Total Synthesis of Prostratin, a Bioactive Tigliane Diterpenoid: Access to Multi-Stereocenter Cyclohexanes from a Phenol

Article abstract of DOI:10.1021/acs.joc.0c00022

Tiglianes such as prostratin and related diterpenoids are biologically significant natural molecules and long-standing targets for organic synthesis community. Due to the complex polycyclic scaffolds, high oxygenation level, and dense functional groups and stereocenters, their de novo chemical syntheses still face formidable challenges despite extensive efforts in the past 40 years. This account details the development of a modular and concise synthesis of prostratin, a potent anti-HIV and anticancer agent. The key approach in this synthesis involved a sequence of oxidative dearomatization and sequential stereoselective installation of peripheral groups to rapidly build the contiguously substituted cyclohexane C-ring. Inspired by Wender's work, an acid- A nd solvent-controlled stereodivergent formation of cyclopropane D-ring was developed. Mechanistic investigations by computational methods revealed that the competition between intra- A nd intermolecular hydrogen bonding led to different conformations, thus favoring different protonation processes. The designed and unexpected chemistry along this campaign reflected the uniqueness of the natural structures and should be amenable to future chemical syntheses of related complex polycyclic molecules.

Full text of DOI:10.1021/acs.joc.0c00022

Subscriber access provided by Uppsala universitetsbibliotek
Article
Total synthesis of prostratin, a bioactive tigliane diterpenoid:
access to multi-stereocenter cyclohexanes from a phenol
Guanghu Tong, zhengwei ding, Zhi Liu, You-Song Ding, Liang Xu, Hailong Zhang, and Pengfei Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00022 • Publication Date (Web): 13 Mar 2020
Downloaded from pubs.acs.org on March 13, 2020
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 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Total synthesis of prostratin, a bioactive tigliane diterpenoid: access to
multi-stereocenter cyclohexanes from a phenol
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
Guanghu Tong,†§ Zhengwei Ding,†§ Zhi Liu,†§ You-Song Ding,† Liang Xu,*‡ Hailong Zhang, Pengfei
Li*†¶
†Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, 710054, China
‡School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of
Xinjiang Bingtuan, Shihezi University, Shihezi, 832003, China
Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710061, China
¶Xi’an Key Laboratory of Sustainable Energy Materials Chemistry, Xi’an Jiaotong University, Xi’an 710049, China
*Email: lipengfei@mail.xjtu.edu.cn (P. Li), xuliang4423@shzu.edu.cn (L. Xu)
OAc
ClMgMe
Me
H
Me
Me
OMe
Me
"core-branching"
strategy
O2
H
Me
H
BrMg
OH
Bpin
O
MgCl
HO
ClMg
OH
Me
prostratin
- singlet oxygen dearomatization
- potent anti-HIV and anti-tumor agent
- high oxidation state
- "double trans" tetracyclic core
- 7 contiguous stereocenters
- directed regio- and stereoselective 1,4-addition
- stereoselective cyclopropane synthesis
- ring closing metathesis
ABSTRACT: Tiglianes such as prostratin and related diterpenoids are biologically significant natural molecules and long-
standing targets for organic synthesis community. Due to the complex polycyclic scaffolds, high oxygenation level and dense
functional groups and stereocenters, their de novo chemical syntheses still face formidable challenges despite extensive
efforts in the last 40 years. This account details the development of a modular and concise synthesis of prostratin, a potent
anti-HIV and anticancer agent. The key approach in this synthesis involved a sequence of oxidative dearomatization and
sequential stereoselective installation of peripheral groups to rapidly building the contiguously substituted cyclohexane C-
ring. Inspired by Wender’s work, an acid- and solvent-controlled stereodivergent formation of cyclopropane D-ring was
developed. Mechanistic investigations by computational methods revealed that the competition between intra- and
intermolecular hydrogen bonding led to different conformations, thus favoring different protonation processes. The designed
as well as unexpected chemistry along this campaign reflected the uniqueness of the natural structures and should be
amenable to future chemical synthesis of related complex polycyclic molecules.
