Total Synthesis of (Nor)illudalane Sesquiterpenes Based on a C(sp3)-H Activation Strategy

Article abstract of DOI:10.1021/acs.joc.9b01669

Three (nor)illudalane sesquiterpenes were synthesized from a common intermediate in racemic and enantioenriched forms using Pd⁰-catalyzed C(sp³)-H arylation as a key step. The configuration of the isolated, highly symmetric quaternar

Full text of DOI:10.1021/acs.joc.9b01669

Subscriber access provided by KEAN UNIV
Article
Total Synthesis of (Nor)illudalane Sesquiterpenes
Based on a C(sp3)–H Activation Strategy
Romain Melot, Marcus V. Craveiro, and Olivier Baudoin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01669 • Publication Date (Web): 19 Jul 2019
Downloaded from pubs.acs.org on July 19, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Total Synthesis of (Nor)illudalane Sesquiterpenes Based on a C(sp3)–
H Activation Strategy
Romain Melot, Marcus V. Craveiro, and Olivier Baudoin*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
ABSTRACT:
Three
(nor)illudalane sesquiterpenes
were synthesized from
common intermediate
a
in
racemic and enantioenriched
forms using Pd0-catalyzed
C(sp3)–H arylation as a key
step. The configuration of the isolated, highly symmetric quaternary stereocenter of the target molecules was controlled through a
matched combination of chiral substrate and catalyst. Moreover, the recently developed Ir-catalyzed C–H borylation/Cu-catalyzed
methylation method was employed to install the methyl group on the benzene ring. This strategy allowed the efficient synthesis of
both racemic and (S)-configured puraquinonic acid, deliquinone and russujaponol F.
INTRODUCTION
Such quaternary stereocenters constitute an interesting
challenge in organic synthesis.5 Indeed, despite a moderate
structural complexity, only two enantioselective syntheses of
puraquinonic acid have been reported before our work,6,7 and
none for russujaponol F and deliquinone. Clive and co-workers
reported the first synthesis of (S)-puraquinonic acid in 31 steps
using an Evans aldol reaction as the enantio-determining step
(Scheme 1a, 89).6c,d This strategy required a large number of
functional group interconversions and manipulations. In
addition, this work established the absolute configuration of
natural puraquinonic acid as (R) upon comparison with a natural
sample. More recently, Gleason and co-workers disclosed a
much more efficient synthesis of (R)-puraquinonic acid
(Scheme 1b).7 The quaternary stereocenter was constructed at
the beginning of the synthesis via sequential diastereoselective
alkylations using a valine-derived chiral auxiliary (11). Then,
the indane core was built using an elegant and effective
combination of enyne metathesis and Diels-Alder
cycloaddition, followed by oxidation with DDQ in a one-pot
procedure (1213). After functional group manipulations,
cleavage of the chiral auxiliary and oxidation of the aromatic
ring to the benzoquinone, this approach yielded enantiopure
(R)-puraquinonic acid in 12 steps and 20% overall yield from
the in-house auxiliary,8 or 15 steps and 14% from (S)-valinol.
Illudalane and norilludalane sesquiterpenes are a large family
of bioactive natural products isolated from mycelial cultures of
woody mushrooms.1 These compounds usually contain a
geminal dimethyl group on a cyclopentane ring fused with
diverse scaffolds (Figure 1a). However, some members of this
family possess a quaternary stereocenter, resulting from the
oxidation of one of the geminal methyl groups to a
hydroxymethyl or a carboxylic acid group, such as the
benzoquinones puraquinonic acid (4)2 and deliquinone (5),3 and
the indane russujaponol F (6)4 (Figure 1b). The former, isolated
from cultures of Mycena Pura showed a mild differentiation-
inducing activity towards HL-60 cells.2
O
(a)
H
H
O
O
H
H
OH OH
O
HO
HO
(b)
1
2
3
sterostrein E ( )
russujaponol H ( )
granulolactone ( )
O
5
O
5
CO2H
4
4'
1
1
1
OH
OH
OH
OH
OH
5'
5'
O
O
In light of our longstanding interest in this field,9 we
considered a different approach to access these molecules,
using Pd0-catalyzed C(sp3)–H activation as the key step
(Scheme 2a). Our retrosynthetic analysis is based on a
disconnection at one of the two C(sp2)–C(sp3) bonds of the
indane 14, which would be constructed via asymmetric C(sp3)–
H arylation.10 The quaternary stereocenter would arise from the
desymmetrization of the two enantiotopic methyl groups in 15
or 16.
4
5
6
(S)-russujaponol F ( )
(R)-puraquinonic acid ( )
(R)-deliquinone ( )
Figure 1. (a) Examples of (nor)illudalanes with a gem-dimethyl
group. (b) (Nor)illudalane targets featuring a highly symmetric
quaternary stereocenter.
In addition to a polysubstituted aromatic or benzoquinone
core, the most intriguing part of molecules 4-6 is probably the
highly symmetric quaternary stereocenter resulting from
different substituents three or four carbons away (Figure 1b).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
1
2
Scheme 1. Previous Enantioselective Total Syntheses of Puraquinonic Acid
3
4
5
6
7
8
9
(a)
O
Evans aldol
& transfer of chirality
O
[3,3]
N
OMe O
OMe
OMe OH
O
O
O
O
O
OMe O
O
BnO
BnO
HO
11 steps
18 steps
iPr
N
O
OH
Bu2BOTf
DIPEA
iPr
RCM
Br
OMe
Stille coupling
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-puraquinonic acid (4)
31 steps - ~1% overall
(b)
enyne metathesis
O
O
iPr
N
O
iPr
O
BzO
O
S
HO
3 steps
5 steps
6 steps
O
OMOM 1 step
NHR
N
H
OH
SH
MeO2C
O
O
CO2Me
H
Diels-Alder
DDQ ox.
O
diastereoselective
alkylations
10
11
12
13
(R)-puraquinonic acid (4)
15 steps - 14% overall
Scheme 2. Retrosynthetic Analysis and Previous Work on
the Generation of Tetrasubstituted Stereocenters via Pd0-
Catalyzed C(sp3)–H Activation
tetrasubstituted stereocenters in the context of indoline
synthesis using a chiral phosphate catalyst.11 In this case, the
stereocenter arouse from the desymmetrization of two methyl
groups on a tetrasubstituted carbon (Scheme 2c), which proved
to be more challenging than desymmetrizing methyl groups on
a trisubstituted carbon.12 Moreover, in both examples the
intramolecular C–H arylation was likely favored by strong
Thorpe-Ingold effects. These precedents suggested that the
asymmetric C(sp3)–H arylation of substrates 15 and 16 leading
to the formation of the all-carbon stereocenter in 14 would be
particularly challenging. Herein, we report our efforts to
synthesize target molecules 1-3 in racemic and enantioselective
manner.13
(a)
OMe
CO2Me
OMe
C(sp3)–H
activation
Br
15
or
H
CO2Me
OMe
14
two possible
disconnections
Br
H
CO2Me
16
RESULTS AND DISCUSSION
(b)
Racemic synthesis – first route. We first explored the
feasibility of our strategy with the synthesis of racemic
puraquinonic acid. Our synthetic plan was inspired from
previous work by Kraus and co-workers on the synthesis of (±)-
puraquinonic acid ethyl ester (24) (Scheme 3) and (±)-
deliquinone.14 They prepared the indane ethyl ester 22,
analogous to our putative C–H activation product 14, through a
four-step sequence from 2,3-dimethylanisole. Hence, we
initially intended to follow the same sequence to complete our
total synthesis. From 22, the phenol methyl group was replaced
with an allyl group, and an aromatic Claisen rearrangement led
to compound 23. The terminal alkene was cleaved via reductive
ozonolysis to give the corresponding alcohol, and the phenol
was oxidized to the corresponding benzoquinone in the
presence of salcomine and oxygen. Finally, the missing methyl
group was introduced by radical methylation using acetic acid
and silver nitrate. Of note, Kraus and co-workers did not report
the saponification of 24 to puraquinonic acid.
Pd2dba3 (1 mol %)
L1 (3 mol %)
iPr
NC
NC
iPr
R
Me
R
K2CO3, DMSO, 90-140 °C
Br
H
17
18
e.r. up to 96:4
d.r. up to 99:1
(c)
R
Pd(PCy3)2 (5 mol %)
BPA* (10 mol %)
CO2Me
N
CO2Me
N
CO2Me
R
Cs2CO3
DME, 4Å MS, 120 °C
CO2Me
Br
19
H
20
e.r. up to 94:6
Ar
O
O
P
P
OH
O
Fe
Ar
BPA*
Ar = (3,5-di-CF3)Ph
L1
We selected aryl bromide 28 to test conditions for the key
C(sp3)–H arylation (Scheme 4). It was readily prepared by
alkylation of the lithium enolate of methyl isobutyrate with 2-
bromobenzyl bromide. After some optimization, we obtained
the best results using IBioxMe4 (L2), an N-heterocyclic carbene
(NHC) ligand developed by Glorius and co-workers,15 which
Previously, we reported the synthesis of enantioenriched
indanes using C(sp3)–H arylation in the presence of a chiral
binepine ligand L1 (Scheme 2b).10 In this case, a quaternary
stereocenter was generated via desymmetrization of two
isopropyl groups. More recently, we achieved the generation of
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
provided a full conversion and ca. 95% of product (Table 1,
entry 1).
fashion17 to give compound 30 in 82% yield over 2 steps. The
latter was engaged in the aromatic Claisen rearrangement. After
screening a few solvents, the best yield (90%) was achieved
with N,N-diethylaniline at 200 °C.
1
2
3
4
5
6
7
Scheme 3. Total synthesis of Puraquinonic Acid Ethyl Ester
by Kraus
Table 1. C(sp3)–H Arylation of Substrates 15, 16 and 28
R1

R1
[Pd( -cinnamyl)Cl]2 (5 mol %)
CO2Me
L2
(10 mol %)
CO2Me
8
9
CsOPiv (1 equiv)
Cs2CO3 (1.5 equiv)
mesitylene, 160 °C
Br
H
R2
R2
, R1 = R2 = H
, R1 = OMe, R2 = H
, R1 = H, R2 = OMe
, R1 = R2 = H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
28
15
16
29
14
O
O
, R1 = OMe, R2 = H
N+
TfO-
L2
N
entry
Reactant
Product
29
conv. (%)a,b
Then, we synthesized aryl bromide 15 from 3-bromo-2-
methylphenol 25 (Scheme 4). The latter is commercially
available, but can be prepared on a large scale via Sandmeyer
reaction from 3-bromo-2-methylaniline.16 Phenol 25 was then
methylated with K2CO3 and methyl iodide to yield the
corresponding anisole. The benzylic position was brominated,
and the corresponding benzyl bromide was employed in the
alkylation of the lithium enolate of methyl isobutyrate, in a
similar fashion to 28. This robust sequence led to substrate 15
in 75% overall yield and with only one column
chromatography. Substrate 16 was prepared in a similar manner
from commercial 2-bromo-1-methoxy-3-methylbenzene 26.
Both substrates were engaged in C(sp3)–H activation under the
same conditions as above. Compound 15 reacted cleanly and
the indane product 14 was isolated in 92% yield (Table 1, entry
2). In contrast, the isomer 16 gave a very low conversion, and
ca. 90% of the starting material was recovered (entry 3). The
lack of reactivity of 16 can be explained by the sterically
difficult oxidative addition of the di-ortho-substituted bromide
to palladium(0).
1
2
3
28
15
16
95
14
96 (92)
6
14
a
Conversion of the aryl bromide to the indane product estimated
by GC/MS analysis. b Yield of isolated product in parentheses.
At this stage, we encountered reproducibility issues in the
ozonolysis of 31, with low yields (ca. 20%) and starting
material decomposition. We assume that the free phenol
undergoes oxidization to the benzoquinone and further
degradation. This ozonolysis problem was already observed by
Clive and co-workers on a similar intermediate, and they found
that the Lemieux–Johnson oxidation gave better results.6a
Accordingly, 31 was oxidized to the corresponding aldehyde
using OsO4 and sodium periodate, and further reduced with
sodium borohydride. This two-step sequence afforded the
corresponding primary alcohol in 87% yield. Then, the phenol
was oxidized to the corresponding benzoquinone using the
same conditions as Kraus and co-workers,14 i. e. with 40 mol%
of salcomine under an oxygen atmosphere, hence furnishing the
unstable benzoquinone 32 in 82% yield.
Scheme 4. Preparation of C–H Arylation Substratesa
Scheme 5. First Route for the Synthesis of (±)-Puraquinonic
Acida
a Reagents and conditions: (a) K2CO3, MeI, DMF, 50 °C; (b) NBS,
i
(BzO)2, CCl4, reflux; (c) PrCO2Me, LDA, 0 °C, then benzyl
bromide, 025 °C.
