, D. M.; Štefane, B.; Miles, T. J.;
Witherington, J. J. Org. Chem. 2006, 71, 8510. (d) Hodgson, D.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H