currently in phase I clinical trials to treat severe pain for
patients with advanced cancer.3
INTRODUCTION
Terpene natural products have long provided effective
drugs or leads, such as paclitaxel (Taxol®) and artemisinin,
for human being in combating various diseases. Tiglianes
and daphnanes are two families of diterpenes with closely
related biosynthetic origin, and mainly isolated from
extracts of Euphorbiaceae and Thymelaeaceae which have
been widely used in traditional Chinese medicine. To date,
over 300 molecular entities within these families have been
identified. Many members exhibited remarkable biological
functions including anti-viral, anti-cancer, analgesic,
neurotrophic and tumor promotional activities.1,2 For
instance, phorbol (2) and phorbol-13-myrisitate-12-acetate
(PMA, 3) are ultra-potent tumor promoters by activation of
protein kinase C (PKC). Resiniferatoxin (RTX, 5), the hottest
chemical ever known, is a potent non-opioid analgesic and
Prostratin (1, Figure 1) was originally isolated from
Pimelea prostrata and structurally elucidated by Hecker and
co-workers in 1976.4 In 1992, Cox and co-workers
ascertained 1 as the active ingredient in Homalanthus
nutans, locally known as mamala tree which had been used
as tribal medicine for viral diseases in Samoa.5 Prostratin is
a potent anti-HIV agent. On one hand, it was reported that
prostratin protected CD4+ T cells by the down-regulation of
HIV receptor CD4 and co-receptors. On the other hand, it
stimulates viral replication in latently infected cells by
interaction with Protein Kinase C (PKC).6 The latter function
renders prostratin as a promising lead in developing an
adjuvant therapy to eradicate HIV-AIDS infection.7 In
addition, prostratin was reported to effectively suppress
pancreatic cancer cells,8 myeloid leukemia cells9 and breast
cancer cells.10
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 29
R1
Figure 2. Semi-synthesis of prostratin from phorbol by
Wender
13 OR2
O
Me
H
1
2
3
4
5
6
7
8
11
Me
H
12
Me
D
15
1
C
9
semi-synthesis of prostratin (1) from crotophorbolone (4)
by the Wender group (Figure 2),11 since early 1980s, many
de novo synthetic approaches have been reported.12 The
first total synthesis of phorbol (2)13 was achieved by
Wender and co-workers featuring an selective
intramolecular oxidopyriylium/alkene [5+2] cycloaddition
approach to rapidly build the B/C rings.14,15 With this
approach, the same group successfully developed an
improved synthesis of 2, the first total synthesis of RTX (5)16
and highly complex non-natural analogues of yuanhuapin
(6)17. Using fully-functionalized C-ring as the bridgehead
radical precursors, Inoue and co-workers developed
delicate chemo- and stereoselective methods to assemble
the tricyclic core, thus accomplished total synthesis of
crotophorbolone18 and very recently RTX19. Despite the
achievements, the challenge to harmonize skeleton
assembly and functional group installation necessitated
long synthetic sequence (>30 steps). In 2016, by judicious
selection of (+)-3-carene as the C,D-ring precursor and
using a dazzling array of reactions including Pauson-Khand
reaction, C-H oxidation and ring reorganization, Baran and
co-workers were able to achieve an asymmetric synthesis
of phorbol in only 19 steps.20
Me
8
Me
2
14
Me
H
H
10 OH
A
4
OH
H
Me
3
7
B
O
HO
O
5
6
HO
OH
OH
: R1 = H, R2 = Ac
prostratin (1)
phorbol (2)
crotophorbolone (4)
: R1 = OH, R2 = H
: R1 = C13H27CO2, R2 = Ac
PMA (3)
9
AcO
Me
Me
12
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
Me
H
Me
H
13
14
O
O
O
O
H
H
Me
Me
O
O
O
Ph
Bn
OR3
O
O
HO
HO
HO
OH
yuanhuapin (6)
resiniferatoxin (5)
R3 = homovanilloyl
Figure 1. representative members of tigliane and daphnane
family diterpenoids
Structurally, tigliane and daphnane diterpenoids share a
[5/7/6] A/B/C tricyclic carbon core with usually
contiguous multi-stereocenters and high oxygenation
pattern (Figure 1). Due to the C4,C10 and C8,C9 double trans
configuration in tigliane and daphnane skeleton and the
congested substitution, these molecules show rigid three-
dimensional representation. Tiglianes further distinguish
themselves by a highly substituted cyclopropane ring D,
while daphananes usually possess a caged orthoester
moiety.