Then, we continued our synthesis as initially planned
(Scheme 5). The two methoxy groups of indane 14 were cleaved
using hydrobromic acid in refluxing acetic acid to obtain the
corresponding phenol-carboxylic acid. The crude mixture was
alkylated with KHCO3/MeI and NaH/allyl bromide in a one-pot
aReagents and conditions: (a) HBr aq., AcOH, reflux; (b) KHCO3,
MeI, DMF, 40 °C, then NaH, allyl bromide; (c) PhNEt2, 200 °C;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
(d) OsO4 (5 mol %), NaIO4, AcOEt/H2O, 25 °C; (e) NaBH4,
more elegant, since it avoids both harsh reaction conditions in
1
2
3
4
5
6
7
8
MeOH, 0 °C; (f) salcomine hydrate, O2 atm., MeCN, 25 °C; (g)
AcOH, AgNO3, (NH4)2S2O8, MeCN/H2O, 70 °C.
the perbromination and debromination steps and a difficult
separation of the undesired benzyl bromide isomer after radical
bromination. Moreover, the borylated intermediate could be
potentially useful to prepare analogues via different reactions.24
Unfortunately, the radical methylation of 3214,18 gave
irreproducible yields in the range of 15-55%. We anyway
isolated some methylated benzoquinone 33 and attempted its
saponification. Unfortunately, we never succeeded to isolate
puraquinonic acid despite numerous attempts, due to the
sensitivity of the benzoquinone ring, and hence we decided to
opt for a different strategy. Nevertheless, these results gave us
important information to design a more effective plan. Indeed,
we encountered three major problems during this synthesis: 1)
instability of benzoquinone intermediates; 2) low yield and
irreproducibility of the radical methylation; 3) impossibility to
hydrolyze the ester on the benzoquinone. These problems led
us to conclude that the saponification has to be performed prior
to the oxidation to benzoquinone. This also precludes the
introduction of the methyl group via radical methylation, which
would be likely incompatible with the carboxylic acid moiety.
Therefore, this methyl group has to be installed earlier in the
synthesis. Besides, a late-stage oxidation of the phenol to the
benzoquinone would be more adapted in light of stability issues.
Scheme 6. Preparation of Methylated Aryl Bromide 36a
OMe
OMe
OH
a-c
d-e
CO2Me
(76%)
(75%)
9
Br
Br
34
35
36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
directed
lithiation
OMe
OMe O
H
formylation
Br
Br
37
38
OMe
OMe
f-g
CO2Me
CO2Me
(78%)
H
Me
Br
15
Br
36
a Reagents and conditions: (a) Br2, AlBr3, CH2Cl2, 0 °C; (b) HI aq.,
reflux; (c) K2CO3, MeI, acetone, reflux; (d) N-bromosuccinimide,
AIBN, CCl4, reflux; (e) iPrCO2Me, LDA, THF, 0 °C, then benzyl
bromide, 025 °C; (f) [Ir(COD)OMe]2 (1.25 mol %), dtbbpy (2.5
mol %), B2Pin2, THF, 50 °C; (g) CuI (10 mol %), LiI (20 mol %),
tBuOLi, PO(OMe)3, DMI, 50 °C. dtbbpy = 4,4′-di-tert-butyl-2,2′-
dipyridyl; DMI = 1,3-dimethyl-2-imidazolidinone.
Racemic synthesis – second route. For this second route, we
decided to start with the methyl group already present at the
beginning. The global strategy remains unchanged until the end,
where the ester would be cleaved first, followed by phenol
oxidation to benzoquinone. This new synthetic plan led us to
consider the possibility to prepare two other natural products,
deliquinone and russujaponol F. Indeed, a common indane
intermediate (40, Scheme 7), would be the divergent point to
prepare these three natural products.
Next, 36 was engaged in the previously optimized C(sp3)–H
arylation in the presence of IBiox ligand L2, to give the indane
39 in 87% yield (Scheme 7). Then, similarly to the first route,
both methoxy groups were cleaved under acidic condition (87%
yield), the corresponding phenol-carboxylic acid was alkylated
and allylated (89% yield) and the aromatic Claisen
rearrangement furnished indane 40 (88% yield). The latter,
obtained in 34.5% overall yield over 9 steps from phenol 25,
was used as a common intermediate to prepare the three target
racemic natural products. Compound 40 was first engaged in
the Lemieux–Johnson oxidation, followed by reduction with
sodium borohydride to yield the corresponding alcohol in 75%
yield over two steps. The saponification of this product
proceeded well and the corresponding carboxylic acid was
directly engaged in the oxidation step without purification. The
benzoquinone formation failed under previous conditions with
salcomine and oxygen. Gratifyingly, we found that this
oxidation proceeded cleanly using conditions developed by
Yakura and Konishi,25 whereby a catalytic hypervalent iodine
reagent is generated from iodophenoxyacetic acid 41 and
Oxone®. Under these mild conditions, (±)-puraquinonic acid
was obtained in 82% yield over two steps and an overall yield
of 22.3% over 13 steps. (±)-Deliquinone was obtained in a
similar fashion. The double bond of 40 was oxidized under
Lemieux–Johnson conditions and both aldehyde and ester
groups were reduced using lithium aluminum hydride. Phenol
oxidation under the same conditions as puraquinonic acid
provided racemic deliquinone in 76% yield over three steps and
an overall yield of 26.2% over 12 steps. To prepare
russujaponol F, phenol 40 was triflated under classic conditions
(87% yield). The corresponding triflate was engaged in a Pd0-
catalyzed cross-coupling under conditions developed by
Woodward and co-workers, using the air-stable DABAL-Me3
Compound 36 was first prepared from 2,5-xylenol 34
(Scheme 6, top). The phenol was perbrominated using bromine
and aluminum tribromide, followed by selective debromination
with hydroiodic acid and phenol methylation with K2CO3 and
MeI as described.19 This sequence yielded the anisole 35 in 76%
overall yield with one distillation as the only purification. Then
selective radical benzylic bromination,20 and enolate alkylation
furnished 36 in 75% yield over two steps and 57% over 5 steps
from phenol 34. We envisaged another strategy to prepare the
same benzyl bromide intermediate via directed lithiation of aryl
bromide 37 and formylation to give aldehyde 38, then reduction
and Appel reaction.21 Unfortunately, we never succeeded to
achieve an efficient lithiation/formylation, probably due to the
generation of the unstable benzyne intermediate.
More recently, we considered a C–H activation approach to
36 based on recent work of Hartwig and co-workers.22 Indeed,
a sequence of iridium-catalyzed C–H borylation and copper-
catalyzed methylation would allow to bridge our first and
second synthetic routes. The C–H borylation of ester 15 should
be selective for the less hindered position, as demonstrated by
Hartwig and co-workers for di- and trisubstituted arenes,23 and
the Cu-catalyzed methylation of the corresponding boronate
would lead to the desired aryl bromide 36. We applied this
method to aryl bromide 15 and were pleased to obtain the
corresponding borylated intermediate in 97% yield in a highly
regio- and chemoselective manner (Scheme 6, bottom). The
subsequent methylation worked well too, providing a yield of
80%. The global sequence from 3-bromo-2-methylphenol 25
(see Scheme 4) is as effective as the previous one from 2,5-
xylenol 34, with an overall yield of 58% for the same number
of steps. However, the C–H borylation approach is arguably
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
[DABCO-bis(trimethylaluminum)] complex.26 These efficient
recovered mother liquor showed an enantiomeric ratio of 96:4.
1
2
3
4
5
6
7
8
and convenient conditions furnished 42 in excellent yield
(98%). Finally, racemic russujaponol F was obtained by
Lemieux–Johnson oxidation and reduction of both carbonyl
groups in 87% yield over two steps and an overall yield of
25.6% over 13 steps. The current syntheses of (±)-puraquinonic
acid and deliquinone are more efficient than the best previously
reported syntheses by Clive and co-workers and Kraus and co-
workers, respectively. Moreover, (±)-russujaponol F was
synthesized for the first time.
Despite this loss of material in the crystallization, this global
sequence of deprotection and recrystallization occurred in 57%
yield. At this point, we tried to determine the absolute
configuration of the generated quaternary stereocenter using X-
ray diffraction analysis, but unfortunately, despite numerous
attempts, neither the enantioenriched compound 45, nor any
derivative that we synthesized28 furnished suitable crystals. The
configuration was finally ascribed as (S) by NOESY NMR of a
Mosher derivative and vibrational circular dichroism,13 and this
assignment was later confirmed by the specific rotation values
of the target products. With the enantioenriched intermediate 45
in hand, we employed the same sequence as for the racemic
synthesis, and obtained comparable yields. In this manner, (S)-
[푎]20
9
Scheme 7. Divergent Synthesis of (±)-Puraquinonic Acid,
(±)-Deliquinone, and (±)-Russujaponola
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
puraquinonic acid (
+1.4, lit. for the (R) enantiomer: –
D
2.2)6c,d was obtained in 15 steps, 9.8% overall yield, (S)-
[푎]20
deliquinone (
+0.9, lit. for the (R) enantiomer: –0.5)3 in 14
D
[푎]20
steps and 9.9% overall yield, and (S)-russujaponol F (
D
+2.1, lit. +1.3)4 in 15 steps and 12.3% overall yield. These
specific rotations confirmed the configuration assignment of
intermediate 45. Therefore, we prepared natural russujaponol F,
ent-puraquinonic acid and ent-deliquinone.
CONCLUSION
In conclusion, three (nor)illudalane sesquiterpenes were
synthesized in racemic and enantioenriched forms from a
common indane intermediate. The latter was obtained by Ir-
catalyzed C–H borylation and Pd0-catalyzed C(sp3)–H arylation
as key steps, and an asymmetric version of the C–H arylation
allowed the construction of the isolated, highly symmetric
quaternary stereocenter. This work, representing the first
application of Pd0-catalyzed enantioselective C(sp3)–H
activation to natural product synthesis, highlights the challenges
and potential of this transformation for the synthesis of chiral
bioactive molecules.
EXPERIMENTAL SECTION
a Reagents and conditions: (a) [Pd(-cinnamyl)Cl]2 (5 mol %), L2
(10 mol %), CsOPiv, Cs2CO3, mesitylene, 160 °C; (b) HBr aq.,
AcOH, reflux; (c) KHCO3, MeI, DMF, 40 °C, then NaH, allyl
bromide; (d) PhNEt2, 200 °C; (e) OsO4 (5 mol %), NaIO4,
AcOEt/H2O, 25 °C; (f) NaBH4, MeOH, 0 °C; (g) LiOH aq.,
dioxane, reflux; (h) 41 (10 mol %), Oxone®, CF3CH2OH/H2O, 25
°C; (i) LiAlH4, THF, 025 °C; (j) Tf2O, pyridine, CH2Cl2, 025
°C; (k) [Pd2dba3•CHCl3] (2.5 mol %), XPhos (5 mol%),
General Methods. All reactions involving air-sensitive
material were carried out in pre-dried glassware under an argon
atmosphere by using Schlenk techniques employing double-line
argon-vacuum lines and working in an argon-filled glove box.
An oil bath was used as heating source unless otherwise noted.
Analytical thin layer chromatography (TLC) was performed
using pre-coated Merck silica gel 60 F254 plates (0.25 mm).
Visualization of the developed chromatogram was performed
by UV absorbance (254 nm) or TLC stains (KMnO4 and
Phosphomolybdic acid). Flash chromatography was performed
using Silicycle SiliaFlash P60 (230-400 mesh) with the
indicated solvent system, using gradients of increasing polarity
in most cases. Anhydrous solvents were purchased from Acros
Organics or Sigma-Aldrich. The solvents were degassed by
three cycles of freeze-pump-thaw and storing in single-necked
flasks equipped with a JYoung PTFE valve when necessary.
Palladium complexes were purchased from Sigma-Aldrich or
Strem. All other chemical reagents were purchased from
Sigma-Aldrich, Acros Organics, Alfa Aesar, Apollo scientific
and Fluorochem and used as received without further
purification unless otherwise stated. GCMS analyses were
performed with a Shimadzu QP2010SB GCMS apparatus on a
Rtx®-5ms-LowBleed column lined with a mass (EI) detection
system. HPLC analyses was performed using a Shimadzu
Prominence system with SIL-20A auto sample, CTO-20AC
column oven, LC-20AD pump system, DGU20A3 degasser and
SPD-M20A Diode Array or UV/VIS detector. The following
DABCO•2AlMe3,
THF,
reflux.
DABCO
=
1,4-
diazabicyclo[2.2.2]octane; XPhos = 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl.
Enantioselective synthesis. After having completed the
racemic syntheses, we directed our efforts towards the
development of enantioselective versions. Investigations of the
asymmetric C(sp3)–H activation of the model aryl bromide 15
(see Table 1), which were detailed earlier,13 led us to opt for a
chiral substrate/chiral ligand combination. We prepared the L-
proline amide 43 in 84% yield via saponification and amide
formation under Schotten-Baumann conditions (Scheme 8).
This substrate was engaged in the asymmetric C(sp3)–H
activation using ligand L3, a chiral bulky NHC developed by
Kündig and co-workers,27 which furnished indane 44 in 87%
yield and 85:15 diastereomeric ratio. Then, the proline and
methoxy groups were cleaved with hydrobromic acid to provide
the corresponding phenol-carboxylic acid 45 in 92% yield.
