Total Synthesis of Isohericerin, Isohericenone, and Erinacerin A: Development of a Copper-Catalyzed Methylboronation of Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.7b00920

Efficient and concise approaches for the synthesis of three bioactive natural products, isohericerin, isohericenone, and erinacerin A, are described in this paper. The key reactions employed include a Mannich reaction with commercially available hydroxybenzoate and subsequent one-pot lactamization to afford the common precursor isoindolinone in 3 steps and a Suzuki-Miyaura coupling reaction to connect geranyl side chains to the isoindolinone core. In addition, the mild and efficient synthesis of the C5′-oxidized geranyl side unit of isohericenone is enabled by developing a highly regioselective and efficient method for the Cu-catalyzed methylboronation of functionalized terminal alkynes.

Full text of DOI:10.1021/acs.joc.7b00920

Subscriber access provided by McMaster University Library
Article
Total Synthesis of Isohericerin, Isohericenone, and Erinacerin A:
Development of a Copper-Catalyzed Methylboronation of Terminal Alkynes
Bohyun Mun, Sangyong Kim, Hongju Yoon, Ki Hyun Kim, and Yunmi Lee
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on May 30, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Total Synthesis of Isohericerin, Isohericenone, and Erinacerin A:
Development of a CopperꢀCatalyzed Methylboronation of
Terminal Alkynes
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
Bohyun Mun,a Sangyong Kim,a Hongju Yoon,a Ki Hyun Kim,b and Yunmi Lee*a
aDepartment of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea
bSchool of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
* To whom correspondence should be addressed.
Tel.: +82ꢀ2ꢀ940ꢀ8116; Fax: +82ꢀ2ꢀ942ꢀ0108; Eꢀmail: ymlee@kw.ac.kr
Table of Contents
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 27
ABSTRACT:
1
2
3
4
5
6
7
8
9
Efficient and concise approaches for the synthesis of three bioactive natural products, isohericerin,
isohericenone, and erinacerin A, are described in this paper. The key reactions employed include a
Mannich reaction with commercially available hydroxybenzoate and subsequent oneꢀpot lactamization
to afford the common precursor isoindolinone in 3 steps and a SuzukiꢀMiyaura coupling reaction to
connect geranyl side chains to the isoindolinone core. In addition, the mild and efficient synthesis of the
C5’ꢀoxidized geranyl side unit of isohericenone is enabled by developing a highly regioselective and
efficient method for the Cuꢀcatalyzed methylboronation of functionalized terminal alkynes.
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
INTRODUCTION
The edible mushroom Hericium erinaceum has been widely used in traditional Chinese medicine
for the treatment of dyspepsia, gastric ulcer and enervation and has been reported to have various
intriguing biological functions, including antioxidant, antihypertensive, antiꢀdiabetic, antitumor,
antibacterial, and plant growth regulation functions.1 The biological effects of the diverse chemical
components, including geranylꢀcontaining resorcylates, sterols, and polysaccharides, isolated from the
fruiting bodies of this mushroom have been examined to identify compounds of interest for medicinal
chemistry. Recently, Lee and coworkers isolated several resorcinol compounds from H. erinaceum and
evaluated their cytotoxic activities against various human cancer cell lines, such as A549, SKOVꢀ3, SKꢀ
MELꢀ2 and HCTꢀ15.2 Among the isolated metabolites, isohericerin (1),1g,3 isohericenone (2)1h,4 and
erinacerin A (3),5 which consist of an isoindolinone framework bearing a geranyl side chain (Figure 1),
exhibited significant inhibitory activity (i.e., IC50 values in the range of 1.9ꢀ7.7 ꢁM) against the
proliferation of SKꢀMELꢀ2 cells. Thus, these natural products are potential targets for antiꢀcancer drug
discovery. To evaluate their biological activities in more detail, efficient and straightforward synthetic
routes must be developed.
2
ACS Paragon Plus Environment

Page 3 of 27
The Journal of Organic Chemistry
Isohericerin (1) was first synthesized by the Kobayashi group using tandem CuBr2ꢀmediated
1
2
3
aromatization for the construction of the resorcinol aromatic unit and subsequent Stille coupling
between the geranyl side chain and the isoindolinone moiety.6 This approach required 12 synthetic steps
and provided low isohericerin yields (~4%). Miranda and coworkers used a fiveꢀstep isohericerin
synthesis method utilizing Claisen rearrangement of the geranyl group and Pdꢀcatalyzed carbonylative
lactamization as key steps, which resulted in an isohericerin yield of 34%.7 The use of toxic CO gas,
however, is a problem in this synthesis method. By contrast, the only synthetic route for obtaining
isohericenone (2) was reported by Kobayashi and coworkers.4a In their synthesis route, synthetic
strategies similar to those developed for the synthesis of isohericerin6 were used to form the main
geranylated isoindolinone scaffold. However, because of the presence of allylic carbons, the oxygen
functionality at the C5’ position on the geranyl side chain presented a synthetic challenge. The synthesis
of the C5’ꢀoxidized geranyl unit required 10 steps, including alkylation of a cyanohydrin ether
intermediate, which was prepared from the addition of cyanide to an aldehyde, and appropriate
manipulation of protecting groups. Thus, the total isohericenone synthesis route consisted of a lengthy
21ꢀstep procedure. To address this issue, we developed a mild and efficient method for converting
functionalized terminal alkynes into cisꢀbranched methyl alkenyl boronates, which are potentially direct
precursors of the cisꢀbranched methyl alkenes composing the terpenoid units found in various
biologically active molecules and natural products.
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
Cuꢀcatalyzed alkylboronation of alkynes with a diboron and an alkyl halide has received
attention as an effective method for synthesizing multisubstituted alkenyl boronates. Tortosa and
coworkers described regioselectiveꢀ and stereoselective synthesis of methyl alkenyl boronates using a
threeꢀcomponent coupling reaction of alkynes, bis(pinacolato)diboron (B2(pin)2) and methyl iodide in
the presence of a Cu catalyst and phosphine ligand.8 However, this method is limited in substrate scope
to arylꢀsubstituted alkynes and 1,3ꢀenynes; reactions with alkylꢀsubstituted terminal alkynes were not
efficient, and only alkynes bearing a propargylic ether group provided moderate methyl alkenyl
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 27
boronate yields. In addition, the need for relatively high catalyst loading (10 mol % of CuCl) and long
reaction times remained unsolved. Subsequently, Ong, Cazin, and Kanai reported an Nꢀheterocyclic
carbene (NHC)ꢀpromoted Cuꢀcatalyzed alkylboronation of internal alkynes with a diboron for
efficiently and selectively synthesizing tetrasubstituted vinyl boronates.9
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
Herein, we described the highly regioselectiveꢀ and stereoselective Cuꢀcatalyzed
methylboronation of alkylꢀsubstituted terminal alkynes for the efficient synthesis of cisꢀbranched methyl
alkenyl boronates. Various readily available terminal alkynes, including those with ether, chloride, and
ester groups, are selectively borylated in the presence of a copper catalyst and B2(pin)2 in situ to form a
CꢀB bond and a CꢀCu bond, which subsequently reacts with methyl iodide, affording good methyl
alkenyl boronate yields. This methodology was successfully applied to construct the functionalized
geranyl unit on isohericenone, enabling the efficient and concise total synthesis of isohericenone in 11
overall steps. In addition, we demonstrated the straightforward synthesis of isohericerin using a
Mannich reaction to install the common isoindolinone core structure and a SuzukiꢀMiyaura coupling
reaction between the isoindolinone unit and geranyl boronate. This synthesis was accomplished in 5
steps and improved the overall yield to 44%.
Figure 1. Structures of isohericerin (1), isohericenone (2), and erinacerin A (3).
RESULTS AND DISCUSSION
Our retrosynthetic analysis of 2 began with palladiumꢀcatalyzed coupling to connect the geranyl
side chain 4 and isoindolinone 5 (Scheme 1). Allylic boronate 4 would be derived from alkyne 7 via the
Cuꢀcatalyzed methylboronation of 7 with diboron and methyliodide to form a methyl alkenyl boronate,
followed by a Matteson homologation. Compound 7 would be obtained via the 1,2ꢀaddition of
4
ACS Paragon Plus Environment

Page 5 of 27
The Journal of Organic Chemistry
propargylzinc bromide to commercially available aldehyde 8. The aromatic scaffold 5 would be
accessed using a Mannich reaction with benzoate 6 and a sequential oneꢀstep lactamization. The
common aromatic unit 5 would be coupled with geranyl boronate 11 (Scheme 2) to achieve the total
synthesis of isohericerin (1).