Remarkably, the previous syntheses all adopted a “C ring
first” strategy where multiple substituents and/or
stereochemical pattern within the cyclohexane ring were
introduced in early stage. However, the distinctive
structural difference between tiglianes and daphananes
resides in the C ring and previous reports had suggested
that subtle variations on the C ring often led to dramatic
changes in biological activities. Consequently, aiming at a
general strategy for both tiglianes and daphananes, and
future full modifications of them, we sought to take a
different strategy. We planned to build the C ring from a
simple, two-dimensional phenol moiety by controlled
stepwise yet rapid manipulation of necessary oxidation
states, substituents and stereocenters. Recently, we have
demonstrated the feasibility of such strategy by a successful
total synthesis of prostratin.21 In this article, we wish to
disclose the full details of our efforts that led to the short
and flexible synthetic strategy.
The combination of biological activities and structural
complexity have rendered tigliane and daphnane
diterpenoids continuously to be attractive yet highly
challenging targets for the synthetic community. Besides an
elegant
OH
12
OH
O
Me
H
Me
H
Me
Me
13
14
Acidic
hydrolysis
Me
Me
H
H
H
OH
OH
Me
O
O
HO
HO
OH
Phorbol (2)
OH
Crotophorbolone (4)
(a) H4N2•H2O, AcOH
(b) pyridine, DIPEA
RESULTS AND DISCUSSION
Strategic Design and Retrosynthetic Analysis
OAc
Me
13
14
Me
H
N
NH
N
Tigliane and daphnane diterpenoids share
a
13
H
H
N
H
Pb(OAc)4
characteristic [5/7/6] tricyclic carbon core structure. We
envisaged a tigliane diterpenoid could be reached by
cyclopropanation of a common intermediate 7, from which
orthoester formation should also lead to a daphnane
diterpenoid. Intermediate 7 might be accessed by oxidative
Me
Me
O
14
Me
Me
OH
Me
OH
Me
OH
O
OH
HO
OH
hv
dearomatization
and
subsequent
stereoselective
OAc
Me
Me
Me
H
functionalizations from 10. Due to its polyfunctional nature,
cyclohexadienone quinol 9 could serve as the key
intermediate for rapid and controllable modification of C-
ring. If successful, such a programmed “core-branching”
synthetic sequence should maximize the potential in
peripheral derivatization, allowing to build various densely
functionalized three-dimensional C-ring from a planar
13
14
Me
H
H
OH
O
HO
OH
Prostratin (1)
ACS Paragon Plus Environment

Page 3 of 29
The Journal of Organic Chemistry
phenol. Oxidative dearomatization22 has been an effective
stereocenters (C4, C8-C10, C11), we took a commercially
1
2
3
4
5
6
7
8
approach for transforming phenolic compounds into
complex three-dimensional structures. In this plan, ring-
closing metathesis (RCM) were to be used for forging the
seven-member ring, and an epoxide opening reaction
available epoxide 14 for our model study (Scheme 1).
Treatment of cyclopentene oxide 14 with Gringnard
reagent 12 in the presence of cuprous iodide provided
epoxide opening product tans-15 in excellent yield (99%).
Exposure of alcohol 15 to Dess-Martin periodinane
followed by addition with allyl magnesium bromide
delivered a diene together with its inseparable C4-epimer
in good yield (81% over two steps, 10:1 dr). Employing
Grubbs second-generation catalyst at a low catalyst loading
(0.1 mol%), RCM reaction successfully delivered the desired
tricyclic compound 16 in 84% yield.
Me
H
OTMS
cyclopropanation
tiglianes
or
daphnanes
O
H
OH
Me
C8 reduction
Me
or
orthoester
formation
O
Me
RO
Me
7
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
O
O
stereoselective
1,4-addition
At this stage, we explored various conditions for the
planned oxidative dearomatization reaction. Direct
treatment of 16 with ceric ammonium nitrate (CAN) in
aqueous acetonitrile mainly afforded ketone 17 (66%),
probably via allylic oxidation and Wagner-Meerwein-type
rearrangement. We then sought to first demethylate the
aryl methyl ether. However, attempts in removing the
methyl group by strong Lewis acids (i.e., BBr3, TMSI etc.) all
led to decomposition or starting material. In addition, using
sodium ethylthiolate at elevated temperature resulted in
unstable yields due to accompanying competitive
dehydration and other side reactions (see SI for more
details). After silylation of the tertiary alcohol, we found
that in situ generated lithium diphenylphosphide23 was best
for this demethylation, giving phenol 18 in 96% yield.