After significant experimentation, we found that this
intermediate slowly recrystallized in a mixture of chloroform
and cyclohexane. The crystalline material was racemic, and the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
chiral columns from Daicel Chemical Industries were used: OJ-
H (Chiralcel®), IA (Chiralpak®) in 4.6 x 250 mm size. Melting
Scheme 8. Divergent Synthesis of (S)-Puraquinonic Acid, (S)-Deliquinone, and (S)-Russujaponola
points were obtained on a Büchi melting point M-565, and are
uncorrected.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reagents and conditions: (a) LiOH aq., THF/MeOH, 80 °C; (b) (COCl)2, DMF cat., CH2Cl2, 25 °C, then L-Pro-OiPr; (c) [Pd(-
cinnamyl)Cl]2 (5 mol %), L3 (10 mol %), CsOPiv, Cs2CO3, mesitylene, 160 °C; (d) HBr aq., AcOH, reflux, then recrystallization
from CHCl3/C6H12 3:1; (e) KHCO3, MeI, DMF, 40 °C, then NaH, allyl bromide; (f) PhNEt2, 200 °C; (g) OsO4 (5 mol %), NaIO4,
AcOEt/H2O, 25 °C; (h) NaBH4, MeOH, 0 °C; (i) LiOH aq., dioxane, reflux; (j) 41 (10 mol %), Oxone®, CF3CH2OH/H2O, 25 °C; (k)
LiAlH4, THF, 025 °C; (l) Tf2O, pyridine, CH2Cl2, 025 °C; (m) [Pd2dba3•CHCl3] (2.5 mol %), XPhos (5 mol %), DABCO•2AlMe3,
THF, reflux. b Measured by HPLC on a chiral stationary phase using the racemic compound as reference.
IR spectra were recorded on an ATR Varian Scimitar 800 and
are reported in reciprocal centimeters (cm-1). Nuclear magnetic
resonance spectra were recorded on a Bruker Advance 400 (400
MHz), Advance 500 (500 MHz) and Advance 600 (600 MHz)
in deuterated chloroform (residual peaks 1H δ 7.26 ppm, 13C δ
77.16 ppm) unless otherwise noted. 19F NMR spectra were
referenced to external CFCl3. Data are reported in parts per
million (ppm) as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet,
sept = septuplet, m = multiplet and brs = broad singlet),
coupling constant in Hz and integration. High resolution mass
spectra were recorded by Dr. H. Nadig, Dr. M. Pfeffer and S.
Mittelheisser (Department of Chemistry, University of Basel)
on a Bruker maXis 4G QTOF ESI mass spectrometer. Optical
rotations were measured on a Perkin Elmer 341 Polarimeter in
a 1 mL micro cuvette (cell length 100mm) with NaD-Line (λ =
589 nm). The concentration (c) was given in g/100 mL.
3-Bromo-2-methylphenol (25).13,16 Freshly distillated 3-
bromo-2-methylaniline (70 g, 376 mmol) was added to an
aqueous 1M solution of sulfuric acid (451 mL, 451 mmol) at 0°
C under vigorous stirring (formation of a white suspension of
anilinium). Then a saturated solution of sodium nitrite (31.1 g,
451 mmol) in water was added dropwise at -5°C. After stirring
at -5° C for 20 min (most of the solid is dissolve at this point),
concentrated sulfuric acid (14 mL, 258 mmol) was added and
the solution was heated at 100°C for 1 h. The mixture was then
diluted with water, extracted with Et2O, dried and concentrated
to yield a black slurry. The residue was purified by sublimation
under vacuum (0.1 mbar), and the obtained orange solid was
recrystallize with cyclohexane to yield 25 as a white crystalline
solid (32 g, 171 mmol, 46 % yield): Rf 0.25 (85:15 PE/AcOEt);
mp 96-98 °C; 1H NMR (500 MHz, CDCl3) δ 7.14 (dd, J = 8.0,
1.1 Hz, 1H), 6.92 (td, J = 8.0, 0.5 Hz, 1H), 6.71 (ddd, J = 8.0,
1.1, 0.5 Hz, 1H), 4.87 (s, 1H), 2.34 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 154.5, 127.6, 126.2, 125.1, 124.6, 114.2, 15.7;
IR νmax/cm-1 (neat) 3283, 1435, 1241, 998, 762 cm-1; GCMS (EI)
m/z [M]+• calcd for C7H779BrO 186, found 186.
Methyl
3-(2-bromo-6-methoxyphenyl)-2,2-
dimethylpropanoate (15).13 3-bromo-2-methylphenol (25)
(17.8 g, 95 mmol) was dissolved in DMF (240 mL) and K2CO3
(39.4 g, 285 mmol, 3 equiv) was added, the mixture was then
stirred during 5 min at room temperature. After this period,
methyl iodide (29.6 mL, 475 mmol, 5 equiv) was added in one
portion and the reaction was stirred at 50°C during 2h. The
reaction was then diluted with water, extracted with EtOAc and
concentrated to yield the corresponding anisole which was used
in the next step without further purification. This anisole was
mixed with N-bromosuccinimide (17.75 g, 100 mmol, 1.05
equiv) and benzoyl peroxide (75%) (1.23 g, 3.8 mmol, 4 mol%)
in CCl4 (190 mL) and was heated to reflux and stirred overnight.
The reaction mixture was then cooled to room temperature and
filtered. The filtrate was diluted with DCM and washed
successively with 2M NaOH, water and brine. The organic layer
was dried over MgSO4, filtered and concentrated under reduced
pressure to give the corresponding benzyl bromide which was
used in the next step without further purification. A solution of
LDA (100 mmol, 1.05 equiv) in THF (190 mL) was prepared
from diisopropylamine (14 mL, 100 mmol, 1.05 equiv) and 2.5
n
M BuLi in hexane (40 mL, 100 mmol, 1.05 equiv), stirred at
0°C during 15 min. To the LDA solution, methyl isobutyrate
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
(10.9 mL, 95 mmol, 1 equiv) was added dropwise at 0°C and mmol, 1 equiv) in THF (8 mL) was added slowly to the solution
1
2
3
4
5
6
7
8
the mixture was stirred at the same temperature for 45 min. The
Benzyl bromide, obtained previously, in THF (95 mL) was
added slowly to the solution always at 0°C. The mixture was
stirred for 16 h with the ice bath warming to room temperature.
Water was then add to the reaction at 0°C. The mixture was
extracted three times with Et2O, the combined organic layers
were washed with brine. The organic layer was dried over
MgSO4, filtered, concentrated under vacuum purified by
column chromatography (Cy/AcOEt: 95/5 to 90/10) to yield 15
as a colorless oil (21.4 g, 71 mmol, 75% over 3 steps) that
solidified upon standing: Rf 0.22 (90:10 PE/AcOEt); mp 42-44
always at 0°C. The mixture was stirred for 16 h with the ice bath
warming to room temperature. Water was then add to the
reaction at 0°C. The mixture was extracted three times with
Et2O, the combined organic layers were washed with brine. The
organic layer was dried over MgSO4, filtered, concentrated
under vacuum purified by column chromatography (Cy/AcOEt:
95/5 to 90/10) to yield 28 (1.97 g, 7.26 mmol, 91%) as a
1
colorless oil: Rf 0.35 (90:10 PE/AcOEt); H NMR (500 MHz,
CDCl3) δ 7.54 (dd, J = 8.0, 1.3 Hz, 1H), 7.20 (td, J = 7.5, 1.3
Hz, 1H), 7.13 (dd, J = 7.8, 1.8 Hz, 1H), 7.06 (ddd, J = 7.9, 7.2,
1.8 Hz, 1H), 3.69 (s, 3H), 3.12 (s, 2H), 1.24 (s, 6H); 13C{1H}
NMR (126 MHz, CDCl3) δ 178.0, 137.9, 133.2, 131.5, 128.2,
127.2, 126.2, 52.0, 44.4, 44.4, 25.1; IR νmax/cm-1 (neat) 2977,
2950, 1728, 1469, 1192, 1134, 1024, 749 cm-1; HRMS (ESI)
m/z [M+Na]+ calcd for C13H1779BrNaO3 323.0253, found
323.0257.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
°C; H NMR (500 MHz, CDCl3) δ 7.16 (dd, J = 8.1, 1.1 Hz,
1H), 7.04 (t, J = 8.1 Hz, 1H), 6.76 (dd, J = 8.1, 1.1 Hz, 1H),
3.74 (s, 3H), 3.67 (s, 3H), 3.18 (s, 2H), 1.21 (s, 6H); 13C{1H}
NMR (126 MHz, CDCl3) δ 178.3, 159.1, 128.4, 127.4, 127.3,
125.2, 109.3, 55.6, 51.8, 43.4, 39.3, 25.6; IR νmax/cm-1 (neat)
2980, 1716, 1265, 1146, 1029, 771 cm-1; HRMS (ESI) m/z
[M+Na]+ calcd for C13H1779BrNaO3 323.0253, found 323.0251.
Methyl 4-methoxy-2-methyl-2,3-dihydro-1H-indene-2-
carboxylate (14).13 In an oven dry Schlenk tube, 15 (1.36 g, 4.5
mmol) was introduced. Then the Schlenk tube was tranfer in
glovebox and [Pd(π-cin)Cl]2 (117 mg, 0.23 mmol, 5 mol%), L2
(161 mg, 0.45 mmol, 10 mol%), cesium pivalate (1.05 g, 4.5
mmol, 1 equiv) and cesium carbonate (2.20 g, 6.75 mmol, 1.5
equiv) were introduced and the tube was close with a septum.
Outside of the glovebox, mesitylene (45 mL) was added. The
reaction was stirred at room temperature for 10 min. The tube
was then introduced in a 160°C preheated oil bath and stirred at
this temperature for 18 hours. After this period the reaction was
cooled to room temperature, filtered over a pad of celite
(washed with DCM). The crude material was analyzed by GC-
MS and then concentrated and purified by flash column
chromatography (Cy/AcOEt: 95/5 to 90/10) to yield the
corresponding indane 14 (915 mg, 4.15 mmol, 92%) as a
Methyl
dimethylpropanoate
3-(2-bromo-3-methoxyphenyl)-2,2-
(16). 2-Bromo-1-methoxy-3-
methylbenzene (26) (1.16 g, 5.77 mmol) was mixed with N-
bromosuccinimide (1.08 g, 6.06 mmol, 1.05 equiv) and benzoyl
peroxide (75%) (75 mg, 0.23 mmol, 4 mol%) in CCl4 (13 mL)
and was heated to reflux and stirred overnight. The reaction
mixture was then cooled to room temperature and filtered. The
filtrate was diluted with DCM and washed successively with
2M NaOH, water and brine. The organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure to
give the corresponding benzyl bromide which was used in the
next step without further purification. A solution of LDA (6.06
mmol, 1.05 equiv) in THF (12 mL) was prepared from
diisopropylamine (0.85 mL, 6.06 mmol, 1.05 equiv) and 2.5 M
nBuLi in hexane (2.43 mL, 6.06 mmol, 1.05 equiv), stirred at
0°C during 15 min. To the LDA solution, methyl isobutyrate
(0.66 mL, 5.77 mmol, 1 equiv) was added dropwise at 0°C and
the mixture was stirred at the same temperature for 45 min. The
Benzyl bromide, obtained previously, in THF (6 mL) was added
slowly to the solution always at 0°C. The mixture was stirred
for 16 h with the ice bath warming to room temperature. Water
was then add to the reaction at 0°C. The mixture was extracted
three times with Et2O, the combined organic layers were
washed with brine. The organic layer was dried over MgSO4,
filtered, concentrated under vacuum purified by column
chromatography (Cy/AcOEt: 95/5 to 90/10) to yield 16 (1.35 g,
4.48 mmol, 78%) as a colorless oil: Rf 0.24 (90:10 PE/AcOEt);
1H NMR (500 MHz, CDCl3) δ 7.16 (t, J = 7.9 Hz, 1H), 6.79-
6.72 (m, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 3.18 (s, 3H), 1.23 (s,
6H); 13C{1H} NMR (126 MHz, CDCl3) δ 178.1, 156.2, 139.8,
127.4, 123.5, 115.9, 110.0, 77.4, 77.2, 76.9, 56.5, 52.0, 44.5,
44.4, 25.2; IR νmax/cm-1 (neat) 2974, 2948, 1728, 1468, 1431,
1029, 1264, 1127, 1068, 780 cm-1; HRMS (ESI) m/z [M+Na]+
calcd for C13H1779BrNaO3 323.0253, found 323.0257.
1
yellowish oil: Rf 0.21 (95:5 PE/AcOEt); H NMR (500 MHz,
CDCl3) δ 7.15 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.68
(d, J = 7.8 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.50 (d, J = 16.0
Hz, 1H), 3.39 (d, J = 16.4 Hz, 1H), 2.84 (d, J = 16.4 Hz, 1H),
2.82 (d, J = 16.0 Hz, 1H), 1.37 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 178.3, 156.3, 143.3, 128.9, 128.2, 117.1, 108.2,
55.3, 52.2, 49.4, 44.5, 41.0, 25.6; IR νmax/cm-1 (neat) 2950,
1730, 1590, 1261, 1075, 766 cm-1; HRMS (ESI) m/z [M+Na]+
calcd for C13H16NaO3 243.0992, found 243.0990.