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
Scheme 1. Retrosynthetic analysis of isohericenone.
Suzuki-Miyaura coupling
O
OH
OMOM
OTBS
Br
+
N
N
Bpin
Ph
Ph
MeO
MeO
4
5
O
O
isohericenone (2)
Mannich reaction &
Lactamization
Methylboronation &
Matteson homologation
OH
OTBS
Br
MeO
O
+ B2(pin)2 + MeI
OMe
H
7
8
6
O
Scheme 2 depicts a synthetic approach to the common core isoindolinone 5 and total synthesis of
10
isohericerin (1). Under modified Mannich reaction conditions,
commercially available
hydroxybenzoate 6 was aminomethylated using phenethylamine and formaldehyde and simultaneously
cyclized to afford an oxazine 9 in 77% yield. Synthesizing lactam moiety 10 from oxazine 9 is expected
to require two steps; a ring opening of 9 under acidic conditions and intramolecular lactamization under
basic conditions. However, upon treatment of an aqueous potassium phosphate solution when refluxing
acetonitrile, oxazine 9 was transformed into the desired lactam 10 in a highly efficient singleꢀstep
reaction (95% yield). Protection of the phenol group with methoxymethyl chloride then resulted in a
MOMꢀprotected 5 in 98% yield. With the core aromatic structure 5 in hand, we focused our efforts on
accomplishing isohericerin synthesis by forming the carbonꢀcarbon bond between the geranyl side chain
and isoindolinone 5 using a SuzukiꢀMiyaura coupling reaction. Although palladiumꢀcatalyzed coupling
reactions with arylꢀ, alkenylꢀ, and alkyl boron species have been intensively developed, couplings with
allyl boron compounds are still challenging.11 After screening various catalytic palladium systems,12 we
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 27
found that using Pd(dppf)Cl2 as a catalyst with cesium carbonate under microwave irradiation promoted
the CꢀC bond coupling reaction of 5 with geranyl boronate 11.13 The obtained product (12) was treated
with hydrochloric acid in methanol to provide the final product (1) with an overall yield of 44% when
using the 5 linear synthetic steps.
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
Scheme 2. Total synthesis of isohericerin (1)
Next, we began synthesizing C5’ꢀoxidized geranyl side chain 4, as shown in Scheme 3.
Propargylzinc bromide derived from the reaction of 13 with zinc was added to aldehyde 8 to provide
allylic alcohol 14 with a yield of 97%; the product was subsequently protected with tertꢀ
butyldimethylsilyl chloride. To prepare functionalized geranyl boronate 4 from alkyne 15, we initially
planned to use trimethylaluminum in the zirconiumꢀcatalyzed carboalumination of alkyne 15 to generate
alkenyl aluminum intermediate 15a, which would then directly react with formaldehyde to provide
allylic alcohol 15b.14 However, alkyne 15 bearing a TBSꢀprotected allylic alcohol group decomposed in
the presence of a catalytic amount of zirconium salt and aluminum reagent, and the desired product was
not obtained (<2% of 15b). As an alternative strategy, we investigated an efficient and mild method for
preparing cisꢀmethyl alkenyl boronate 16a from the terminal alkyne using a selective copperꢀcatalyzed
methylboronation with bis(pinacolato)diboron and methyl iodide.
6
ACS Paragon Plus Environment

Page 7 of 27
The Journal of Organic Chemistry
Scheme 3. Synthesis of geranyl boronate 4
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
Under the basic conditions previously reported by the Tortosa group,8 alkyne 15 was treated
with B2(pin)2, methyl iodide and sodium tertꢀbutoxide in the presence of 10 mol % of CuCl and
Xantphos ligand to generate methyl alkenyl boronate 16a. Pleasingly, as illustrated in entry 1 of Table 1,
the anticipated product 16a was provided with >98% Eꢀselectivity; however, low yield (33%) and
moderate regioselectivity of the boron addition (85:15 16a:16b) were observed. Thus, we examined the
abilities of various NHCꢀcopper complexes15 to promote the efficient and regioselective addition of
boron and methyl groups to the terminal alkyne (Table 1). In the presence of NQIMesCuCl (Figure 2),
which has shown good activity and regioselectivity for the methylboration of dialkylꢀsubstituted internal
alkynes,9a the reaction of 15 proceeded to complete conversion within 3 hours, affording the desired
product (16a) with a yield of 86% (entry 2). When IPrCuCl was used, the catalytic reaction was not
efficient or regioselective (32% yield and 67:33 16a:16b, entry 3). As shown in entries 4ꢀ7 of Table 1,
the BenzICyCuCl complex is the optimum copper catalyst for the methylboronation of 15. Although
only 3 mol % of BenzICyCuCl was used, the reaction proceeded to complete conversion in 3 h with
high efficiency and regioselectivity (entry 8). Therefore, under the optimal reaction conditions, the
desired cisꢀmethyl alkenyl boronate 16a was synthesized with a yield of 84% after purification.
Subsequently, treating alkeny boronate 16a with chloroiodomethane and nꢀbutyllithium provided allylic
boronate 4 with a yield of 88%, as shown in Scheme 3.16
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
Table 1. Optimization of the Cuꢀcatalyzed methylboronation of alkyne 15a
1
2
3
4
5
6
OTBS
OTBS
TBSO
3-10 mol % Cu complex
B(pin)
B2(pin)2
+
+
B(pin)
MeI, KOt-Bu
THF, 22 C
15
16a
16b
7
8
9
yield of
entry
Cu complex
Cu (mol %)
base
time (h) conv (%)b 16a:16bb
16a (%)b
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
2
3
4
5
6
7
8
Xantphos+CuCl
NQIMesCuCl
IPrCuCl
10
10
10
10
10
10
5
NaOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
12
3
39
85:15
86:14
67:33
88:12
93:7
33
>98
48
86
32
88
93
92
94
92
3
SIMesCuCl
IMesCuCl
3
>98
>98
>98
>98
>98
3
ICyCuCl
3
92:8
BenzICyCuCl
BenzICyCuCl
3
94:6
3
3
92:8
aReactions run at 0.12 mmol scale with respect to 15. Conditions: 1.0 equiv. of alkyne 15, 3.0 equiv. of MeI,
1.3 equiv. of B2(pin)2, 1.5 equiv. of base and THF (0.2 M) under N2. bDetermined by 1H NMR spectrum analysis
using 1,3,5ꢀtrimethoxybenzene as an internal standard.
Figure 2. Various NHCꢀCu complexes studied for methylboronation.
With the optimized reaction conditions for the Cuꢀcatalyzed methylboronation of alkynes in
hand, we examined a wide range of readily available terminal alkynes, as depicted in Table 2. All
reactions were performed in THF at ambient temperature in the presence of 3 mol % of the
BenzICyCuCl catalyst (Figure 2), providing various cisꢀmethyl alkenyl boronates with good yields
(77~86%) and high stereoꢀ and regioselectivities. First, normal alkylꢀsubstituted alkynes were employed
8
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
for the catalytic system, affording the desired methyl boronates 20aꢀb and 20e efficiently (80ꢀ83%
yields, entries 2ꢀ3 and entry 6). Entries 4ꢀ5 showed that the catalytic process tolerated different
functional groups, including a chloro and ester group, to give products 20cꢀd with high regioselectivities
and good yields. When terminal alkynes bearing a sterically demanding cyclohexyl or tertꢀbutyl
substituent were used, the corresponding methylboronated products were obtained with yields of 83ꢀ
86% (entries 7ꢀ9), although a longer reaction time was required for the reaction with the tertꢀbutyl
substituted alkyne (24 h instead of 3 h). The methylboronation of phenylacetylene was less efficient
than that of the alkylꢀsubstituted terminal alkynes; the reaction was conducted for 24 h and furnished the
phenylꢀsubstituted product 20i with a yield of 77% (entry 10). For the reaction with phenylacetylene,
lithium tertꢀbutoxide was used because of the preferable deprotonation of a hydrogen on
phenylacetylene by potassium tertꢀbutoxide.