H
H
8
O
OH
Me
O
OH
O
Me
RO
O
Me
RO
Me
Me
Me
9
8
oxidative
dearomatization
HO
OMe
OH
H
RCM
HO
Me
9
10
+
11
O
and epoxide
opening
O
Me
RO
MgCl
MgBr
Me
Me
10
13
12
Figure 3. Retrosynthetic analysis of tigliane and daphnane
natural product
for the C9-C10 bond. Therefore, 10 could be modularly
assembled from three simple building blocks (11, 12, 13)
(Figure 3).
Numerous methods had been reported for oxidative
dearomatization of phenols. Among them, hypervalent
iodine reagents emerged as the convenient option and had
been widely used. In our case, however, treatment of 18
with PhI(OAc)2 led to formation of oxetane 19 as the major
Model Studies
In order to test the above strategy and quickly establish
the [5/7/6] tricyclic core with five key contiguous
Scheme 1. ABC Model System and Attempted Oxidative Dearomatizationa
OMe
OMe
e) CAN,
OMe
b) DMP, 85%
H
H
c) AllylMgBr, 95%
d) Grubbs-II, 84%
12
a) , CuI
O
aq. MeCN
99%
66%
d.r. = 10:1
OH
OH
HO
14
15
O
17
16
O
H
f) TMSOTf, 99%
g) Ph2PLi, 96%
22
OHC
k) PhI(OAc)2
O
19
70%
OH
OH
aq. MeCN
OH
h) PhI(OAc)2,
aq. MeCN
MeO
l) PhI(OAc)2,
MeOH
H
42%
H
j) TBAF
99%
69%
i) [Ru], TBHP
TMSO
23
49%
HO
H
18
O
21
O
O
Me
H
O
tBuOO
n) LiHMDS,
MeMgBr
m) TPP, hv, O2,
then PPh3
H
OH
OH
63%
74%
TMSO
TMSO
TMSO
20
24
25
aReagents and conditions: (a) 12, CuI (10 mol%), THF, 0 °C to rt, 99%; (b) DMP, NaHCO3, CH2Cl2, 0 °C to rt, 85%; (c) AllylMgBr,
Et2O, -78 °C, 95%; (d) Grubbs second-generation catalyst (0.1 mol%), toluene, 80 °C, 84%, 10:1 dr; (e) CAN, MeCN/H2O (3:1), rt,
66%; (f) TMSOTf, Et3N, CH2Cl2, 0 °C to rt, 99%; (g) n-BuLi, Ph2PH, THF, 0 °C to 60 °C, 96%; (h) PhI(OAc)2, NaHCO3, MeCN/H2O (3:1),
0 °C to rt, 42%; (i) Ru(PPh3)3Cl2 (3 mol%), TBHP, PhH, rt, 49%; (j) TBAF, THF, 0 °C, 99%; (k) PhI(OAc)2, MeCN/H2O (3:1), rt, 70%;
(l) PhI(OAc)2, MeOH, rt, 69%; (m) TPP (5 mol%), hv, O2, CHCl3, 0 °C, then PPh3, 0 °C, 74%; (n) LiHMDS, 0 °C, then added HMPA,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 29
MeMgBr, THF, -78 °C, 63%. THF = tetrahydrofuran, DMP = Dess-Martin periodinane, dr = diastereomeric ratio, CAN = ceric
ammonium nitrate, TMSOTf = trimethylsilyl triflate, TBHP = tert-butyl hydroperoxide, TBAF = tetrabutylammonium fluoride, TPP =
tetraphenylporphyrin, LiHMDS = lithium hexamethyldisilazide, HMPA = hexamethylphosphoramide.
1
2
3
4
5
6
7
8
9
product via an intramolecular reaction. Also, treatment of
desilylated phenol 21 with PhI(OAc)2 in aqueous
acetonitrile produced naphthol 22 with ring rearrangement
and C-C bond cleavage. When the solvent was methanol,
crystalline 23 with a 10-membered ring was isolated in 69%
yield, probably via C-C bond cleavage and benzylic cation
of TMS moiety (Figure 4). Furthermore, removing TMS
group of 25 under acidic or fluoride conditions all led to full
conversion to
Me
H
O
[H]
intermediate.
dearomatization
Interestingly,
with TBHP
ruthenium-catalysed
could form the
8
OH
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
8
TMSO
dearomatization product 20 in 49% yield. However,
cleavage of corresponding O-O bond in various conditions
(TiCl4, PPh3, Mg/MeOH, P(OPh)3, Pd/C) were all
unsuccessful.