Methyl 4-(allyloxy)-2-methyl-2,3-dihydro-1H-indene-2-
carboxylate (30). 14 (911 mg, 4.14 mmol) was dissolved in
glacial acetic acid (11 mL) and 48% aqueous hydrobromic acid
(54 mL). The reaction mixture was refluxed for 2 hours. After
this period, the reaction was diluted with water and extracted
with DCM. The organic layer was dried over MgSO4 and
concentrated under vacuum. Two portions of toluene were
added and evaporated to remove excess of AcOH. The crude
product was then diluted in DMF (6 mL) and KHCO3 (1.12 g,
12.42 mmol, 3 equiv) was added. The suspension was stirred 10
minutes at room temperature and then, methyl iodide (0.77 mL,
12.42 mmol, 3 equiv) was added. The mixture was stirred at
40°C until total consumption of starting material
Methyl
3-(2-bromophenyl)-2,2-dimethylpropanoate
(28).13 A solution of LDA (8.4 mmol, 1.05 equiv) in THF (17
mL) was prepared from diisopropylamine (1.18 mL, 8.4 mmol,
1.05 equiv) and 2.5 M nBuLi in hexane (3.36 mL,8.4 mmol, 1.05
equiv), stirred at 0°C during 15 min. To the LDA solution,
methyl isobutyrate (0.92 mL, 8 mmol, 1 equiv) was added
dropwise at 0°C and the mixture was stirred at the same
temperature for 45 min. Then 2-bromobenzyl bromide (2 g, 8
(approximatively
3 hours). To remove the excess of
iodomethane, the reaction was heated to 65°C under a flow of
argon for 15 min. After this period, the temperature was
lowered to 40°C then NaH (300 mg, 12.42 mmol, 3 equiv) and
allyl bromide (1.07 mL, 12.42 mmol, 3 equiv.) were added
successively carefully. The reaction mixture was stirred for 30
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
min and then cooled with an ice bath, and then water was added.
Page 8 of 14
(neat) 3416, 3296, 2933, 1710, 1437, 1283, 1214, 1114, 1039,
809 cm-1; HRMS (ESI) m/z [M+Na]+ calcd for C14H18NaO4
1
2
3
4
5
6
7
8
The reaction was extracted three times with DCM. The
combined organic phases were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography (Cy/AcOEt: 90/10)
leading to 30 as a light yellow oil (835 mg, 3.39 mmol, 82%
over 2 steps): Rf 0.33 (90:10 PE/AcOEt); 1H NMR (400 MHz,
CDCl3) δ 7.12 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.67
(d, J = 8.1 Hz, 1H), 6.06 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.42
(dq, J = 17.3, 1.6 Hz, 1H), 5.27 (dq, J = 10.4, 1.6 Hz, 1H), 4.54
(dt, J = 5.1, 1.6 Hz, 2H), 3.72 (s, 3H), 3.51 (d, J = 16.0 Hz, 1H),
3.42 (d, J = 16.4 Hz, 1H), 2.89 (d, J = 16.4 Hz, 1H), 2.82 (d, J
= 16.0 Hz, 1H), 1.38 (s, 3H); 13C{1H} NMR (63 MHz, CDCl3)
δ 178.3, 155.3, 143.4, 133.6, 129.3, 128.1, 117.3, 117.2, 109.5,
68.7, 52.2, 49.4, 44.5, 41.1, 25.6; IR νmax/cm-1 (neat) 2950,
1730, 1590, 1480, 1262, 1112, 1061, 767 cm-1; HRMS (ESI)
m/z [M+Na]+ calcd for C15H18NaO3 269.1148, found 269.1151.
273.1097, found 273.1098.
Methyl 5-(2-hydroxyethyl)-2-methyl-4,7-dioxo-2,3,4,7-
tetrahydro-1H-indene-2-carboxylate (32). In a round bottom
flask, 31a (385 mg, 1.54 mmol) and Salcomine (202 mg, 0.62
mmol, 40 mol%) were mixed in acetonitrile (20 mL). Oxygen
was bubbled through the stirred suspension during 5 minutes.
Then the reaction was stirred under oxygen atmosphere during
24h. After this period, acetonitrile was removed under reduced
pressure and the crude was purified by flash chromatography
(Cy/AcOEt: 50/50) leading to 32 (280 mg, 1.06 mmol, 69 %) as
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
a yellow oil: Rf 0.23 (50:50 PE/AcOEt); H NMR (600 MHz,
CDCl3) δ 6.58 (t, J = 1.2 Hz, 1H), 3.82 (t, J = 5.5 Hz, 2H), 3.72
(s, 3H), 3.38-3.31 (m, 2H), 2.74-2.69 (m, 2H), 2.68 (tt, J = 6.0,
1.0 Hz, 2H), 1.74 (brs, 1H), 1.39 (s, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 186.3, 185.9, 177.0, 146.6, 146.2, 146.0, 134.5,
61.2, 52.6, 47.3, 42.5, 42.2, 32.6, 26.1; IR νmax/cm-1 (neat) 3492,
3447, 2955, 1729, 1650, 1268, 1211, 1039, 851 cm-1; HRMS
(ESI) m/z [M+Na]+ calcd for C14H16NaO5 287.0890, found
287.0886.
Methyl
5-allyl-4-hydroxy-2-methyl-2,3-dihydro-1H-
indene-2-carboxylate (31). A sealed tube charged with 30 (409
mg, 1.66 mmol) and N,N-diethylaniline (3 mL) was heated
under stirring at 200°C for 24 h. After this period, the reaction
was poured into 1M HCl and extracted three times with DCM.
The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude material
was purified by flash chromatography (Cy/AcOEt: 90/10)
leading to 31 (368 mg, 1.49 mmol, 90%) as a yellow oil: Rf 0.20
(85:15 PE/AcOEt); 1H NMR (400 MHz, CDCl3) δ 6.93 (d, J =
7.5 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.01 (ddt, J = 16.5, 10.0,
6.4 Hz, 1H), 5.21-5.10 (m, 2H), 4.99 (brs, 1H), 3.72 (s, 3H),
3.47 (d, J = 16.0 Hz, 1H), 3.42-3.35 (m, 3H), 2.80 (d, J = 16.0
Hz, 1H), 2.80 (d, J = 15.9 Hz, 1H), 1.38 (s, 3H); 13C{1H} NMR
(63 MHz, CDCl3) δ 178.4, 150.8, 141.8, 137.0, 129.2, 127.3,
123.3, 116.9, 116.3, 52.3, 49.9, 44.2, 40.3, 35.0, 25.5; IR
νmax/cm-1 (neat) 3460, 2952, 1712, 1445, 1284, 1209, 1114, 913
cm-1; HRMS (ESI) m/z [M+Na]+ calcd for C15H18NaO3
269.1148, found 269.1147.
Methyl
5-(2-hydroxyethyl)-2,6-dimethyl-4,7-dioxo-
2,3,4,7-tetrahydro-1H-indene-2-carboxylate (33). A solution
of 33 (90.6 mg, 0.343 mmol), acetic acid (63.0 mg, 60 μL, 3
equiv) in acetonitrile/H2O 1:1 (1 mL) was heated at 70 °C.
Subsequently, silver nitrate (17.5 mg, 0.103 mmol, 0.3 equiv)
and ammonium persulfate (102 mg, 0.446 mmol, 1.3 equiv)
were added and the reaction was stirred for 2 h. After this
period, the solution was diluted with ethyl acetate (15 mL). The
organic layer was washed with water (10 mL), dried over
MgSO4 and concentrated under vacuum. The crude was purified
by flash chromatography (Cy/AcOEt: 50/50) leading to 33 (52
mg, 0.187 mmol, 55%) as a yellow oil: Rf 0.25 (50:50
PE/AcOEt); 1H NMR (600 MHz, CDCl3) δ 3.77-3.73 (m, 1H),
3.72 (s, 3H), 3.38-3.31 (m, 2H), 2.78 (t, J = 6.5 Hz, 2H), 2.75-
2.69 (m, 2H), 2.07 (s, 3H), 1.65 (brs, 1H), 1.38 (s, 3H); 13C{1H}
NMR (151 MHz, CDCl3) δ 186.4, 185.9, 177.1, 146.0, 145.6,
142.9, 141.5, 61.7, 52.6, 47.2, 42.6, 42.6, 30.1, 26.1, 12.3; IR
νmax/cm-1 (neat) 3443, 2953, 1730, 1646, 1207, 1042, 714 cm-1;
HRMS (ESI) m/z [M+Na]+ calcd for C15H18NaO5 301.1046,
found 301.1042.
2,4,5-Tribromo-3,6-dimethylphenol (34a).13,19 Aluminium
(4.01 g, 0.15 mol, 0.45 equiv) was cautiously added in small
portions to bromine (100 mL, 1.94 mol, 5.8 equiv) cooled to
0°C, and the mixture was stirred for 20 min. A solution of 2,5-
dimethylphenol (35) (40.3 g, 330 mmol) in DCM (200 mL) was
added over 2 h, and the mixture was stirred for additional 2 h at
0°C (Caution! a copious amount of HBr is evolved in this
reaction which can be trapped by a water trap connected to an
aqueous sodium carbonate scrubber). The reaction was then
diluted at 0°C with DCM (200 mL) and water (200 mL). Then
a 5% aqueous NaHSO3 solution was added until the color of
bromine disappear. The phases were separated and the aqueous
layer was extracted twice with DCM, the combined organic
layers were dried with MgSO4, filtered and concentrated under
reduced pressure to yield 34a (115 g, 320 mmol) as a white solid
which was used in the next step without further purification: Rf
0.39 (90:10 PE/AcOEt); mp 179-182 °C; 1H NMR (400 MHz,
CDCl3) δ 5.83 (s, 1H), 2.66 (s, 3H), 2.47 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 149.9, 136.2, 128.2, 125.3, 118.4, 112.7,
Methyl
4-hydroxy-5-(2-hydroxyethyl)-2-methyl-2,3-
dihydro-1H-indene-2-carboxylate (31a). In a round bottom
flask containing a stirred biphasic solution of 31 (441 mg, 1.79
mmol) in EtOAc (20 mL) and water (12 mL) was added OsO4
(23 mg, 90.5 μmol, 5 mol%). After 5 minutes, NaIO4 (957 mg,
4.48 mmol, 2.5 equiv) was added in two portions separated by
5 min. The solution was vigorously stirred for 3 h at room
temperature. The layers were separated and the aqueous phase
was extracted twice with ethyl acetate. The combined organic
layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was diluted in MeOH (20
mL) and cooled to 0°C. After this, NaBH4 (205 mg, 5.42 mmol,
3 equiv) was added and the reaction was allowed to reach room
temperature. After 30 min, H2O was added and the reaction was
extracted three times with ethyl acetate. The combined organic
phases were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (Cy/AcOEt: 60/40) leading to 31a (389 mg,
1.55 mmol, 87%) as a light yellow oil. Rf 0.19 (70:30
PE/AcOEt); 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 7.5 Hz,
1H), 6.69 (d, J = 7.5 Hz, 1H), 4.01-3.93 (m, 2H), 3.71 (s, 3H),
3.46 (d, J = 16.0 Hz, 1H), 3.40 (d, J = 16.2 Hz, 1H), 2.89-2.83
(m, 3H), 2.79 (d, J = 16.0 Hz, 1H), 1.37 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 178.5, 152.0, 142.3, 129.9, 128.7, 124.6,
116.6, 65.1, 52.3, 49.7, 44.3, 40.9, 34.5, 25.6; IR νmax/cm-1
8
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
[M+Na]+ calcd for C19H28B79BrNaO5 449.1109, found
26.5, 19.1; IR νmax/cm-1 (neat) 3491, 1365, 1444, 1032, 654 cm-
1; HRMS (ESI) m/z [M-H]- calcd for C8H679Br3O 354.7974,
449.1098.
1
2
3
4
5
6
7
8
9
found 354.7976.
Methyl
3-(2-bromo-6-methoxy-4-methylphenyl)-2,2-
3-Bromo-2,5-dimethylphenol (34b).13,19 A suspension of
the 34a (115 g, 320 mmol) in aqueous HI (57%, 250 mL) was
heated at reflux under argon for 16 h and cooled. TBME (500
mL) was added, and at 0°C under stirring, NaHSO3 (40%, 900
mL) was added dropwise. The layers were separated and the
aqueous layer was extracted twice with TBME (300 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure to yield 34b (54.7 g, 272
mmol) nearly pure as a light brown solid which was used in the
next step without further purification: Rf 0.29 (85:15
PE/AcOEt); mp 85-88 °C; 1H NMR (400 MHz, CDCl3) δ 6.98
(s, 1H), 6.54 (s, 1H), 4.73 (s, 1H), 2.29 (s, 3H), 2.24 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 154.1, 137.8, 125.8, 125.7,
121.3, 115.1, 20.78, 15.3; IR νmax/cm-1 (neat) 3306, 2921, 1399,
1272, 1124, 1007, 814 cm-1; HRMS (ESI) m/z [M-H]- calcd for
C8H879BrO 198.9764, found 198.9765.