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
Table 2. CuꢀCatalyzed methylboronation of various alkynesa
entry
products
20:21b
94:6
93:7
92:8
92:8
yield (%)c
1
2
3
4
84
83
81
84
16a
20a
20b
20c
5
98:2
84
20d
6
7
91:9
94:6
80
83
20e
20f
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 27
1
2
3
4
5
6
7
8
9
8
96:4
86
86
77
20g
20h
20i
9d
>98:<2
>98:<2
10e
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
aReactions run on 0.4 mmol scale with respect to the alkyne. Conditions: 1.0 equiv. of terminal alkyne 19, 3.0
1
equiv. of MeI, 1.3 equiv. of B2(pin)2, 1.5 equiv. of base and THF (0.2 M) under N2. bDetermined by H NMR
spectrum analysis of unpurified mixtures. cYields of the isolated products. d24 h reaction time. eLiOtꢀBu and 24 h
reaction time used.
Next, with geranyl boronate product 4 in hand, we investigated the final stage of the synthesis of
isohericenone and erinacerin A: forming the CꢀC bond between 4 and aryl bromide 5 via palladiumꢀ
catalyzed crossꢀcoupling (Scheme 4). The coupling reaction in the presence of 7 mol % Pd(dppf)Cl2 and
cesium carbonate afforded the desired product 17 with a yield of 68%. After deprotection of the TBS
group with TBAF, the alcohol intermediate was oxidized with 5 mol % of 2ꢀazaadamantaneꢀNꢀoxyl
(AZADO) and iodobenzene diacetate (PhI(OAc)2), installing the carbonyl group at the C5’ position of
18.4a The MOMꢀprotecting group in 18 would be removed under acidic conditions; however,
isohericenone (2) was prone to further intramolecular cyclization to form erinacerin A (3) under acidic
conditions. Hence, after briefly screening acids and reaction temperatures, we found that the MOM
group of 18 was cleaved under mildly acidic conditions when pyridinium pꢀtoluenesulfonate (PPTS)
was used, providing the final isohericenone (2) product with a yield of 50% yield. By contrast, when 18
was subjected to HCl, the intramolecular ring closing reaction readily proceeded in one pot to deliver
another natural product, erinacerin A (3), with a yield of 92%. The NMR spectral data of the three
synthesized compounds (1ꢀ3) were identical to those of the natural products reported in the literature.2,4a
10
ACS Paragon Plus Environment

Page 11 of 27
The Journal of Organic Chemistry
Scheme 4. Total synthesis of isohericenone and erinacerin A
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
CONCLUSIONS
In summary, we have successfully achieved efficient and straightforward total syntheses of
isohericerin, isohericenone, and erinacerin A. The common isoindolinone core was synthesized in 3
steps. Specifically, Mannich reaction with hydroxybenzonate and an intramolecular cyclization with
oxazine afforded bromoꢀsubstituted isoindolinone, which was then coupled with the geranyl boronate
side chain under SuzukiꢀMiyaura conditions. For forming the C5’ꢀoxidized geranyl unit in
isohericenone and erinacerin A, we developed a mild and selective methylboronation reaction of
terminal alkynes with B2(pin)2 and methyl iodide promoted by an NHCꢀCu catalyst. This reacation
effectively furnished the cisꢀmethyl alkenyl boronate, which was transformed into the oxidized geranyl
boronate under Matteson homologation conditions. Readily accessible terminal alkynes, including those
normal alkyl, sterically demanding alkyl, ether, chloro, and ester substituents, were tolerated in the
copper catalytic system, providing versatile cisꢀmethyl alkenyl boronates with good yields. In the future,
their biological activities will be evaluated.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 27
EXPERIMENTAL SECTION
1
2
General. Infrared (IR) spectra were recorded in reciprocal centimeters (cmꢀ1). Bands are characterized
3
4
5
6
1
as broad (br), strong (s), medium (m), and weak (w). H NMR spectra were recorded on a 400 MHz
7
8
9
spectrometer. Chemical shifts are reported in ppm from tetramethylsilane, with the solvent resonance as
the internal standard (CDCl3: δ 7.27 ppm). Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), coupling constants (Hz), and integration.
13C NMR spectra were recorded on a 100 MHz spectrometer with complete proton decoupling.
Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal
standard (CDCl3: δ 77.00 ppm). Highꢀresolution mass spectra (HRMS) were obtained using an
electrospray ionization (ESI) timeꢀofꢀflight mass spectrometer. Melting points were determined using a
melting point apparatus and are uncorrected. Microwave reactions were conducted in sealed glass tubes
(capacity 10 mL) using a CEM Discover microwave reactor (Model No. 908005) with temperature
control via external infrared sensor. Unless otherwise noted, all reactions were carried out with distilled
solvents under an atmosphere of dry N2 in ovenꢀdried (130 °C) glassware. N,N’ꢀDimethylformamide
was purified by simple distillation over magnesium sulfate, and methanol was purified by distillation
from sodium. Tetrahydrofuran and diethyl ether were purified by distillation from sodium
benzophenone ketyl immediately prior to use, unless otherwise specified. Acetonitrile and
dichloromethane were purified by distillation from calcium hydride. All workꢀup and purification
procedures were carried out with reagent grade solvents in air. NHCꢀCu complexes were prepared
according to reported experimental procedures.15
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
Experimental procedures for the synthesis of isohericerin (1), isohericenone (2), and erinacerin A
(3):
Methyl 8-bromo-7-methoxy-3-phenethyl-3,4-dihydro-2H-benzo[e][1,3]oxazine-5-carboxylate (9).
Methyl 4ꢀbromoꢀ3ꢀhydroxyꢀ5ꢀmethoxybenzoate (6) (50.0 mg, 0.191 mmol), phenethylamine (30.0 ꢁL,
0.230 mmol), 38% aqueous formaldehyde (55.6 ꢁL, 0.230 mmol) and methanol (0.8 mL) were added
12
ACS Paragon Plus Environment

Page 13 of 27
The Journal of Organic Chemistry
into a sealed tube. The reaction mixture was allowed to heat to 110 °C and stir for 3 h. Then, the
reaction was quenched with water (3 mL) and washed with EtOAc (3 mL × 3). The organic layers were
combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel
column chromatography (hexanes/EtOAc, 1:4), affording the desired product 9 (59.7 mg, 0.147 mmol,
77%) as a white solid. mp 115.7ꢀ116.6 °C; IR (neat): 1713 (w), 1659 (w), 1589 (w), 1466 (w), 1366
(w), 1319 (w), 1273 (w), 1134 (w), 1088 (w), 1049 (w), 1011 (w), 964 (w), 918 (w), 841(w), 756 (s); 1H
NMR (400 MHz, CDCl3): δ 7.30ꢀ7.26 (m, 2H), 7.21ꢀ7.17 (m, 4H), 5.02 (s, 2H), 4.38 (s, 2H), 3.93 (s,
3H), 3.90 (s, 3H), 3.00 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3):
166.7, 155.0, 152.7, 139.7, 128.7, 128.4, 127.8, 126.2, 117.1, 106.0, 105.6, 83.2, 56.3, 53.1, 52.1, 49.6,
34.8; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C19H21BrNO4 406.0654, Found 406.0651.
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
5-Bromo-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (10). An aqueous solution of K3PO4
(2.5 M, 0.63 mL) was added to a solution of compound 9 (57.1 mg, 0.140 mmol) in acetonitrile (0.31
mL). The reaction mixture was allowed to heat to 100 °C and stir for 15 h. The reaction was quenched
with brine (30 mL) and washed with CHCl3 (3 × 30 mL). The organic layers were combined, dried over
MgSO4, filtered and concentrated. The crude product was purified by washing with hexane to obtain the
desired product 10 (48.3 mg, 0.133 mmol, 95%) as a white solid. mp 237.5ꢀ237.7 °C; IR (neat): 1643
(s), 1566 (s), 1474 (s), 1435 (m), 1342 (m), 1296 (s), 1242 (w), 1165 (m), 1142 (m), 1088 (s), 1026 (w),
972 (w), 895 (w), 833 (m), 748 (m), 702 (s), 617 (m); 1H NMR (400 MHz, DMSOꢀd6): δ 7.28ꢀ7.20 (m,
5H), 6.80 (s, 1H), 4.25 (s, 2H), 3.86 (s, 3H), 3.75 (t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H); 13C NMR
(100 MHz, DMSOꢀd6): δ 166.9, 157.1, 150.1, 139.0, 133.0, 128.6, 128.5, 126.3, 121.3, 103.5, 97.0,
56.6, 47.8, 43.3, 33.9; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H17BrNO3 362.0392, Found
362.0393.