25
top view
side view
Figure 4. Crystal structure of 25 from top view and side view
bridged tetracycle 27 (97%). When ketone 25 was
subjected to Luche reduction conditions (NaBH4, CeCl3),
quantitative and stereoselective formation of 1,4-cis-diol
was observed. Treatment of the resulting diol with m-
chloroperoxybenzoic acid (mCPBA) directly provided triol
28 in 70% yield as a single isomer. In this case, the oxa-
bridged ring was again formed by facile intramolecular
epoxide opening.
Fortunately, the required oxidative dearomatization
proceeded smoothly at ambient temperature with singlet
oxygen24 using tetraphenylporphyrin (TPP) as the
photosensitizer and 400 W sodium lamp as the light source.
After consumption of starting material, the unstable peroxy
quinol intermediate was reduced by triphenylphosphine to
the desired cyclohexadienone 24. To our delight, 24 was
isolated in good yield (74%) and as a single diastereoisomer.
The above work demonstrated the potential of our
strategy in building the tricyclic framework with a highly
simplified A-ring. Furthermore, we conducted studies for
incorporation and manipulation of a functionalized A-ring
more relevant to the natural products (scheme 3). We
started from protection of the known racemic diol 11
(synthesized from cyclopentadiene through 3 steps, see
experimental section for more details) with acetonide
group and a one-pot stereoselective epoxidation (75%).
Following the route similar to Scheme 1, a copper-catalysed
epoxide opening of SI-13 with 12 (74% yield), DMP
oxidation, followed by allylation with 13 furnished diene 29
(58% yield, over two steps), whose relative configuration
was confirmed by X-ray crystallography. Ring-closing
metathesis smoothly forged the 7-membered ring of 30 (78%
yield). Next, removal of acetonide group with
camphorsulfonic acid in refluxing aqueous methanol
produced the corresponding triol which was selectively
pivalated at the primaryl alcohol to form 31 in 81% yield
over two steps. Furthermore, using Iwabuchi’s method,26 i.e.
2-azaadamantane-N-oxyl (AZADO) and CuCl catalyzed
aerobic oxidation, pivalate 31 was cleanly transformed to
exo-enone 33 in 85% yield with concomitant elimination of
pivalic acid. Notably, attempts using other methods such as
Swern, PCC, IBX, Corey-Kim, Ley, Pfitzner-Moffatt,
Oppenauer, or Fetizon’s reagent all failed27. In most cases,
1,2-diol cleavage was observed as the major side reaction
(see SI for more details). For example, Dess−Martin
periodinane led to formation of bridged ketone 32 in 71%
yield. Considering that bridged ketones are commonly
found in synthetically challenging natural products (e.g.
hyperforin), this discovery may provide a novel method for
their preparation. In addition, Parikh-Doering oxidation27j
of 31 gave 33 in low yield (40%), while Anelli’s conditions
(TEMPO, NaClO, KBr, NaHCO3) gave 33 in irreproducible
yields (30~74%). Going forward, an exo to endo
isomerization of the enone was realized in 82% yield by
using catalytic amount of rhodium(III) chloride28 after in
Scheme 2. Attempts to construction of C8
stereochemistrya
various
conditions
Me
H
O
Me
H
O
8
8
H
OH
OH
TMSO
TMSO
25
26
b) NaBH4, 96%
c) mCPBA, 70%
a) CSA, 97%
Me
H
O
Me
H
OH
OH
OH
OH
O
O
27
28
aReagents and conditions. (a) CSA, CH2Cl2, -78 °C to rt, 97%;
(b) NaBH4, CeCl37H2O, MeOH, -78 °C, 96%; (c) mCPBA, NaHCO3,
CH2Cl2; silica gel, 70%. mCPBA = meta-chloroperoxybenzoic
acid.