1-Bromo-3-methoxy-2,5-dimethylbenzene (35).13,19 34b
(54.4 g, 271 mmol) was dissolved in acetone (500 mL), then
potassium carbonate (56.0 g, 405 mmol, 1.5 equiv) and methyl
iodide (51.0 mL, 115 g, 810 mmol, 3.0 equiv) were added. The
resulting dark brown mixture was stirred under reflux for 24h,
after 12h, another equivalent of methyl iodide (16.0 mL, 270
mmol, 1.0 equiv) was added. The dark brown suspension was
concentrated carefully under reduced pressure. The residue was
diluted with diethyl ether (700 mL) and water (500 mL) and the
layers were separated. The aqueous phase was extracted twice
with diethyl ether (200 mL). The combined organic phases were
washed twice with water (200 mL), then with brine (100 mL),
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was obtained as a brown liquid
which was distilled under reduced pressure to give 35 as a
colorless liquid (53.47 g, 249 mmol, 76% over 3 steps): Rf 0.53
(95:5 PE/AcOEt); bp 54-59 °C at 0.1 mbar; 1H NMR (400 MHz,
CDCl3) δ 7.00 (s, 1H), 6.59 (s, 1H), 3.81 (s, 3H), 2.30 (s, 3H),
2.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 137.4,
125.6, 125.0, 123.8, 110.4, 55.9, 21.3, 15.4; IR νmax/cm-1 (neat)
2925, 1264, 1144, 1046, 828 cm-1; GCMS (EI) m/z [M]+• calcd
for C9H1179BrO 214, found 214.
dimethylpropanoate (36).13 From 35: 35 (3.50 g, 16.3 mmol)
was dissolved in tetrachloromethane (20mL) and N-
bromosuccinimide (3.77 g, 21.2 mmol, 1.32 equiv) was added
followed by AIBN (321 mg, 1.86 mmol, 12 mol%). The
resulting light yellow suspension was stirred under refluxed
overnight. The reaction mixture was cooled in an ice bath,
filtered and washed with a minimal amount of cold DCM. The
filtrate was concentrated under reduced pressure to give an
orange oil which was used without further purification. A
solution of LDA (25.3 mmol, 1.55 equiv) in THF (25 mL) was
prepared from freshly distillated diisopropylamine (25.3 mmol,
1.55 equiv) and 2.5 M (titrated) n-BuLi in hexane (10.1 mL,
25.3 mmol, 1.55 equiv), mixed for 15 min at 0°C. To the LDA
solution, methyl isobutyrate (24.5 mmol, 1.5 equiv) was added
dropwise at 0°C and the mixture was stirred at 0°C for 45 min.
Freshly prepared crude 3-Bromo-2- bromomethyl-5-methyl-
methoxybenzene from the previous step was diluted in THF (16
mL) and added slowly to the LDA solution at 0°C. The mixture
was slowly warmed to room temperature and stirred for 16 h.
The reaction was quenched at 0°C with water (30 mL). The
mixture was extracted three times with diethyl ether (30 mL),
the combined organic layers were washed with brine, dried over
MgSO4, filtered and then concentrated in vacuum to give the
crude ester. The crude material was purified by flash column
chromatography to yield 36 as a colorless oil, which crystallize
on standing (3.85 g, 12.2 mmol, 75% yield over 2 steps). From
15a: in an oven dry Schlenk tube, 15a (1.28 g, 3 mmol) was
introduced. Then, this Schlenk tube was transfer in glovebox
and CuI (57 mg, 0.3 mmol, 10 mol%), LiI (80 mg, 0.6 mmol,
20 mol%) and tBuOLi (480 mg, 6 mmol, 2 equiv) were added.
The tube was closed with a septum and transferred outside of
the glovebox. The reaction was diluted with DMI (4.5 mL) and
trimethyl phosphate (0.73 mL, 6 mmol, 2 equiv) was added. The
mixture was heated at 50 °C during 16h. The reaction was
quenched by H2O, extracted by toluene. The organic layer was
condensed, and the residue was purified by flash column
chromatography to yield 36 as a colorless oil, which crystallized
on standing (3.85 g, 12.2 mmol, 75% yield over 2 steps): Rf 0.26
(90:10 PE/AcOEt); mp 63-65 °C; 1H NMR (400 MHz, CDCl3)
δ 7.00 (s, 1H), 6.57 (s, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.13 (s,
2H), 2.29 (s, 3H), 1.20 (s, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 178.4, 158.8, 138.6, 126.9, 125.6, 124.2, 110.4, 55.5,
51.8, 43.4, 39.0, 25.6, 21.3; IR νmax/cm-1 (neat) 2968, 1719,
1266, 1148, 1042, 822 cm-1; HRMS (ESI) m/z [M+Na]+ calcd
for C14H1979BrNaO3 337.0410, found 337.0413.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
3-(2-bromo-6-methoxy-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethylpropanoate
(15a). In an oven dry Schlenk tube, 15 (1.0 g, 3.32 mmol), 4,4’-
di-tert-butyl-2,2’-dipyridyl (22.3 mg, 83 μmol, 2.5 mol%) and
Bis(pinacolato)diboron (843 mg, 3.32 mmol, 1 equiv) were
charged. Then, this Schlenk tube was transfer in glovebox and
[Ir(COD)OMe]2 (27.5 mg, 41.5 μmol, 1.25 mol%) was added.
The tube was closed with a septum and transferred outside of
the glovebox. The reaction was diluted with THF (10 mL) and
heat at 50 °C during 48h. Afterward, THF was removed under
vacuum, and the crude was purified by column chromatography
to yield 15a as a white solid (1.38 g, 3.23 mmol, 97% yield): Rf
Methyl 4-methoxy-2,6-dimethyl-2,3-dihydro-1H-indene-
2-carboxylate (39).13 In an oven dry catalysis tube, 36 (506 mg,
1.15 mmol) was introduced. Then the tube was transferred in
glovebox and [Pd(π-cin)Cl]2 (29.8 mg, 57.5 μmol, 5 mol%), L2
(67.7 mg, 115 μmol, 10 mol%), cesium pivalate (269 mg, 1.15
mmol, 1 equiv) and cesium carbonate (562 mg, 1.72 mmol, 1.5
equiv) were introduced and the tube was close with a septum.
Outside of the glovebox, mesitylene (6 mL) was added. The
reaction was stirred at room temperature for 10 min, then, under
pressure of argon, the septum was rapidly exchange for a screw
cap. The tube was then introduced in a 160°C preheated
aluminium heating block and stirred at this temperature for 18
hours. After this period the reaction was cooled to room
1
0.3 (80:20 PE/AcOEt); mp 81-84 °C; H NMR (500 MHz,
CDCl3) δ 7.61 (s, 1H), 7.14 (s, 1H), 3.78 (s, 3H), 3.66 (s, 3H),
3.20 (s, 2H), 1.34 (s, 12H), 1.20 (s, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 178.2, 158.6, 131.5, 130.5, 127.2, 114.6, 84.3,
55.7, 51.9, 43.5, 39.5, 25.6, 25.0; IR νmax/cm-1 (neat) 2977,
1720, 1350, 1141, 1046, 853, 694 cm-1; HRMS (ESI) m/z
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
temperature, diluted with DCM (6 mL), filtered over a pad of Isopropyl ((S)-4-methoxy-2,6-dimethyl-2,3-dihydro-1H-
indene-2-carbonyl)-L-prolinate (44).13 In an oven dry
catalysis tube, 43 (506 mg, 1.15 mmol) was introduced. Then
the tube was tranfer in glovebox and [Pd(π-cin)Cl]2 (29.8 mg,
57.5 μmol, 5 mol%), L3 (67.7 mg, 115 μmol, 10 mol%), cesium
pivalate (269 mg, 1.15 mmol, 1 equiv) and cesium carbonate
(562 mg, 1.72 mmol, 1.5 equiv) were introduced and the tube
was close with a septum. Outside of the glovebox, mesitylene
(6 mL) was added. The reaction was stirred at room temperature
for 10 min, then, under pressure of argon, the septum was
rapidly exchange for a screw cap. The tube was then introduced
in a 160°C preheated aluminium heating block and stirred at this
temperature for 18 hours. After this period the reaction was
cooled to room temperature, diluted with DCM (6 mL), filtered
over a pad of celite (washed three times with 6 mL of DCM).
The crude material was analyzed by GC-MS, then concentrated
and purified by flash column chromatography to yield 44 as a
wax (361 mg, 1.00 mmol, 87%): Rf 0.29 (70:30 PE/AcOEt); 1H
NMR (500 MHz, CDCl3) δ 6.64 (s, 1H), 6.50 (s, 1H), 5.02 (sept,
J = 6.2 Hz, 1H), 4.48 (dd, J = 8.6, 4.8 Hz, 1H), 3.79 (s, 3H),
3.78-3.59 (m, 2H), 3.56 (d, J = 16.3 Hz, 1H), 3.33 (d, J = 16.2
Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H), 2.80 (d, J = 16.3 Hz, 1H),
2.33 (s, 3H), 2.21-2.10 (m, 1H), 2.09-2.00 (m, 1H), 1.97-1.81
(m, 2H), 1.34 (s, 3H), 1.25 (d, J = 6.2 Hz, 3H), 1.19 (d, J = 6.2
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.9, 172.2,
156.1, 143.1, 138.2, 125.6, 117.7, 109.2, 68.2, 60.9, 55.2, 49.7,
47.7, 44.7, 40.4, 28.3, 25.9, 25.4, 21.9, 21.8, 21.8; IR νmax/cm-1
(neat) 2976, 1736, 1626, 1400, 1185, 1108, 1085, 830 cm-1;
HRMS (ESI) m/z [M+Na]+ calcd for C21H29NNaO4 382.1989,
found 382.1994; HPLC separation: with L2 Chiralpak® IA; 95:5
(n-heptane/i-PrOH), 1.0 ml.min-1, 205 nm, tR (major) = 12.8
min, tR (minor) = 22.2 min, 66:34 d.r., with L3 Chiralpak® IA;
95:5 (n-heptane/i-PrOH), 1.0 ml.min-1, 205 nm, tR (major) =
12.8 min, tR (minor) = 21.7 min, 85:15 d.r.
1
2
3
4
5
6
7
8
celite (washed three times with 6 mL of DCM). The crude
material was analyzed by GC-MS, then concentrated and
purified by flash column chromatography to yield 39 as a
yellowish liquid (361 mg, 1.00 mmol, 87%): Rf 0.38 (95:5
1
PE/AcOEt); H NMR (500 MHz, CDCl3) δ 6.64 (s, 1H), 6.50
(s, 1H), 3.80 (s, 7H), 3.71 (s, 6H), 3.45 (d, J = 16.0 Hz, 3H),
3.33 (d, J = 16.1 Hz, 3H), 2.79 (d, J = 16.1 Hz, 3H), 2.76 (d, J
= 16.0 Hz, 3H), 2.33 (s, 8H), 1.36 (s, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 178.4, 156.0, 143.3, 138.3, 125.9, 117.7, 109.4,
77.4, 77.2, 76.9, 55.3, 52.2, 49.5, 44.4, 40.8, 25.6, 21.8; IR
νmax/cm-1 (neat) 2950, 2843, 1730, 1593, 1461, 1317, 1199,
1111, 1083, 829 cm-1; HRMS (ESI) m/z [M+Na]+ calcd for
C14H18NaO3 257.1154, found 257.1148.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2-Bromo-6-methoxy-4-methylphenyl)-2,2-
dimethylpropanoic acid (36a).13 36 (3.5 g, 11.1 mmol) was
dissolved in a mixture THF (20 mL), MeOH (20 mL) and 2M
aqueous LiOH (20 ml). The reaction was then heat at 80°C for
6 hours. After cooling to room temperature, the organic solvents
were removed under reduced pressure. The obtained aqueous
solution was washed with diethyl ether, acidified to pH<0 and
extracted three times with DCM. The combined organic layers
were then dry over MgSO4, filtered and concentrated under
reduced pressure to yield 36a as a yellow solid, which was
engaged in the next step without further purifications: Rf 0.3
(70:30 PE/AcOEt); mp 100-103 °C; 1H NMR (400 MHz,
CDCl3) δ 7.01 (s, 1H), 6.57 (s, 1H), 3.69 (s, 3H), 3.19 (s, 2H),
2.29 (s, 3H), 1.22 (s, 6H); 13C{1H} NMR (63 MHz, CDCl3) δ
184.9, 158.8, 138.7, 126.9, 125.6, 123.8, 110.4, 54.9, 43.2, 39.1,
25.2, 21.3; IR νmax/cm-1 (neat) 2974, 2939, 1691, 1271, 1159,
1045, 830 cm-1; HRMS (ESI) m/z [M+Na]+ calcd for
C13H1779BrNaO3 323.0253, found 323.0259.
Isopropyl (3-(2-bromo-6-methoxy-4-methylphenyl)-2,2-
dimethylpropanoyl)-L-prolinate (43).13 36a from previous
step was dissolved in dry DCM (90 mL), and then oxalyl
chloride (1.05 mL, 12.2 mmol, 1.1 equiv) was added, follow by
few drops of DMF to initiate the reaction. After 1 hour of
stirring at room temperature, the reaction was cooled to 0°C and
H-L-Pro-OiPr•HCl (6.45 g, 33.3 mmol, 3 equiv) and 1M
aqueous NaOH (110 mL, 110 mmol, 10 equiv) were added in
one portion. The mixture was vigorously stirred for 16 hours
with the ice bath warming to room temperature. The organic
layer was then separated, washed with 2M HCl, dried over
MgSO4, filtered and concentrated under reduced pressure.