5-Bromo-6-me hoxy-4-(methoxymethoxy)-2-phenethylisoindolin-1-one (5). To a solution of
compound 10 (9.00 mg, 0.0248 mmol) in N,N’ꢀdimethylformamide (0.1 mL) was added NaH (60% in
paraffin, 1.50 mg, 0.0372 mmol) at 0 °C (ice bath). The mixture was allowed to stir at 0 °C for 5 min,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 27
then warm to room temperature and stir for 15 min under N2 gas. Next, chloromethylmethyl ether (2.82
ꢁL, 0.0372 mmol) was added, and the reaction mixture was allowed to stir at 0 °C for 5 min and stir at
room temperature for 15 min. The resulting solution was quenched with water (2 mL) and washed with
CH2Cl2 (3 × 3 mL). The organic layers were washed with 1 M NaOH (9 mL), dried over MgSO4,
filtered and concentrated. The crude product was purified by silica gel column chromatography
(hexanes/EtOAc, 1:1), affording the desired product 5 (9.90 mg, 0.0244 mmol, 98%) as a white solid.
mp 85ꢀ86 °C; IR (neat): 2361 (w), 1690 (m), 1612 (w), 1466 (m), 1427 (w), 1327 (w), 1265 (w), 1157
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
1
(w), 1080 (w), 980 (w), 918 (w), 825 (w) 733 (s); H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.23 (m, 5H),
7.18 (s, 1H), 5.11 (s, 2H), 4.24 (s, 2H), 3.97 (s, 3H), 3.87 (t, J = 7.2 Hz, 2H), 3.51 (s, 3H), 3.00 (t, J =
13
7.2 Hz, 2H); C NMR (100 MHz, CDCl3): δ 167.6, 157.9, 150.5, 138.8, 134.0, 128.8, 128.7, 126.7,
125.6, 110.2, 101.9, 98.2, 57.2, 56.9, 49.0, 44.3, 34.8; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C19H21BrNO4 406.0654, Found 406.0645.
(E)-5-(3,7-dimethylocta-2,6-dien-1-yl)-6-methoxy-4-(methoxymethoxy)-2-phenethylisoindolin-1-
one (12). PdCl2(dppf)•CH2Cl2 (3.30 mg, 3.97x10ꢀ3 mmol), cesium carbonate (27.7 mg, 0.0851 mmol)
and compound 5 (23.0 mg, 0.0566 mmol) were added into a 10 mL microwave tube in a glove box.
After removing the tube from the glove box, it was filled with N2 gas and then a solution of (E)ꢀ2ꢀ(3,7ꢀ
dimethyloctaꢀ2,6ꢀdienꢀ1ꢀyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (11) (22.5 mg, 0.0851 mmol) in
DMF (0.2 mL) was added. The reaction mixture was sealed in a microwave tube and stirred at 110 °C
under focused microwave irradiation (100 W) for 2 h, maintaining the temperature using an external IR
sensor. The resulting solution was cooled to room temperature, quenched with water (2 mL) and washed
with EtOAc (3 × 1 mL). The organic layers were washed with a saturated aqueous solution of NaHCO3
(3 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel
column chromatography (hexanes/EtOAc, 1:1), furnishing the desired product 12 (16.5 mg, 0.0356
mmol, 63%) as a white solid. (This compound has been previously reported, and its spectral data match
those described in the literature).7 1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.23 (m, 5H), 7.14 (s, 1H), 5.13
14
ACS Paragon Plus Environment

Page 15 of 27
The Journal of Organic Chemistry
(t, J = 6.6 Hz, 1H), 5.05 (t, J = 6.7 Hz, 1H), 5.00 (s, 2H), 4.25 (s, 2H), 3.88 (s, 3H), 3.85 (br t, J = 7.4
Hz, 2H), 3.48 (s, 3H), 3.41 (d, J = 6.8 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.06ꢀ2.02 (m, 2H), 1.98ꢀ1.94
(m, 2H), 1.76 (s, 3H), 1.64 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3): 168.4, 159.1, 150.9,
139.0, 135.5, 132.6, 131.4, 128.8, 128.7, 126.5, 126.4, 124.4, 124.3, 122.1, 101.0, 97.9, 56.7, 56.0, 49.4,
44.1, 39.7, 34.9, 26.6, 25.6, 23.4, 17.6, 16.1.
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
(E)-5-(3,7-Dimethylocta-2,6-dienyl)-6-methoxy-4-(methoxy-methoxy)-2-phenethylisoindolin-1-one
(isohericerin, 1). To a solution of compound 12 (2.50 mg, 5.39x10ꢀ3 mmol) in methanol (0.3 mL) was
added 0.2 M HCl (in methanol, 269 ꢁL, 0.0539 mmol). The reaction mixture was allowed to stir at room
temperature for 3 h. The reaction was quenched by adding a saturated aqueous solution of NaHCO3 (1
mL) and washed with EtOAc (3 × 1 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated. The crude product was purified by silica gel column chromatography
(hexanes/EtOAc, 2:1) to provide isohericerin (2.20 mg, 0.00524 mmol, 97%) as a white solid. (This
compound has been previously reported, and its spectral data match those described in the literature).2,7
1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.22 (m, 5H), 6.97 (s, 1H), 5.77 (s, 1H), 5.25 (t, J = 6.7 Hz, 1H),
5.05ꢀ5.02 (m, 1H), 4.14 (s, 2H), 3.87ꢀ3.84 (m, 5H), 3.50 (d, J = 7.1 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H),
2.13ꢀ2.11 (m, 4H), 1.82 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H); 13C NMR (100 MHz, CDCl3): 169.0, 158.6,
150.6, 139.4, 138.8, 132.2, 132.2, 128.7, 128.6, 126.5, 123.7, 121.3, 121.2, 118.5, 97.6, 56.1, 48.1, 44.2,
39.6, 34.8, 26.2, 25.6, 22.7, 17.6, 16.1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C27H34NO3
420.2539, Found 420.2532.
6-Methylhept-5-en-1-yn-4-ol (14). Zinc activated by HCl (149 mg, 2.28 mmol) and THF (2.5 mL)
were added into a 2ꢀneck flask at 0 °C (ice bath) under N2 gas. Iodine (20.0 mg) was added and the
mixture was allowed to stir until the dark brown color of iodine faded. A solution of propargyl bromide
(13) (80% in toluene, 201 µL, 1.81 mmol) in THF (2 mL) was added to the reaction mixture slowly by
using a dropping funnel, and the resulting solution was allowed to stir at 0 °C for 1 h. Next, 3ꢀmethylꢀ2ꢀ
butenal (8) (91.0 µL, 0.951 mmol) was added, and the mixture was allowed to stir at 0 °C for an
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 27
additional 30 min. The resulting solution was passed through a short plug of Celite, quenched by adding
a saturated aqueous solution of NaHCO3 (10 mL) and washed with ether (15 mL × 3). The organic
layers were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by
silica gel column chromatography (hexanes/Et2O, 3:1) to provide the desired alcohol product 14 (114
mg, 0.918 mmol, 97%) as a yellow oil. (This compound has been previously reported, and its spectral
data match those described in the literature).17 1H NMR (400 MHz, CDCl3): δ 5.26 (d, J = 8.5 Hz, 1H),
4.55ꢀ4.49 (m, 1H), 2.42ꢀ2.39 (m, 2H), 2.04 (t, J = 2.6 Hz, 1H), 1.95 (d, J = 3.9 Hz, 1H), 1.74 (s, 3H),
1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.9, 125.9, 80.8, 70.4, 66.7, 27.6, 25.6, 18.2.
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
tert-Butyldimethyl((6-methylhept-5-en-1-yn-4-yl)oxy)silane (15). To a solution of compound 14 (927
mg, 7.47 mmol), 4ꢀdimethylaminopyridine (456 mg, 3.73 mmol) and tertꢀbutyldimethylchlorosilane
(2.30 g, 14.9 mmol) in CH2Cl2 (25 mL) was added Et3N (2.30 mL, 16.4 mmol). The reaction mixture
was allowed to stir at room temperature for 15 h. The reaction was quenched by adding a saturated
aqueous solution of NaHCO3 (30 mL) and washed with CH2Cl2 (3 × 30 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel
column chromatography (hexanes/Et2O, 20:1) to provide product 15 (1.47 g, 6.19 mmol, 83%) as a
yellow oil. (This compound has been previously reported, and its spectral data match those described in
the literature).17 1H NMR (400 MHz, CDCl3): δ 5.15 (d, J = 8.8 Hz, 1H), 4.55ꢀ4.49 (m, 1H), 2.39 (ddd,
J = 16.3, 6.3, 2.4 Hz, 1H), 2.28 (ddd, J = 16.6, 6.3, 2.4 Hz, 1H), 1.94ꢀ1.93 (m, 1H), 1.72 (s, 3H), 1.67 (s,
13
3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); C NMR (100 MHz, CDCl3): δ 133.0, 127.9, 81.8, 69.2,
68.4, 28.5, 25.7, 25.6, 18.4, 18.1, ꢀ4.5, ꢀ4.9.