With a concise and scalable route to cyclohexadienone 24,
we proceeded to explore the possibility of stereocontrolled
transformations on the C-ring. An alkoxide directed
conjugate addition procedure reported by Liotta and co-
workers was adopted.25 Thus, deprotonation of
cyclohexadienone 24 with lithium hexamethyldisilazide
(LiHMDS) followed by the addition of methyl magnesium
bromide in the presence of HMPA delivered C11-methyl
adduct 25 in 63% yield as a single diastereoisomer. We next
attempted to set C8 stereochemistry (scheme 2). Attempts
to generate 26 from 25 by employing a variety of conditions,
including conjugate addition (Stryker‘s reagent, Rh/Et3SiH,
L-selectride, NiCl2/NaBH4, etc), selective olefin reduction
(Pd/C, Crabtree’s catalyst), or dissolving metal reduction, to
our dismay, did not give any desired product. Presumably,
this failure was due to unfavorable attachment of a
hydrogen atom from the concave face and a shielding effect
ACS Paragon Plus Environment

Page 5 of 29
The Journal of Organic Chemistry
situ protection of the hydroxyl group with TMSOTf. The silyl considered for installing C11-methyl and C8-vinyl
1
2
3
group was essential to prevent side reactions. Interestingly,
during this isomerization, TMS group was also removed.
substituents from 37. Cyclohexadienone 37, an oxidative
dearomatization product from phenol 38 should be rapidly
accessed from diol 11 and reagent 39.
4
5
6
7
8
9
Thus, started from diol 11 (scheme 4), synthesis of phenol
38 involved one-pot acetal protection and epoxidation,
copper-catalyzed epoxide opening of with 39, protection of
the resulting secondary alcohol with TBS group, and
removal of the methyl with Ph2PLi. These steps were
smoothly done
Scheme 3. Synthesis of A-ring Model Compounda
OMe
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
OAc
Me
Me
OAc
Me
Me
Me
H
H
a) Me2C(OMe)2;
Me
H
mCPBA, 75%
HO
12
b) , CuI, 74%
RCM
Me
O
H
H
H
OH
OH
OH
Me
29
HO
c) DMP
O
O
Me
13
d) , 58%, 2 steps
O
HO
Me
OH
Me
35
11
O
Me
OH
Me
prostratin (1)
OMe
cyclopropane
formation
H
e) Grubbs-II
78%
O
O
O
11
Me
H
O
Me
stereoselective
1,4-addition
HO
30
f ) CSA
H
9
Me
Me
9
Me
Me
OH
8
OH
O
O
OTBS
O
g) PivCl, 81%, 2 steps
OTBS
36
Me
O
OMe
Me
Me
37
OMe
H
Me
oxidative
dearomatization
H
O
DMP
71%
5
6
PivO
PivO
HO
OH
OMe
16
epoxide
opening
HO
H
Me
H
HO
H
HO
HO
32
Me
+
31
O
NOESY
h) AZADO, DMAP,
CuCl, bpy, air, 85%
OTBS
38
MgBr
39
O
Me
11
Me
OMe
OMe
Figure 5. Retrosynthetic analysis of prostratin
H
H
i) TMSOTf, then
RhCl33H2O
Me
in >20g scale and good yields. According to our previous
oxidative dearomatization conditions using TPP as the
sensitizer and chloroform as the solvent, only low
conversion of 38 was observed. After extensive
experiments, it was found that by changing the sensitizer to
rose bengal and solvent to mixed methanol/chloroform
(1:1), the desired C9-hydroxylated cyclohexadienone 37
was observed in 85% yield. Interestingly, intermediate
peroxy quinol was not detectable, presumably because
protic solvent accelerated rupture of the initially formed O-
O bond. Theoretically, addition of a Grignard reagent to 37
could form six regio- or diastereoisomers. In practice,
treatment of 37 with LiHMDS and then
O
O
HO
82%
HO
Me
Me
33
34
aReagents and conditions. (a) Me2C(OMe)2, PPTs (10 mol%),
CH2Cl2, 0 °C to rt, then NaHCO3, mCPBA, 0 °C to rt, 75%; (b) 12,
CuI (10 mol%), THF, 0 °C to rt, 74%; (c) DMP, NaHCO3, CH2Cl2,
rt; (d) 13, THF, 0 °C to rt, 58%, 2 steps; (e) Grubbs second
generation catalyst (10 mol%), toluene, 110 °C, 78%; (f) CSA,
MeOH/H2O (5:1), 90 °C; (g) PivCl, pyridine, DMAP, CH2Cl2, 0 °C
to rt, 81%, 2 steps; (h) AZADO (10 mol%), DMAP, CuCl (20
mol%), bpy (20 mol%), MeCN, rt, 85%; (i) TMSOTf, Et3N,
CH2Cl2, 0 °C to rt, then RhCl3·3H2O (10 mol%), EtOH/H2O
(10:1), 100 °C, 82%. PPTs = pyridinium p-toluenesulfonate,
CSA = (±)-camphor-10-sulfonic acid, PivCl = pivaloyl chloride,
Scheme 4. Synthesis of ketone 40a
DMAP
=
4-dimethylaminopyridine,
AZADO
=
2-
azaadamantane-N-oxyl, bpy = 2,2’-bipyridine.