Crude material was then purified by flash column
chromatography to yield 43 as a colorless wax, which
crystallized on standing (4.25 g, 9.66 mmol, 87%): Rf 0.24
(70:30 PE/AcOEt); mp 75-79 °C; 1H NMR (500 MHz, CDCl3)
δ 6.99 (s, 1H), 6.58 (s, 1H), 5.02 (sept, J = 6.3 Hz, 1H), 4.51-
4.42 (m, 1H), 3.87-3.67 (m, 2H), 3.73 (s, 3H), 3.21 (d, J = 13.6
Hz, 1H), 3.13 (d, J = 13.6 Hz, 1H), 2.28 (s, 3H), 2.20-2.09 (m,
1H), 2.09-1.97 (m, 1H), 1.95-1.76 (m, 2H), 1.29 (s, 3H), 1.25
(d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.17 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 176.4, 172.5, 158.9, 138.6,
126.9, 125.7, 124.2, 110.5, 68.1, 61.6, 55.5, 48.5, 44.1, 36.5,
28.0, 26.4, 26.0, 25.4, 21.9, 21.8, 21.2; IR νmax/cm-1 (neat) 2977,
2932, 1741, 1615, 1400, 1161, 1040, 833 cm-1; HRMS (ESI)
m/z [M+Na]+ calcd for C21H3079BrNNaO4 462.1250, found
462.1257; [α]23 -39.4° (c = 1.00, CHCl3).
(S)-4-Hydroxy-2,6-dimethyl-2,3-dihydro-1H-indene-2-
carboxylic acid (45).13 To 44 (931 mg, 2.59 mmol) was added
glacial acetic acid (8 mL) and 48% aqueous hydrobromic acid
(40 mL). The reaction mixture was refluxed for 2 hours. After
this period, the reaction was diluted with water (50 mL) and
extracted with DCM (3 x 50 mL). The combined organic layers
were dried over MgSO4, filtered and concentrated under
reduced pressure. Two portions of toluene (10 mL) were added
and evaporated to remove the last traces of AcOH. The crude
material was purified by flash chromatography using
cyclohexane/EtOAc (6:4) affording 45 (491 mg, 2.38 mmol,
92%) as a light yellow solid. Then the product was
enantioenriched by recrystallization as follow: the purified
product was solubilized under heating in a mixture of CHCl3
and cyclohexane (3:1) (proportion 40 mg/mL). The solution
was then stored at room temperature for 4 days for
crystallization. After separation, nearly racemic crystals (187
mg, 0.908 mmol, 35%) and concentrated enantioenriched
mother liquor (304 mg, 1.47 mmol, 57%) were engaged in the
next step to measure the enantiomeric ratio by HPLC using a
chiral stationary phase. Racemic material was prepared using
the same procedure from racemic 39 (890 mg, 3.80 mmol),
glacial acetic acid (12 mL) and 48% aqueous hydrobromic acid
(58 mL) to yield racemic 45 (682 mg, 3.31 mmol, 87%): Rf 0.25
1
(60:40 PE/AcOEt); H NMR (500 MHz, DMSO-d6) δ 12.24
(brs, 1H), 9.03 (brs, 1H), 6.45 (s, 1H), 6.39 (s, 1H), 3.27 (d, J =
16.3 Hz, 1H), 3.16 (d, J = 16.3 Hz, 1H), 2.60 (d, J = 16.3 Hz,
10
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
1H), 2.63 (d, J = 16.3 Hz, 1H), 2.16 (s, 3H), 1.25 (s, 3H);
= 15.6 Hz, 1H), 2.26 (s, 3H), 1.38 (s, 3H); 13C{1H} NMR (126
13C{1H} NMR (126 MHz, DMSO-d6) δ 178.7, 153.3, 143.2,
136.9, 123.9, 116.0, 113.7, 48.8, 43.8, 40.2, 25.1, 21.0; IR
νmax/cm-1 (neat) 3282, 2924, 1696, 1306, 1121, 835 cm-1; HRMS
(ESI) m/z [M+Na]+ calcd for C12H14NaO3 229.0835, found
229.0838; [α]23 + 6.9° (c = 0.57, CHCl3).
MHz, CDCl3) δ 178.2, 150.6, 1401.0, 136.8, 136.0, 124.6,
121.6, 118.9, 115.5, 52.3, 49.8, 44.3, 40.3, 30.8, 25.6, 20.0; IR
νmax/cm-1 (neat) 3464, 2929, 1712, 1195, 1113, 909 cm-1; HRMS
(ESI) m/z [M+Na]+ calcd for C16H20NaO3 283.1305, found
283.1308; HPLC separation: Chiralpak® IA; 97:3 (n-heptane/i-
PrOH), 1.0 ml.min-1, 208 nm, tR (minor) = 14.6 min, tR (major)
= 16.8 min, 96:4 e.r.; [α]23 + 10.8° (c = 1.00, CHCl3).
1
2
3
4
5
6
7
8
Methyl
(S)-4-(allyloxy)-2,6-dimethyl-2,3-dihydro-1H-
indene-2-carboxylate (45a).13 45 (304 mg, 1.47 mmol) was
dissolved in DMF (12 mL) and KHCO3 (442 g, 4.41 mmol, 3
equiv) was added. The suspension was stirred for 10 minutes at
room temperature, and then iodomethane (0.28 mL, 4.41 mmol,
3 equiv) was added. The mixture was stirred at 40°C until total
consumption of starting material (approximatively 3 hours). To
remove the excess of iodomethane, the reaction was heated to
65°C under a flow of argon for 15 min. After this period, the
temperature was lowered to 40°C then NaH (106 mg, 4.41
mmol, 3 equiv) and allyl bromide (0.40 mL, 4.41 mmol, 3
equiv.) were added successively carefully. The reaction mixture
was stirred for 30 min and then cooled with an ice bath, and
then water (30 mL) was added. The reaction was extracted three
times with DCM (15 mL); the combined organic phases were
dried over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash column
chromatography using cyclohexane/EtOAc (9:1) leading to 45a
as a light yellow oil (315 mg, 1.21 mmol, 82%). Racemic
material was prepared using the same procedure from racemic
45 (650 mg, 3.15 mmol), KHCO3 (947 mg, 9.45 mmol, 3 equiv),
iodomethane (0.59 mL, 9.45 mmol, 3 equiv), NaH (227 mg,
9.45 mmol, 3 equiv) and allyl bromide (0.82 mL, 9.45 mmol, 3
equiv) to yield racemic 45a (730 mg, 2.80 mmol, 89%): Rf 0.25
(95:5 PE/AcOEt); 1H NMR (500 MHz, CDCl3) δ 6.65 (s, 1H),
6.50 (s, 1H), 6.06 (ddt, J = 17.2, 10.5, 5.1 Hz, 1H), 5.42 (dq, J
= 17.2, 1.6 Hz, 1H), 5.27 (dq, J = 10.5, 1.6 Hz, 1H), 4.53 (dt, J
= 5.1, 1.6 Hz, 2H), 3.72 (s, 3H), 3.47 (d, J = 16.1 Hz, 1H), 3.37
(d, J = 16.1 Hz, 1H), 2.84 (d, J = 16.1 Hz, 1H), 2.77 (d, J = 16.1
Hz, 1H), 2.32 (s, 3H), 1.37 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 178.3, 155.1, 143.3, 138.1, 133.7, 126.3, 117.9, 117.1,
110.6, 68.7, 52.2, 49.5, 44.4, 40.8, 25.6, 21.8; IR νmax/cm-1
(neat) 2926, 1730, 1591, 1315, 1112, 1073, 829 cm-1; HRMS
(ESI) m/z [M+Na]+ calcd for C16H20NaO3 283.1305, found
283.1307; HPLC separation: Chiralpak® IA; 99:1 (n-heptane/i-
PrOH), 1.0 ml.min-1, 208 nm, tR (major) = 5.0 min, tR (minor) =
6.1 min, 96:4 e.r.; [α]23 + 5.2° (c = 1.00, CHCl3).
Methyl (S)-4-hydroxy-5-(2-hydroxyethyl)-2,6-dimethyl-
2,3-dihydro-1H-indene-2-carboxylate (46).13 In a round
bottom flask containing a stirred biphasic solution of 40 (102
mg, 0.392 mmol) in EtOAc (10 mL) and water (5 mL) was
added OsO4 (5.0 mg, 19.6 μmol, 5 mol%). After 5 minutes,
NaIO4 (210 mg, 0.98 mmol, 2.5 equiv) was added in two
portions separated by 5 min. The solution was vigorously stirred
for 3 h at room temperature. The layers were separated and the
aqueous phase was extracted twice with ethyl acetate (6 mL).
The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude material
was diluted in MeOH (10 mL) and cooled to 0°C. After this,
NaBH4 (44.5 mg, 1.18 mmol, 3 equiv) was added and the
reaction was allowed to reach room temperature. After 30 min,
H2O was added and the reaction was extracted three times with
ethyl acetate (6 mL). The combined organic phases were dried
over MgSO4, filtered and concentrated under reduced pressure.
The crude material was purified by flash chromatography using
cyclohexane/EtOAc (6:4) leading to 46 (78 mg, 0.295 mmol,
75%) as a light yellow oil. Racemic material was prepared using
the same procedure from racemic 40 (257 mg, 0.987 mmol),
OsO4 (12.5 mg, 49.4 μmol, 5 mol%), NaIO4 (528 mg, 2.47
mmol, 2.5 equiv) and NaBH4 (112 mg, 2.96 mmol, 3 equiv) to
yield racemic 46 (195 mg, 0.737 mmol, 75%): Rf 0.26 (70:30
PE/AcOEt); 1H NMR (500 MHz, CDCl3) δ 6.63 (s, 1H), 3.95-
3.86 (m, 2H), 3.71 (s, 3H), 3.42 (d, J = 16.0 Hz, 1H), 3.37 (d, J
= 16.0 Hz, 1H), 2.88 (dd, J = 6.4, 4.6 Hz, 2H), 2.82 (d, J = 16.0
Hz, 1H), 2.75 (d, J = 16.0 Hz, 1H), 2.24 (s, 3H), 1.36 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 178.6, 151.9, 141.3, 136.1,
126.2, 123.1, 118.7, 64.0, 52.2, 49.6, 44.3, 40.9, 29.4, 25.6,
20.3; IR νmax/cm-1 (neat) 3313, 2924, 1722, 1188, 1110, 905 cm-
1; HRMS (ESI) m/z [M+Na]+ calcd for C15H20NaO4 287.1254,
found 287.1256; [α]23 + 1.5° (c = 1.00, CHCl3).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-(+)-Puraquinonic acid (4).2,6,7,13 Following a procedure
of Yakura.25 In a round bottom flask equipped with a condenser,
46 (66 mg, 0.25 mmol) and LiOH (157 mg, 3.75 mmol, 15
equiv) in 1,4-dioxane/H2O (1:1, 6 mL) were refluxed for 1.5 h.
After this period, the mixture was acidified with 1M HCl and
extracted three times with EtOAc (15 mL). The combined
organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material was
diluted in a mixture of 2,2,2-trifluoroethanol/H2O (1:2, 3 mL).
Then Oxone® (305 mg, 0.992 mmol, 4 equiv) and 4-
iodophenoxyacetic acid (7.0 mg, 24.8 μmol, 10 mol%) were
added at room temperature. The reaction mixture was stirred
until total consumption of starting material (approximatively 1
hour) then EtOAc and water were added (5 mL each). The
layers were separated and the aqueous layer was extracted with
EtOAc, The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
material was purified by flash chromatography using
DCM/MeOH (93:7) leading to (S)-(+)-puraquinonic acid (4)
(54.0 mg, 0.204 mmol, 82% over two steps) as a yellow oil.
Methyl (S)-5-allyl-4-hydroxy-2,6-dimethyl-2,3-dihydro-
1H-indene-2-carboxylate (40).13 A sealed tube charged with
45a (204 mg, 0.784 mmol) and N,N-diethylaniline (3 mL) was
heated under stirring at 200°C for 24 h. After this period, the
reaction was poured into 1M HCl (30 mL) and extracted three
times with DCM (30 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash
chromatography using cyclohexane/EtOAc (9:1) leading to 40
(163 mg, 0.626 mmol, 80%) as a yellow oil which solidified on
standing. Racemic material was prepared using the same
procedure from racemic 45a (700 mg, 2.69 mmol) to yield
racemic 40 (616 mg, 2.37 mmol, 88%): Rf 0.25 (85:15
PE/AcOEt); mp 65-67 °C; 1H NMR (500 MHz, CDCl3) δ 6.65
(s, 1H), 5.95 (ddt, J = 17.1, 10.2, 5.9 Hz, 1H), 5.07 (dq, J = 10.2,
1.8 Hz, 1H), 5.05 (dq, J = 17.1, 1.8 Hz, 1H), 4.79 (s, 1H), 3.72
(s, 3H), 3.44 (d, J = 16.0 Hz, 1H), 3.40 (dt, J = 5.9, 1.8 Hz, 2H),
3.37 (d, J = 15.6 Hz, 1H), 2.77 (d, J = 16.0 Hz, 1H), 2.76 (d, J
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
Racemic material was prepared using the same procedure from in DCM (1.2 mL), pyridine (54 μL, 0.669 mmol, 3 equiv) and
1
2
3
4
5
6
7
8
racemic 46 (29.2 mg, 0.110 mmol), LiOH (39.7 mg, 1.66 mmol,
15 equiv), Oxone® (135.8 mg, 0.442 mmol, 4 equiv) and 4-
iodophenoxyacetic acid (3.1 mg, 11.0 μmol, 10 mol%) to yield
racemic puraquinonic acid (4) (25.1 mg, 0.095 mmol, 86%): Rf
trifluoromethanesulfonic anhydride (41 μL, 0.245 mmol, 1.1
equiv) were added. The reaction mixture was stirred a room
temperature during 6 hours. The reaction was then concentrated
and purified by flash column chromatography to yield 40a (80.9
mg, 0.206 mmol, 93%) as a colorless liquid. Racemic material
was prepared using the same procedure from racemic 40 (50
mg, 0.192 mmol), pyridine (47 μL, 0.576 mmol, 3 equiv) and
trifluoromethanesulfonic anhydride (36 μL, 0.211 mmol, 1.1
equiv) to yield racemic 40a (87.1 mg, 0.167 mmol, 87%): Rf
0.25 (95:5 PE/AcOEt); 1H NMR (500 MHz, CDCl3) δ 7.03 (s,
1H), 5.83 (ddt, J = 17.1, 10.1, 5.8 Hz, 1H), 5.04 (dq, J = 10.1,
1.7 Hz, 1H), 4.89 (dq, J = 17.1, 1.7 Hz, 1H), 3.72 (s, 3H), 3.54
(d, J = 16.3 Hz, 1H), 3.49 (d, J = 16.1 Hz, 1H), 3.45 (dt, J = 5.8,
1.7 Hz, 2H), 2.95 (d, J = 16.3 Hz, 1H), 2.82 (d, J = 16.1 Hz,
1H), 2.30 (s, 2H), 1.37 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 177.3, 144.3, 142.9, 139.0, 134.4, 132.0, 129.2, 126.7,
118.7 (q, J = 319.8 Hz), 116.0, 52.4, 50.1, 44.1, 41.9, 31.2, 25.0,
19.9; 19F{1H} NMR (376 MHz, CDCl3) δ -73.8; IR νmax/cm-1
(neat) 2955, 1735, 1405, 1206, 1137, 817 cm-1; HRMS (ESI)
m/z [M+Na]+ calcd for C17H19F3NaO5S 415.0798, found
415.0795; [α]23 + 4.0° (c = 1.09, CHCl3).