(E)-tert-Butyl((2,6-dimethyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hepta-1,5-dien-4-
yl)oxy)dimethylsilane (16a). Bis(pinacolato)diboron (132 mg, 0.520 mmol), BenzICyCuCl (4.60 mg,
0.012 mmol) and KOtꢀBu (67.3 mg, 0.600 mmol) were added into an 8 mL vial in a glove box. The vial
was sealed with a PTFE/silicone septa using an open top screw cap and removed from the glove box.
The vial was filled with N2 gas and THF (1.6 mL) was added at 0 °C (ice bath). The mixture was
16
ACS Paragon Plus Environment

Page 17 of 27
The Journal of Organic Chemistry
allowed to stir at 0 °C for 10 min. Next, a solution of compound 15 (95.2 mg, 0.400 mmol) in THF (0.4
mL) and iodomethane (74.0 ꢁL, 0.12 mmol) were added at ꢀ78 °C (dry ice/acetone bath). The resulting
mixture was allowed to warm to room temperature and stir for 3 h. The reaction was quenched by
adding a saturated aqueous solution of NH4Cl (2 mL) and washed with ether (3 × 2 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by
silica gel column chromatography (hexanes/Et2O, 60:1), affording the desired product 16a (128 mg,
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
1
0.337 mmol, 84%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 5.14ꢀ5.11 (m, 2H), 4.51ꢀ4.45 (m,
1H), 2.28 (dd, J = 12.7, 8.0 Hz, 1H), 2.13 (dd, J = 12.9, 5.1 Hz, 1H), 2.00 (s, 3H), 1.67 (s, 3H), 1.60 (s,
3H), 1.25 (s, 12H), 0.84 (s, 9H), 0.00 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) :δ 160.1,
131.0, 129.4, 116.2, 82.4, 69.4, 51.1, 25.8, 25.5, 24.7, 24.7, 22.1, 18.1, 18.1, ꢀ4.4, ꢀ5.0; HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C21H42BO3Si 381.2996, Found 381.2974.
(E)-tert-Butyl((2,6-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octa-2,6-dien-4-
yl)oxy)dimethylsilane (4). To a solution of compound 16a (61.9 mg, 0.163 mmol) in diethyl ether (1
mL) was added chloroiodomethane (18.0 µL, 0.244 mmol) at ꢀ78 °C (dry ice/acetone bath). Next, nꢀ
BuLi (72.0 µL, 0.179 mmol) was added very slowly at ꢀ78 °C. The resulting mixture (light sensitive)
was allowed to stir at ꢀ78 °C for 1 h. Then, the reaction mixture was allowed to warm to room
temperature and stir for 19 h. The reaction was quenched with water (2 mL) and washed with ether (3 ×
2 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude
product was purified by silica gel column chromatography (hexanes/Et2O, 20:1 with 1% Et3N),
1
providing the desired product 4 (56.4 mg, 0.143 mmol, 88%) as a yellow oil. H NMR (400 MHz,
CDCl3): δ 5.25 (t, J = 7.2 Hz, 1H), 5.10 (d, J = 8.8 Hz, 1H), 4.42ꢀ4.37 (m, 1H), 2.20 (dd, J = 12.9, 6.8
Hz, 1H), 2.02 (dd, J = 12.9, 5.8 Hz, 1H) 1.67 (s, 3H), 1.60 (s, 6H), 1.24 (s, 12H), 0.86 (s, 9H), 0.01 (s,
3H), ꢀ0.01 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 131.9, 130.7, 129.7, 121.4, 83.0, 69.3, 48.7, 25.8,
25.6, 24.7, 18.1, 16.7, ꢀ4.5, ꢀ4.9; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C22H43BO3SiNa
417.2972, Found 417.2979.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 27
(E)-5-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-dien-1-yl)-6-methoxy-4-
1
2
3
4
5
6
7
8
9
(methoxymethoxy)-2-phenethylisoindolin-1-one (17). PdCl2(dppf)•CH2Cl2 (7.00 mg, 0.00861 mmol),
cesium carbonate (60.3 mg, 0.185 mmol) and compound 5 (50.0 mg, 0.123 mmol) were added into a 10
mL microwave tube in a glove box. After removing the tube from the glove box, it was filled with N2
gas and a solution of compound 4 (73.0 mg, 0.185 mmol) in DMF (0.8 mL) was added into the tube.
The reaction mixture was sealed in a microwave tube and stirred at 110 °C under focused microwave
irradiation (100 W) for 2 h, maintaining the temperature using an external IR sensor. Next, the reaction
was cooled, quenched with water (2 mL) and washed with EtOAc (3 × 2 mL). The organic layers were
washed with a saturated aqueous solution of NaHCO3 (2 mL), dried over MgSO4, filtered and
concentrated. The crude product was purified by silica gel column chromatography (hexanes/EtOAc,
2:1 with 1% Et3N), providing the desired product 17 (49.8 mg, 0.0839 mmol, 68%) as a yellow oil.
(This compound has been previously reported, and its spectral data match those described in the
literature).4a 1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.20 (m, 5H), 7.13 (s, 1H), 5.17 (t, J = 6.9 Hz, 1H),
5.05 (d, J = 8.8 Hz, 1H), 5.00 (s, 2H), 4.42ꢀ4.36 (m, 1H), 4.24 (s, 2H), 3.88ꢀ3.84 (m, 5H), 3.48 (s, 3H),
3.41ꢀ3.38 (m, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.15 (dd, J = 12.9, 7.0 Hz, 1H), 1.99 (dd, J = 13.1, 5.6 Hz),
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
13
1.78 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H), 0.82 (s, 9H), ꢀ0.04 (s, 3H), ꢀ0.05 (s, 3H); C NMR (100 MHz,
CDCl3): δ 168.4, 159.0, 150.9, 139.0, 132.6, 132.2, 130.8, 129.5, 128.8, 128.7, 126.5, 126.2, 124.9,
124.2, 100.9, 97.8, 68.8, 56.7, 56.0, 49.4, 48.7, 44.1, 34.9, 25.8, 25.7, 25.5, 23.5, 18.1, 18.0, 16.9, ꢀ4.5, ꢀ
5.0.
(E)-5-(5-Hydroxy-3,7-dimethylocta-2,6-dien-1-yl)-6-methoxy-4-(methoxymethoxy)-2-
phenethylisoindolin-1-one (17`). To a solution of compound 17 (8.70 mg, 0.0146 mmol) in THF (1.6
mL) was added tetrabutylammonium fluoride (1 M in THF, 66.0 µL, 0.0659 mmol). The reaction
mixture was allowed to stir at 40 °C for 4 h. Next, the resulting solution was directly loaded on silica gel
for column chromatography (hexanes/EtOAc, 1:1 with 1% Et3N), providing the desired product 17`
(5.10 mg, 0.0106 mmol, 73%) as a yellow oil. (This compound has been previously reported, and its
18
ACS Paragon Plus Environment

Page 19 of 27
The Journal of Organic Chemistry
spectral data match those described in the literature).4a 1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.21 (m,
5H), 7.14 (s, 1H), 5.26 (t, J = 6.5 Hz, 1H), 5.12 (d, J = 8.5 Hz, 1H), 5.03ꢀ4.99 (m, 2H), 4.44ꢀ4.40 (m,
1H), 4.24 (s, 2H), 3.88ꢀ3.84 (m, 5H), 3.48 (s, 3H), 3.46ꢀ3.43 (m, 2H), 2.99 (t, J = 7.4 Hz, 2H), 2.16ꢀ2.06
1
2
3
4
5
6
7
8
9
13
(m, 2H), 1.82 (s, 3H), 1.69 (s, 3H), 1.68 (s, 3H); C NMR (100 MHz, CDCl3): δ 168.3, 159.0, 150.8,
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
139.0, 134.9, 132.9, 132.0, 128.8, 128.7, 127.5, 126.6, 126.6, 125.6, 124.2, 101.0, 97.7, 65.7, 56.8, 56.1,
49.4, 48.1, 44.1, 34.9, 25.7, 23.5, 18.1, 16.2.