1
0.12 (95:5 DCM/MeOH); H NMR (500 MHz, CDCl3) δ 3.76
(t, J = 6.4 Hz, 2H), 3.41-3.34 (m, 2H), 2.79 (t, J = 6.4 Hz, 2H),
2.77-2.71 (m, 2H), 2.07 (s, 3H), 1.42 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 186.4, 185.9, 181.7, 145.9, 145.5, 143.0,
141.5, 61.6, 47.1, 42.5, 42.4, 30.0, 25.8, 12.4; IR νmax/cm-1
(neat) 3394, 2925, 1706, 1221, 1172, 1103, 914 cm-1; HRMS
(ESI) m/z [M+Na]+ calcd for C14H16NaO5 287.0890, found
287.0891; [α]23 + 1.4° (c = 0.50, CHCl3) {lit.2 [α]22 – 2.2° (c =
0.55, CHCl3) (R)-ent}.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-(+)-Deliquinone (5).3,13,14 In a round bottom flask
containing a stirred biphasic solution of 40 (114 mg, 0.438
mmol) in EtOAc (14 mL) and water (7 mL) was added OsO4
(5.57 mg, 21.9 μmol, 5 mol%). After 5 minutes, NaIO4 (234 mg,
1.10 mmol, 2.5 equiv) was added in two portions separated by
5 min. The solution was vigorously stirred for 3 h at room
temperature. The layers were separated and the aqueous layer
was extracted twice with EtOAc (8 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was diluted in dry THF
(10 mL) and cooled to 0°C. After this, LiAlH4 (49.9 mg, 1.31
mmol, 3 equiv) was added and the reaction was allowed to reach
room temperature. After 1 h, H2O was added and the reaction
was extracted three times with ethyl acetate (8 mL). The
combined organic phases were dried over MgSO4, filtered and
concentrated under reduced pressure. Then Following a
procedure of Yakura.24 The crude material was diluted in a
mixture of 2,2,2-trifluoroethanol/H2O (1:2, 9 mL). Then
Oxone® (541 mg, 1.76 mmol, 4 equiv) and 4-iodophenoxyacetic
acid (12.2 mg, 44.0 μmol, 10 mol%) were added at room
temperature. The reaction mixture was stirred until total
consumption of the starting material (approximatively 1 hour)
then EtOAc and water were added (10 mL each). The layers
were separated and the aqueous layer was extracted with
EtOAc, The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
material was purified by flash chromatography using
DCM/MeOH (93:7) leading to (S)-(+)-deliquinone (5) (62.7
mg, 0.276 mmol, 62% over two steps) as a yellow oil. Racemic
material was prepared using the same procedure from racemic
40 (220 mg, 0.845 mmol), OsO4 (11.1 mg, 43.7 μmol, 5 mol%),
NaIO4 (450 mg, 2.10 mmol, 2.5 equiv), LiAlH4 (98.0 mg, 2.58
mmol, 3 equiv), Oxone® (1,04 g, 3.38 mmol, 4 equiv) and 4-
iodophenoxyacetic acid (22.1 mg, 84.5 μmol, 10 mol%) to yield
racemic deliquinone (5) (153 mg, 0.647 mmol, 76%): Rf 0.28
(95:5 DCM/MeOH); 1H NMR (500 MHz, CDCl3) δ 3.74 (t, J =
6.5 Hz, 2H), 3.49 (s, 2H), 2.87-2.80 (m, 2H), 2.78 (t, J = 6.5 Hz,
2H), 2.53-2.47 (m, 2H), 2.06 (s, 3H), 1.75 (brs, 1H), 1.69 (brs,
1H), 1.16 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 187.0,
186.4, 147.2, 146.8, 142.8, 141.4, 70.2, 61.7, 43.0, 40.8, 40.7,
30.1, 25.0, 12.3; IR νmax/cm-1 (neat) 3395, 2925, 1644, 1249,
1033 cm-1; HRMS (ESI) m/z [M+Na]+ calcd for C14H18NaO4
273.1097, found 273.1095; [α]23 + 0.9° (c = 1.00, CHCl3) {lit.3
[α]22 – 0.5° (c = 0.6, CHCl3) (R)-ent}.
Methyl
(S)-5-allyl-2,4,6-trimethyl-2,3-dihydro-1H-
procedure of
indene-2-carboxylate (42).13 Following
a
Woodward.26 In an oven dry catalysis tube, 40a (80 mg, 0.204
mmol) was introduced. Then the tube was tranfer in glovebox
and [Pd2dba3•CHCl3] (5.3 mg, 5.1 μmol, 2.5 mol%) and Xphos
(5.0 mg, 10.2 μmol, 5 mol%) were introduced and the tube was
close with a septum. Outside of the glovebox, THF (2.5 mL)
and DABAL-Me3 (41.8 mg, 0.163 mmol, 0.8 equiv, as a
solution in 0.8 mL of THF) were added. The septum was rapidly
exchange for a screw cap. The tube was then introduced in a
75°C preheated aluminium heating block and stirred at this
temperature for 4 hours. After this period the reaction was
coolded to room temperature and quenched with 2M HCl (2
mL) and extracted three times with diethyl ether (3 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography to yield 42 as a
colorless liquid (51.7 mg, 0.200 mmol, 98%). Racemic material
was prepared using the same procedure from racemic 40a (50.2
mg, 0.128 mmol), [Pd2dba3•CHCl3] (3.3 mg, 3.2 μmol, 2.5
mol%), Xphos (3.2 mg, 6.4 μmol, 5 mol%) and DABAL-Me3
(26.3 mg, 0.102 mmol, 0.8 equiv) to yield racemic 42 (32.4 mg,
1
0.167 mmol, 98%): Rf 0.33 (95:5 PE/AcOEt); H NMR (500
MHz, CDCl3) δ 6.88 (s, 1H), 5.88 (ddt, J = 17.1, 10.1, 5.7 Hz,
1H), 4.99 (dq, J = 10.1, 1.8 Hz, 1H), 4.88 (dq, J = 17.1, 1.8 Hz,
1H), 3.72 (s, 3H), 3.46 (d, J = 15.9 Hz, 1H), 3.40 (d, J = 15.9
Hz, 1H), 3.38 (dt, J = 5.7, 1.8 Hz, 3H), 2.79 (d, J = 15.9 Hz,
1H), 2.78 (d, J = 15.9 Hz, 1H), 2.27 (s, 3H), 2.18 (s, 3H), 1.37
(s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 178.5, 138.8,
138.3, 135.8, 135.3, 134.3, 132.7, 124.0, 114.9, 52.2, 49.1, 44.3,
43.7, 33.7, 25.8, 20.3, 16.0; IR νmax/cm-1 (neat) 2931, 1732,
1208, 1112, 911 cm-1; HRMS (ESI) m/z [M+Na]+ calcd for
C17H22NaO2 281.1512, found 281.1508; [α]23 + 9.4° (c = 1.05,
CHCl3).
(S)-(+)-Russujaponol F (6).4,13 In a round bottom flask
containing a stirred biphasic solution of 42 (51.7 mg, 0.200
mmol) in EtOAc (4 mL) and water (2 mL) was added OsO4 (2.5
mg, 10.0 μmol, 5 mol%). After 5 minutes, NaIO4 (107 mg,
Methyl
(S)-5-allyl-2,6-dimethyl-4-
(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-indene-2-
carboxylate (40a).13 To a solution of 40 (58.1 mg, 0.223 mmol)
12
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
0.500 mmol, 2.5 equiv) was added in two portions separated by
REFERENCES
(1) (a) Kokubun, T.; Scott-Brown, A.; Kite, G. C.; Simmonds, M. S.
1
2
3
4
5
6
7
8
5 min. The solution was vigorously stirred for 3 h at room
temperature. The layers were separated and the aqueous layer
was extracted twice with EtOAc (5 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was diluted in dry THF (5
mL) and cooled to 0°C. After this, LiAlH4 (22.8 mg, 0.600
mmol, 3 equiv) was added and the reaction was allowed to reach
room temperature overnight. After this period, H2O was added
and the reaction was extracted three times with ethyl acetate (5
mL). The combined organic phases were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
material was purified by flash column chromatography to yield
(S)-(+)-russujaponol F (6) as a colorless oil (39.8 mg, 0.170
mmol, 85%). Racemic material was prepared using the same
procedure from racemic 42 (20.5mg, 0.079 mmol), OsO4 (1.0
mg, 4.0 μmol, 5 mol%), NaIO4 (42.5 mg, 0.199 mmol, 2.5
equiv) and LiAlH4 (9.1 mg, 0.238 mmol, 3 equiv) to yield
racemic russujaponol F (6) (16.2 mg, 0.069 mmol, 87%): Rf
0.23 (50:50 DCM/MeOH); 1H NMR (400 MHz, C5D5N) δ 6.90
(s, 1H), 5.76 (brs, 2H), 3.99 (t, J = 7.6 Hz, 2H), 3.75 (s, 2H),
3.18 (d, J = 15.9 Hz, 1H), 3.15 (t, J = 7.6 Hz, 2H), 3.09 (d, J =
15.8 Hz, 1H), 2.71 (d, J = 15.8 Hz, 1H), 2.60 (d, J = 15.9 Hz,
1H), 2.37 (s, 3H), 2.24 (s, 3H), 1.35 (s, 3H); 13C{1H} NMR (126
MHz, C5D5N) δ 140.9, 140.7, 135.3, 134.1, 133.3, 125.0, 70.3,
J.
Protoilludane,
Illudane,
Illudalane,
and
Norilludane
Sesquiterpenoids from Granulobasidium vellereum. J. Nat. Prod.
2016, 79, 1698-1701. (b) Yoshikawa, K.; Matsumoto, Y.; Hama, H.;
Tanaka, M.; Zhai, H.; Fukuyama, Y.; Arihara, S.; Hashimoto, T.
Russujaponols G-L, Illudoid Sesquiterpenes, and Their Neurite
Outgrowth Promoting Activity from the Fruit Body of Russula
japonica. Chem. Pharm. Bull. 2009, 57, 311-314. (c) Isaka, M.;
Srisanoh, U.; Sappan, M.; Supothina, S.; Boonpratuang, T. Sterostreins
F–O, Illudalanes and Norilludalanes From Cultures of the
Basidiomycete Stereum ostrea BCC 22955. Phytochemistry 2012, 79,
116-120.
(2) Becker, U.; Erkel, G.; Anke, T.; Sterner, O. Puraquinonic Acid,
a Novel Inducer of Differentiation of Human HL-60 Promyelocytic
Leukemia Cells from Mycena pura (Pers. Ex Fr.). Nat. Prod. Lett.
1997, 9, 229-236.
(3) Clericuzio, M.; Han, F.; Pan, F.; Pang, Z.; Sterner, O. The
Sesquiterpenoid Contents of Fruit Bodies of Russula delica. Acta
Chem. Scand. 1998, 52, 1333-1337.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Yoshikawa, K.; Kaneko, A.; Matsumoto, Y.; Hama, H.; Arihara,
S. Russujaponols A−F, Illudoid Sesquiterpenes from the Fruiting Body
of Russula japonica. J. Nat. Prod. 2006, 69, 1267-1270.
(5) (a) Fuji, K. Asymmetric Creation of Quaternary Carbon Centers.
Chem. Rev. 1993, 93, 2037-2066. (b) Corey, E. J.; Guzman-Perez, A.
The Catalytic Enantioselective Construction of Molecules with
Quaternary Carbon Stereocenters. Angew. Chem. Int., Ed. 1998, 37,
388-401. (c) Christoffers, J.; Mann, A. Enantioselective Construction
of Quaternary Stereocenters. Angew. Chem., Int. Ed. 2001, 40, 4591-
4597. (d) Denissova, I.; Barriault, L. Stereoselective Formation of
Quaternary Carbon Centers and Related Functions. Tetrahedron 2003,
59, 10105-10146. (e) Trost, B. M.; Jiang, C. Catalytic Enantioselective
Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006,
369-396. (f) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N.
Enantioselective Catalytic Formation of Quaternary Stereogenic
Centers. Eur. J. Org. Chem. 2007, 5969-5994. (g) Bella, M.; Gasperi,
T. Organocatalytic Formation of Quaternary Stereocenters. Synthesis
2009, 1583-1614. (h) Hawner, C.; Alexakis, A. Metal-Catalyzed
Asymmetric Conjugate Addition Reaction: Formation of Quaternary
Stereocenters. Chem. Commun. 2010, 46, 7295-7306. (i) Prusov, E. V.
Construction of Quaternary Stereogenic Centers in the Total
Synthesis of Natural Products. Angew. Chem. Int. Ed. 2017, 56,
14356-14358.
(6) Racemic synthesis of puraquinonic acid: (a) Hisaindee, S.; Clive,
D. J. D. A Synthesis of Puraquinonic Acid. Tetrahedron Lett. 2001, 42,
2253-2255. (b) Clive, D. L. J.; Sannigrahi, M.; Hisaindee, S. Synthesis
of (±)-Puraquinonic Acid:ꢀ An Inducer of Cell Differentiation. J. Org.
Chem. 2001, 66, 954-961. Enantioselective synthesis: (c) Clive, D. L.
J.; Yu, M. Synthesis of (+)-Puraquinonic Acid. Chem. Commun. 2002,
2380-2381. (d) Clive, D. L. J.; Yu, M.; Sannigrahi, M. Synthesis of
Optically Pure (+)-Puraquinonic Acid and Assignment of Absolute
Configuration to Natural (-)-Puraquinonic Acid. Use of Radical
Cyclization for Asymmetric Generation of a Quaternary Center. J. Org.
Chem. 2004, 69, 4116-4125.
1
62.0, 45.4, 43.9, 43.1, 34.5, 25.6, 20.9, 16.5; H NMR (400
MHz, CDCl3) δ 6.86 (s, 1H), 3.74 (t, J = 7.5 Hz, 2H), 3.52 (s,
2H), 2.95 (t, J = 7.5 Hz, 2H), 2.88 (d, J = 16.0 Hz, 1H), 2.84 (d,
J = 16.0 Hz, 1H), 2.63 (d, J = 16.0 Hz, 1H), 2.59 (d, J = 16.0
Hz, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.18 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 140.3, 139.8, 135.3, 133.2, 132.3, 124.4,
71.1, 62.1, 44.3, 43.1, 42.4, 32.9, 24.6, 20.5, 16.2; IR νmax/cm-1
(neat) 3313, 2920, 2867, 1460, 1037 cm-1; HRMS (ESI) m/z
[M+Na]+ calcd for C15H22NaO2 257.1512, found 257.1514;
[α]23 + 1.0° (c = 1.07, CHCl3); [α]23 + 2.1° (c = 0.53, MeOH)
{lit.4 [α]20 + 1.3° (c = 3.1, MeOH) (S)}.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS
Publication website at DOI:
Copies of NMR spectra and HPLC chromatograms.
AUTHOR INFORMATION
Corresponding Author
*E-mail: olivier.baudoin@unibas.ch.
ORCID
Olivier Baudoin: 0000-0002-0847-8493
(7) Tiong, E. A.; Rivalti, D.; Williams, B. M.; Gleason, J. L. A
Concise Total Synthesis of (R)-Puraquinonic Acid. Angew. Chem., Int.
Ed. 2013, 52, 3442-3445.
Notes
The authors declare no competing financial interest.
(8) Arpin, A.; Manthorpe, J. M.; Gleason, J. L. A Practical Chiral
Bicyclic Thioglycolate Lactam Auxiliary for Stereoselective
Quaternary Carbon Formation. Org. Lett. 2006, 8, 1359-1362.
(9) Baudoin, O. Ring Construction by Palladium(0)-Catalyzed
C(sp3)-H Activation. Acc. Chem. Res. 2017, 50, 1114-1123.
(10) (a) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N.
Catalytic Enantioselective Transformations Involving C-H Bond
Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117,
8908-8976. (b) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.;
Yu, J.-Q. Enantioselective C(sp3)-H Bond Activation by Chiral
Transition Metal Catalysts. Science 2018, 359, 759.
ACKNOWLEDGMENT
This work was financially supported by the University of Basel and
Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil
(FAPESP - process 2016/22636-2). We thank A. Huber, University
of Basel, for preparative work, Prof. Dr. T. Bürgi, University of
Geneva, for VCD analyzes, Dr. D. Häussinger, University of Basel,
for assistance with NMR experiments, S. Mittelheisser, Dr. H.
Nadig, and Dr. M. Pfeffer, University of Basel, for MS analyses.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
(10) (a) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.; Baudoin, O.
High Turnover Numbers, Room Temperature Reactions, and Isolation
Diastereo‐ and Enantioselective Intramolecular C(sp3)-H Arylation for
the Synthesis of Fused Cyclopentanes. Chem. Eur. J. 2012, 18, 4480-
4484. (b) Holstein, P. M.; Vogler, M.; Larini, P.; Pilet, G.; Clot, E.;
Baudoin, O. Efficient Pd0-Catalyzed Asymmetric Activation of
Primary and Secondary C-H Bonds Enabled by Modular Binepine
Ligands and Carbonate Bases. ACS Catal. 2015, 5, 4300-4308.
(11) Yang, L.; Melot, R.; Neuburger, M.; Baudoin, O. Palladium(0)-
Catalyzed Asymmetric C(sp3)–H Arylation Using a Chiral Binol-
Derived Phosphate and an Achiral Ligand. Chem. Sci. 2017, 8, 1344-
1349.
of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390-391. (b)
Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. A Stoichiometric
Aromatic C-H Borylation Catalyzed by Iridium(I)/2,2′‐Bipyridine
Complexes at Room Temperature. Angew. Chem. Int. Ed. 2002, 41,
3056-3058.
1
2
3
4
5
6
7
8
(24) For examples of post-functionalization of ArB(pin), see: (a)
Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. One-Pot Synthesis of
Arylboronic Acids and Aryl Trifluoroborates by Ir-Catalyzed
Borylation of Arenes. Org. Lett. 2007, 9, 757-760. (b) Tzschucke, C.
C.; Murphy, J. M.; Hartwig, J. F. Arenes to Anilines and Aryl Ethers
by Sequential Iridium-Catalyzed Borylation and Copper-Catalyzed
Coupling. Org. Lett. 2007, 9, 761-764. (c) Liskey, C. W.; Liao, X.;
Hartwig, J. F. Cyanation of Arenes via Iridium-Catalyzed Borylation.
J. Am. Chem. Soc. 2010, 132, 11389-11391. (d) Partridge, B. M.;
Hartwig, J. F. Sterically Controlled Iodination of Arenes via Iridium-
Catalyzed C-H Borylation. Org. Lett. 2013, 15, 140-143. (e) Fier, P. S.;
Luo, J.; Hartwig, J. F. Copper-Mediated Fluorination of Arylboronate
Esters. Identification of a Copper(III) Fluoride Complex. J. Am. Chem.
Soc. 2013, 135, 2552-2559.
(25) Yakura, T.; Konishi, T. A Novel Catalytic Hypervalent Iodine
Oxidation of p-Alkoxyphenols to p-Quinones Using 4-
Iodophenoxyacetic Acid and Oxone®. Synlett 2007, 2007, 765-768.
(26) Cooper, T.; Novak, A.; Humphreys, L. D.; Walker, M. D.;
Woodward, S. User‐Friendly Methylation of Aryl and Vinyl Halides
and Pseudohalides with DABAL‐Me3. Adv. Synth. Catal. 2006, 348,
686-690.
(27) (a) Kündig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G.
Bulky Chiral Carbene Ligands and their Application in the Palladium-
Catalyzed Asymmetric Intramolecular Alpha-Arylation Of Amides.
Angew. Chem. Int. Ed. 2007, 46, 8484-8487. (b) Nakanishi, M.;
Katayev, D.; Besnard, C.; Kündig, E. P. Fused Indolines by Palladium-
Catalyzed Asymmetric C-C Coupling Involving an Unactivated
Methylene Group. Angew. Chem., Int. Ed. 2011, 50, 7438-7441.
(28) Holstein, P. M.; Holstein, J. J.; Escudero-Adán, E. C.; Baudoin,
O.; Echavarren, A. M. Ferrocene Derivatives of Liquid Chiral
Molecules Allow Assignment of Absolute Configuration by X-Ray
Crystallography. Tetrahedron: Asymmetry 2017, 28, 1321-1329.
(12) For other examples of Pd0-catalyzed enantioselective
desymmetrizations of methyl groups: (a) Anas, S.; Cordi, A.; Kagan,
H. B. Enantioselective Synthesis of 2-Methyl Indolines by Palladium
Cata-Lysed Asymmetric C(sp3)-H Activation/Cyclisation. Chem.
Commun. 2011, 47, 11483-11485. (b) Saget, T.; Lemouzy, S. J.;
Cramer, N. Chiral Monodentate Phosphines and Bulky Carboxylic
Acids: Cooperative Effects in Palladium‐Catalyzed Enantioselective
C(sp3)-H Functionalization. Angew. Chem. Int. Ed. 2012, 51, 2238-
2242. (c) Katayev, D.; Nakanishi, M.; Bürgi, T.; Kündig, E. P.
Asymmetric C(sp3)-H/C(Ar) Coupling Reactions. Highly Enantio-
Enriched Indolines via Regiodivergent Reaction of a Racemic Mixture.
Chem. Sci. 2012, 3, 1422-1425. (d) Pedroni, J.; Cramer, N. Chiral γ-
Lactams by Enantioselective Palladium(0)-Catalyzed Cyclopropane
Functionalizations. Angew. Chem. Int. Ed. 2015, 40, 11992-11995. (e)
Holstein, P. M.; Dailler, D.; Vantourout, J.; Shaya, J.; Baudoin, O.
Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)-H
Alkenylation and Application to Alkaloid Synthesis. Angew. Chem. Int.
Ed. 2016, 55, 2805-2809. (f) Dailler, D.; Rocaboy, R.; Baudoin, O.
Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)-H
Carbamoylation. Angew. Chem. Int. Ed. 2017, 56, 7218-7222.
(13) This work was partially reported earlier: Melot, R.; Craveiro,
M.; Bürgi, T.; Baudoin, O. Divergent Enantioselective Synthesis of
(Nor)illudalane Sesquiterpenes via Pd0-Catalyzed Asymmetric C(sp3)-
H Activation. Org. Lett, 2019, 21, 812-815.
(14) Kraus, G. A.; Choudhury, P. K. J. Synthesis of Puraquinonic
Acid Ethyl Ester and Deliquinone via a Common Intermediate. J. Org.
Chem. 2002, 67, 5857-5859.
(15) Quan, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Sterically
Demanding, Bioxazoline-Derived N-Heterocyclic Carbene Ligands
with Restricted Flexibility for Catalysis. J. Am. Chem. Soc. 2004, 126,
15195-15201.
(16) Knölker, H.-J.; Knöll, J. First Total Synthesis of the Neuronal
Cell Protecting Carbazole Alkaloid Carbazomadurin a by Sequential
Transition Metal-Catalyzed Reactions. Chem. Commun. 2003, 10,
1170-1171.
(17) Guo, W.; Li, J.; Fan, N.; Wu, W.; Zhou, P.; Xia, C. A Simple
and Effective Method for Chemoselective Esterification of Phenolic
Acids. Synth. Commun. 2005, 35, 145-152.
(18) Jacobsen, N.; Torssell, K. Radikalische Alkylierung von
Chinonen: Erzeugung von Radikalen in Redoxreaktionen. Liebigs Ann.
Chem. 1972, 763, 135-147.
(19) Gore, M. P.; Gould, S. J.; Weller, D. D. Synthesis of Putative
Intermediates in the Biosynthesis of the Kinamycin Antibiotics: Total
Synthesis of Phenanthroviridin Aglycon and Related Compounds. J.
Org. Chem. 1992, 57, 10, 2774-2783
(20) Hirano, Y.; Tokudome, K.; Takikawa, H.; Suzuki, K. Synthetic
Study on Acremoxanthone A: Construction of Bicyclo [3.2.2]nonane
CD Skeleton and Fusion of AB Rings. Synlett 2017, 28, 214-220.
(21) For a similar strategy, see: Weinstabl, H; Suhartono, M.;
Qureshi, Z.; Lautens, M. Total Synthesis of (+)‐Linoxepin by Utilizing
the Catellani Reaction. Angew. Chem., Int. Ed. 2013, 52, 5305-5308.
(22) He, Z.-T.; Li, H.; Haydl, A. M.; Whiteker, G. T.; Hartwig, J. F.
Trimethylphosphate as a Methylating Agent for Cross Coupling: A
Slow-Release Mechanism for the Methylation of Arylboronic Esters. J.
Am. Chem. Soc. 2018, 140, 17197-17202.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(23) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anasrasi,
N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of Arenes.
14
ACS Paragon Plus Environment