(E)-5-(3,7-dimethyl-5-oxoocta-2,6-dien-1-yl)-6-methoxy-4-(methoxymethoxy)-2-
phenethylisoindolin-1-one (18). A solution of compound 17` (20.6 mg, 0.0429 mmol), PhI(OAc)2
(68.9 mg, 0.215 mmol) and AZADO (0.340 mg, 0.00215 mmol) in CH2Cl2 (1 mL) was allowed to stir at
room temperature for 6 h under N2 gas. Then, additional PhI(OAc)2 (27.0 mg, 0.0838 mmol) and
AZADO (1.00 mg, 0.00657 mmol) were added. The resulting mixture was allowed to stir for additional
30 min. The reaction was quenched by adding a saturated aqueous solution of NaHCO3 (1 mL), and a
saturated aqueous solution of NaS2CO3 (1 mL) and was washed with EtOAc (3 × 2 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by
silica gel column chromatography (hexanes/EtOAc, 1:1 with 1% Et3N) to afford the desired product 18
(12.7 mg, 0.0266 mmol, 62%) as a yellow oil. (This compound has been previously reported, and its
spectral data match those described in the literature).4a 1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.21 (m,
5H), 7.14 (s, 1H), 6.07 (s, 1H), 5.28 (t, J = 6.8 Hz, 1H), 5.01 (s, 2H), 4.25 (s, 2H), 3.88ꢀ3.84 (m, 5H),
13
3.48ꢀ3.46 (m, 5H), 3.02ꢀ2.98 (m, 4H), 2.13 (s, 3H), 1.84 (s, 3H), 1.79 (s, 3H); C NMR (100 MHz,
CDCl3): δ 199.4, 168.3, 159.1, 155.6, 150.9, 139.0, 132.8, 130.1, 128.8, 128.7, 127.0, 126.5, 125.5,
124.2, 122.9, 100.9, 97.8, 56.7, 56.0, 55.4, 49.4, 44.1, 34.9, 27.6, 23.6, 20.6, 16.4.
(E)-5-(3,7-Dimethyl-5-oxoocta-2,6-dien-1-yl)-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one
(isohericenone, 2). To a solution of compound 18 (3.10 mg, 0.00649 mmol) in methanol (0.2 mL) was
added PPTS (16.3 mg, 0.0649 mmol), and the reaction mixture was allowed to warm to 60 °C and stir
for 8 h. The resulting solution was quenched by adding a saturated aqueous solution of NaHCO3 (0.5
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 27
mL) and washed with EtOAc (3 × 0.5 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated. The crude product was purified by silica gel column chromatography
(hexanes/EtOAc, 1:1), providing the desired product isohericenone (1.40 mg, 0.00323 mmol, 50%) as a
yellow oil. (This compound has been previously reported, and its spectral data match those described in
the literature).2,4a 1H NMR (400 MHz, CDCl3): δ 7.31ꢀ7.22 (m, 5H), 6.98 (s, 1H), 6.33 (s, 1H), 6.08 (s,
1H), 5.31 (t, J = 6.8 Hz, 1H), 4.19 (s, 2H), 3.88ꢀ3.84 (m, 5H), 3.57 (d, J = 7.1 Hz, 2H), 3.16 (s, 2H),
2.99 (t, J = 7.3 Hz, 2H), 2.17 (s, 3H), 1.90 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.8,
168.8, 158.4, 156.9, 150.8, 138.9, 133.4, 132.5, 128.8, 128.6, 126.5, 126.3, 123.1, 122.1, 118.1, 97.8,
56.1, 54.5, 48.1, 44.1, 34.8, 29.6, 27.7, 23.0, 20.9.
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
5-Methoxy-2-methyl-2-(4-methyl-2-oxopent-3-en-1-yl)-8-phenethyl-3,4,8,9-tetrahydropyrano[2,3-
e]isoindol-7(2H)-one (erinacerin A, 3). A solution of compound 18 (3.00 mg, 0.00628 mmol) and 6 M
HCl (in methanol, 200 µL) in methanol (0.4 mL) was allowed to stir at 50 °C for 30 min. Next, the
solvent was removed, and the crude product was purified by silica gel column chromatography
(hexanes/EtOAc, 1:1), affording the desired product erinacerin A (2.50 mg, 0.00577 mmol, 92%) as a
yellow oil. (This compound has been previously reported, and its spectral data match those described in
the literature).4a,5 1H NMR (400 MHz, CDCl3): δ 7.33ꢀ7.21 (m, 5H), 6.91 (s, 1H), 6.05 (s, 1H), 4.15 (d,
J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.86ꢀ3.82 (m, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.76 (d, J = 14.1 Hz, 1H),
2.71ꢀ2.67 (m, 2H), 2.64 (d, J = 14.4 Hz, 1H), 2.15 (s, 3H), 2.06ꢀ1.99 (m, 1H), 1.95ꢀ1.89 (m, 1H), 1.85
13
(s, 3H), 1.41 (s, 3H); C NMR (100 MHz, CDCl3): δ 198.2, 169.0, 158.6, 155.7, 148.7, 138.8, 132.3,
128.8, 128.7, 126.5, 125.1, 121.9, 113.5, 96.2, 75.9, 55.9, 52.2, 47.9, 44.1, 34.9, 30.5, 27.8, 24.7, 20.7,
17.3.
Representative experimental procedures for the Cu-catalyzed methylboronation of terminal
alkynes:
20
ACS Paragon Plus Environment

Page 21 of 27
The Journal of Organic Chemistry
General procedure A: Bis(pinacolato)diboron (132 mg, 0.520 mmol), BenzICyCuCl (4.60 mg, 0.012
mmol) and KOtꢀBu (67.3 mg, 0.600 mmol) were added into an 8 mL vial in a glove box. The vial was
sealed with a PTFE/silicone septa using an open top screw cap and removed from the glove box. The
vial was filled with N2 gas and THF (1.6 mL) was added at 0 °C (ice bath). The mixture was allowed to
stir at 0 °C for 10 min. Then, a solution of compound 15 (95.2 mg, 0.400 mmol) in THF (0.4 mL) and
iodomethane (74.0 ꢁL, 0.12 mmol) were added at ꢀ78 °C (dry ice/acetone bath). The resulting mixture
was allowed to warm to room temperature and stir for 3 h. The reaction was quenched by adding a
saturated aqueous solution of NH4Cl (2 mL) and washed with ether (3 × 2 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel
column chromatography (hexanes/Et2O, 60:1), providing the desired product 16a (128 mg, 0.337 mmol,
84%) as a yellow oil.
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
General procedure B: Bis(pinacolato)diboron (66.0 mg, 0.260 mmol), BenzICyCuCl (2.30 mg, 0.006
mmol) and LiOtꢀBu (24.0 mg, 0.300 mmol) were added into an 8 mL vial in a glove box. The vial was
sealed with a PTFE/silicone septa using an open top screw cap and removed from the glove box. The
vial was filled with N2 gas and THF (1.5 mL) was added at room temperature. The mixture was allowed
to stir for 10 min, and then phenylacetylene (22.0 µL, 0.200 mmol) and iodomethane (37.0 ꢁL, 0.600
mmol) were added at room temperature. The resulting mixture was allowed to stir at room temperature
for 3 h. The reaction was quenched by adding a saturated aqueous solution of NH4Cl (2 mL) and
washed with ether (3 × 2 mL). The combined organic layers were dried over MgSO4, filtered and
concentrated. The crude product was purified by silica gel column chromatography (hexanes/Et2O,
60:1), providing the desired product 20i (37.7 mg, 0.154 mmol, 77%) as a colorless oil.
(E)-4,4,5,5-Tetramethyl-2-(2-methyloct-1-en-1-yl)-1,3,2-dioxaborolane (20a). According to general
procedure A, compound 20a was synthesized using 1ꢀoctyne (59.0 ꢁL, 0.400 mmol) and obtained as a
colorless oil with a yield of 83% (83.3 mg, 0.330 mmol). (This compound has been previously reported,
and its spectral data match those described in the literature.)18 1H NMR (400 MHz, CDCl3): δ 5.10 (s,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 27
1H), 2.07 (t, J = 7.7 Hz, 2H), 1.96 (s, 3H), 1.44ꢀ1.39 (m, 2H), 1.25 (s, 18H), 0.86 (t, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 163.4, 112.8, 82.5, 42.1, 31.7, 28.9, 27.5, 24.7, 22.5, 21.0, 14.0. (E)-
4,4,5,5-tetramethyl-2-(non-2-en-3-yl)-1,3,2-dioxaborolane (21a). 1H NMR (400 MHz, CDCl3): δ 6.08
(q, J = 6.8 Hz, 1H), 2.08 (t, J = 7.1 Hz, 2H), 1.88 (d, J = 6.8, 3H), 1.35ꢀ1.25 (m, 8H), 1.28 (s, 12H), 0.88
(t, J = 7.0Hz , 3H); 13C NMR (100 MHz, CDCl3): δ 140.1, 82.8, 36.9, 31.7, 30.2, 28.9, 24.7, 22.5, 17.1,
14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H30BO2 253.2339, Found 253.2332.
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
(E)-4,4,5,5-Tetramethyl-2-(2-methylhex-1-en-1-yl)-1,3,2-dioxaborolane (20b). According to general
procedure A, compound 20b was synthesized using 1ꢀhexyne (45.8 ꢁL, 0.400 mmol) and obtained as a
1
colorless oil with a yield of 81% (72.8 mg, 0.325 mmol). H NMR (400 MHz, CDCl3): δ 5.11 (s, 1H),
2.09 (t, J = 7.6 Hz, 2H), 1.97 (s, 3H), 1.46ꢀ1.38 (m, 2H), 1.34ꢀ1.30 (m, 2H), 1.26 (s, 12H), 0.88 (t, J =
7.2, 3H); 13C NMR (100 MHz, CDCl3): δ 163.4, 112.5, 82.5, 41.8, 29.7, 24.8, 22.3, 21.1, 13.9; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H25BO2Na 247.1845, Found 247.1851.
(E)-2-(5-Chloro-2-methylpent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20c). Compound
20c was synthesized according to general procedure A using 5ꢀchloroꢀ1ꢀpentyne (42.4 ꢁL, 0.400 mmol)
to obtain as colorless oil in 84% yield (81.7 mg, 0.334 mmol). 1H NMR (400 MHz, CDCl3): δ 5.13 (s,
1H), 3.52 (t, J = 6.8 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 1.98 (s, 3H), 1.96ꢀ1.89 (m, 2H), 1.26 (s, 12H);
13C NMR (100 MHz, CDCl3): δ 160.8, 113.7, 82.7, 44.5, 38.8, 30.3, 24.8, 24.7, 21.1; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C12H22BClO2Na 267.1299, Found 267.1306.
(E)-tert-Butyl
6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hept-6-enoate
(20d).
According to general procedure A, compound 20d was synthesized using tertꢀbutyl heptꢀ6ꢀynoate (73.0
1
mg, 0.400 mmol)19 and obtained as a colorless oil with a yield of 84% (108.6 mg, 0.335 mmol). H
NMR (400 MHz, CDCl3): δ 5.09 (s, 1H), 2.19 (t, J = 7.3 Hz, 2H), 2.08 (t, J = 7.4 Hz, 2H), 1.95 (s, 3H),
1.59ꢀ1.53 (m, 2H), 1.46ꢀ1.45 (m, 2H), 1.42 (s, 9H), 1.24 (s, 12H); 13C NMR (100 MHz, CDCl3): δ
22
ACS Paragon Plus Environment

Page 23 of 27
The Journal of Organic Chemistry
173.1, 162.6, 113.0, 82.5, 79.9, 41.6, 35.3, 28.0, 26.9, 24.7, 24.6, 20.9; HRMS (ESIꢀTOF) m/z: [M +
1
2
3
4
H]+ Calcd for C18H34BO4 325.2550, Found 325.2570.
5
6
7
8
9
(E)-4,4,5,5-Tetramethyl-2-(2-methyl-4-phenylbut-1-en-1-yl)-1,3,2-dioxaborolane (20e). According
to general procedure A, compound 20e was synthesized using 4ꢀphenylꢀ1ꢀbutyne (56.2 ꢁL, 0.400 mmol)
and obtained as a colorless oil with a yield of 80% (87.2 mg, 0.320 mmol). (This compound has been
previously reported, and its spectra data match those described in the literature.)18a,20 1H NMR (400
MHz, CDCl3): δ 7.37ꢀ7.32 (m, 2H), 7.27ꢀ7.25 (m, 3H), 5.28 (d, J = 1.0 Hz, 1H), 2.86ꢀ2.82 (m, 2H),
2.49ꢀ2.45 (m, 2H), 2.11 (s, 3H), 1.35 (s, 12H); 13C NMR (100 MHz, CDCl3): δ 162.2, 142.2, 128.4,
128.3, 125.8, 112.9, 82.6, 43.8, 34.2, 24.8, 21.3.
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
(E)-2-(3-Cyclohexyl-2-methylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(20f).
According to general procedure A, compound 20f was synthesized using cyclohexylꢀ1ꢀpropyne (58.0
1
ꢁL, 0.400 mmol) and obtained as a colorless oil with a yield of 83% (87.9 mg, 0.333 mmol). H NMR
(400 MHz, CDCl3): δ 5.06 (s, 1H), 1.97 (d, J = 7.1 Hz, 2H), 1.95 (d, J = 0.7 Hz, 3H), 1.67ꢀ1.65 (m, 4H),
13
1.49ꢀ1.43 (m, 1H), 1.26 (s, 12H), 1.22ꢀ1.13 (m, 4H), 0.87ꢀ0.78 (m, 2H); C NMR (100 MHz, CDCl3):
δ 161.8, 114.3, 82.5, 50.7, 35.5, 33.2, 26.5, 26.3, 24.8, 21.1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C16H29BO2Na 287.2158, Found 287.2156.
(E)-2-(2-Cyclohexylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20g). According to
general procedure A, compound 20g was synthesized using cyclohexylacetylene (52.3 ꢁL, 0.400 mmol)
and obtained as a colorless oil with a yield of 86% (85.9 mg, 0.343 mmol).18a 1H NMR (400 MHz,
CDCl3): δ 5.10 (s, 1H), 1.96 (s, 3H), 1.91ꢀ1.86 (m, 1H), 1.76ꢀ1.64 (m, 4H), 1.26 (s, 12H), 1.20ꢀ1.13 (m,
6H); 13C NMR (100 MHz, CDCl3): δ 168.0, 110.5, 82.5, 49.4, 31.7, 26.6, 26.2, 24.8, 19.6.; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C15H28BO2 251.2182, Found 251.2182.
(E)-4,4,5,5-Tetramethyl-2-(2,3,3-trimethylbut-1-en-1-yl)-1,3,2-dioxaborolane (20h). According to
general procedure A, compound 20h was synthesized using 3,3ꢀdimethylꢀ1ꢀbutyne (49.0 ꢁL, 0.400
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
mmol) and obtained as a colorless oil with a yield of 86% (77.0 mg, 0.343 mmol).21 1H NMR (400
MHz, CDCl3): δ 5.21 (s, 1H), 2.00 (s, 3H), 1.27 (s, 12H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
170.2, 109.4, 82.6, 38.1, 28.9, 24.8, 17.4; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C13H26BO2
225.2026, Found 225.2030.
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
(E)-4,4,5,5-Tetramethyl-2-(2-phenylprop-1-en-1-yl)-1,3,2-dioxaborolane (20i). According to general
procedure B, compound 20i was synthesized using phenylacetylene (22.0 µL, 0.200 mmol) and obtained
as a colorless oil with a yield of 77% (37.7 mg, 0.154 mmol). (This compound has been previously
reported, and it spectral data match those described in the literature.)8,18a 1H NMR (400 MHz, CDCl3): δ
13
7.53ꢀ7.51 (m, 2H), 7.36ꢀ7.29 (m, 3H), 5.77 (d, J = 0.7, 1H), 2.43 (s, 3H), 1.33 (s, 12H); C NMR (100
MHz, CDCl3): δ 157.9, 143.8, 128.2, 128.0 125.8, 115.5, 82.9, 24.8, 22.0.
ASSOCIATED CONTENT
1
13
Supporting Information. H NMR and C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +82ꢀ2ꢀ940ꢀ8116. Eꢀmail: ymlee@kw.ac.kr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS. This research was supported by the Bio & Medical Technology
Development Program of the National Research Foundation (NRF) & funded by the Korean
government (MSIP&MOHW) (NRFꢀ2015M3A9E6029594). This work was also partially supported by
24
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRFꢀ
2017R1A2B4008310) and by the Research Grant of Kwangwoon University in 2016. The authors thank
the Korea Basic Science Institute for technical assistance with mass spectrometry.
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
REFERENCES
1. (a) Wong, J.ꢀY.; Abdulla, M. A.; Raman, J.; Phan, C.ꢀW.; Kuppusamy, U. R.; Golbabapour, S.; Sabaratnam, V.
Evidence-based Complement. Altern. Med. 2013, 492976. (b) Hui, X.; PinꢀRu, W.; ZhengꢀYu, S.; XiangꢀDong, C.
Int. J. Biol. Macromol. 2010, 47, 33. (c) Hyuong, L. D.; Ho, K. M.; Sik, P. J.; Jun, C. Y.; Soo, L. J. Peptides 2004,
25, 621. (d) Omolo, J. O.; Anke, H.; Sterner, O. Phytochemistry 2002, 60, 431. (e) Mizuno, T. J. Med.
Mushrooms 1999, 1, 105. (f) Mizuno, T.; Wasa, T.; Ito, H.; Suzuki, C.; Ukai, N. Biosci. Biotechnol. Biochem.
1992, 56, 347. (g) Kimura, Y.; Nishibe, M.; Nakajima, H.; Hamasaki, T.; Shimada, A.; Tuneda, A.; Shigematsu,
N. Agric. Biol. Chem. 1991, 55, 2673. (h) Kawagishi, H.; Ando, M.; Mizuno, T. Tetrahedron Lett. 1990, 31, 373.
(i) Kawagishi, H.; Ando, M.; Mizuno, T.; Yokota, H.; Konishi, S. Agric. Biol. Chem. 1990, 54, 1329.
2. Kim, K. H.; Noh, H. J.; Choi, S. U.; Lee, K. R. J. Antibiot. 2012, 65, 575.
3. Hericerin was renamed to isohericerin after the revision of the original structure. For details, see: (a) Miyazawa,
M.; Takahashi, T.; Horibe, I.; Ishikawa, R. Tetrahedron 2012, 68, 2007. (b) ref. 2.
4. The original structure of hericenone B was revised and renamed to isohericenone. For details, see: (a)
Kobayashi, S.; Tamanoi, H.; Hasegawa, Y.; Segawa, Y.; Masuyama, A. J. Org. Chem. 2014, 79, 5227. (b) ref. 2.
5. Yaoita, Y.; Danbara, K.; Kikuchi, M. Chem. Pharm. Bull. 2005, 53, 1202.
6. (a) Kobayashi, S.; Inoue, T.; Ando, A.; Tamanoi, H.; Ryu, I.; Masuyama, A. J. Org. Chem. 2012, 77, 5819. (b)
Kobayashi, S.; Ando, A.; Kuroda, H.; Ejima, S.; Masuyama, A.; Ryu, I. Tetrahedron 2011, 67, 9087.
7. GómezꢀPrado, R. A.; Miranda, L. D. Tetrahedron Lett. 2013, 54, 2131.
8. Alfaro, R.; Parra, A.; Alemán, J.; Luis, J.; Ruano, G.; Tortosa, M. J. Am. Chem. Soc. 2012, 134, 15165.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
7
8
9
9. (a) Itoh, T.; Shimizu, Y.; Kanai, M. J. Am. Chem. Soc. 2016, 138, 7528. (b) Su, W.; Gong, T.ꢀJ.; Zhang, Q.;
Zhang, Q.; Xiao, B.; Fu, Y. ACS Catal. 2016, 6, 6417. (c) Bin, H.ꢀY.; Wei, X.; Zi, J.; Zuo, Y.ꢀJ.; Wang, T.ꢀC.;
Zhong, C.ꢀM. ACS Catal. 2015, 5, 6670. (d) Bidal, Y. D.; Lazreg, F.; Cazin, C. S. J. ACS Catal. 2014, 4, 1564.
(e) Tai, C.ꢀC.; Yu, M.ꢀS.; Chen, Y.ꢀL.; Chuang, W.ꢀH.; Lin, T.ꢀH.; Yap, G. P. A.; Ong, T.ꢀG. Chem. Commun.
2014, 50, 4344. (f) Yoshida, H; Kageyuki, I.; Takaki, K. Org. Lett. 2013, 15, 952.
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
10. Inoue, S.; Kim, R.; Hoshino, Y.; Honda, K. Chem. Commun. 2006, 1974.
11. For reviews of Pdꢀcatalyzed SuzukiꢀMiyaura coupling reactions, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95. 2457. (b) Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
12. (a) Wang. G.ꢀZ.; Jiang, J.; Bu, X.ꢀS.; Dai, J.ꢀJ.; Xu, J.; Fu, Y.; Xu, H.ꢀJ. Org. Lett. 2015, 17, 3682. (b) Sun,
H.; Li, Y.; Zhang, X.; Lei, Y.; Ding, W.; Zhao, X.; Wang, H.; Song, X.; Yao, Q.; Zhang, Y.; Ma, Y.; Wang, R.;
Zhu, T.; Yu, P. Bioorg. Med. Chem. Lett. 2015, 25, 4567. (c) Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2013,
135, 10642. (d) Glasspoole, B. W.; Ghozati, K.; Moir, J. W.; Crudden, C. M. Chem. Commun. 2012, 48, 1230. (e)
Gerbino, D. C.; Mandolesi, S. D.; Schmalz, H.ꢀG.; Podestá, J. C. Eur. J. Org. Chem. 2009, 3964.
13. Zhang, P.; Roundtree, I. A.; Morken, J. P. Org. Lett. 2012, 14, 1416.
14.(a) Salvaggio, F.; Hodgkinson, J. T.; Carro, L.; Geddis, S. M.; Galloway, W. R. J. D. Welch, M.; Spring, D. R.
Eur. J. Org. Chem. 2016, 434. (b) Morimoto, H.; Harada, T. Eur. J. Org. Chem. 2015, 7378. (c) Zhu, G.; Negishi,
E.ꢀi. Chem. Eur. J. 2008, 14, 311. (d) Lipshutz, B. H.; Butler, T.; Lower, A. J. Am. Chem. Soc. 2006, 128, 15396.
15. For synthesis of NQIMesCuCl, see: (a) ref. 9 (a). For synthesis of IPrCuCl, see: (b) Yoo, W.ꢀJ.; Nguyen, T. V.
Q.; Kobayashi, S. Angew. Chem., Int. Ed. 2014, 53, 10213. For synthesis of SIMesCuCl and BenzICyCuCl, see:
(c) Opalka, S. M.; Park, J. K.; Longstreet, A. R.; McQuade, D. T. Org. Lett. 2013, 15, 996. For synthesis of
IMesCuCl, see: (d) Xie, W.; Chang, S. Angew. Chem., Int. Ed. 2016, 55, 1876. For synthesis of ICyCuCl, see: (e)
McIntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12, 1996.
16. (a) Moore, C. M.; Medina, C. R.; Cannamela, P. C.; McIntosh, My. L.; Ferber, C. J.; Roering, A. J.; Clark, T.
B. Org. Lett. 2014, 16, 6056. (b) Wang, C.; Wu, C.; Ge, S. ACS Catal. 2016, 6, 7585.
26
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
1
2
3
17. Sawama, Y.; Sawama, Y.; Krause, N. Org. Biomol. Chem. 2008, 6, 3573.
4
5
6
7
8
18. (a) Kliman, L. T.; Mlynarski, S. N.; Ferris, G. E.; Morken, J. P. Angew. Chem., Int. Ed. 2012, 51, 521. (b)
Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E.ꢀi. Org. Lett. 2009, 11, 4092.
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
19. Zhang, N.; Jiang, J.; Liu, M.; Taniguchi, M.; Mandal, A. K.; EvansꢀStorms, R. B.; Pitner, J. B.; Bocian, D. F.;
Holten, D.; Lindsey, J. S. New. J. Chem. 2016, 40, 7750.
20. Kirai, N.; Iguchi, S.; Ito, T.; Takaya, J.; Iwasawa, N. Bull. Chem. Soc. Jpn. 2013, 86, 784.
21. Harada, K.; Nogami, M.; Hirano, K.; Kurauchi, D.; Kato, H.; Miyamoto, K.; Saito, T.; Uchiyama, M. Org.
Chem. Front. 2016, 3, 565.
27
ACS Paragon Plus Environment