Retrosynthetic Analysis of Prostratin (1)
On the basis of the above investigations, a retrosynthetic
analysis of prostratin (1) was designed. As delineated in
Figure 5, our synthetic approach relied on the late-stage
RCM to forging B-ring from diene 35 with fully
functionalized A, C, D rings. The D ring should be formed by
cyclopropanation of enone 36. In order to solve the problem
of C8 chemistry that we could not set in the model study
(see Scheme 2), a double directed addition approach was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 29
11
Me
H
O
OH
Me
H
O
a) Me2C(OMe)2;
mCPBA, 75%
H
1
2
3
a) ATPH
vinylMgCl
8
HO
HO
39
b) , CuI, 77%
OH
OTBS
41
OH
OTBS
40
O
O
O
66%
c) TBSCl, imidazole
d) Ph2PH, nBuLi
95%, 2 steps
O
OTBS
38
O
O
Me
Me
4
5
Me
Me
Me
11
Me
e)
b) NaBH4, 98%
H-
TBSOTf
Et3N
6
7
8
9
rose bengal,
hv, O2, 85%
Mg2+
O
Me
H
OTBS
Me
Mg
O
H
H
O
11
Me
H
11
O
O
O
Me
HO
H
H
H
O
8
9
9
OTBS
O
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
Me
OH
OTBS
OH
Me
TS-41
f) LiHMDS,
MeMgCl
73%, d.r. = 1:1
42
O
O
Me
OTBS
c) BnBr, 81%
O
O
Me
40
37
Me
Me
Me
OBn
Me
OBn
d) TBAF
e) DMP
aReagents and conditions. (a) Me2C(OMe)2, PPTs (10 mol%),
CH2Cl2, 0 °C to rt, then NaHCO3, mCPBA, 0 °C to rt, 75%; (b) 39,
CuI (10 mol%), THF, 0 °C to rt, 77%; (c) TBSCl, imidazole,
CH2Cl2, 0 °C to rt; (d) n-BuLi, Ph2PH, THF, 0 °C to 80 °C, 95%, 2
steps; (e) Rose bengal (5 mol%), hv, O2, MeOH/CHCl3 (1:1),
85%; (f) LiHMDS, -60 oC, then added DMPU, MeMgCl, -78 °C to
-30 °C, 73%, 1:1 dr. TBSCl = tert-butyldimethylsilyl chloride,
DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
H
H
OH
OH
O
O
O
OTBS
43
O
O
Me
Me
44
(58%)
Me
Me
+
·
13
f) LaCl3 2LiCl,
NOESY
g) Grubbs-II, 46%, 2 steps
OBn
H
Ha
Hb
OBn
Me
H
11
4
with methylmagnesium chloride in the presence of DMPU,
1,4-cis-addition product 40 was isolated together with the
other 1,4-cis-diastereomer SI-16 in approximately 1:1 ratio.
The isomers were readily separated by column
chromatography on silica gel. Similar to the previous model
synthesis (24 to 25), the 1,4- over 1,2- selectivity and the
cis- over trans- selectivity could be understood by invoking
an alkoxide-guided methyl addition process.25
Me
O
H
OH
O
O
O
O
O
HO
46
Me
Me
45
(34%)
Me
Me
Me
aReagents and conditions. (a) Me3Al, 2,6-diphenylphenol,
vinylMgCl, THF, -78 °C to rt, 66%; (b) NaBH4, CeCl37H2O,
MeOH/CH2Cl2 (1:1), -78 °C, 98%; (c) NaH, BnBr, TBAI, 0 °C to
rt, 81%; (d) TBAF, THF, rt; (e) DMP, NaHCO3, t-BuOH, rt, 58%
44, 34% 45, two steps; (f) LaCl32LiCl, 13, THF, -78 °C to 0 °C;
(g) Grubbs second-generation catalyst, toluene (50 mol%), 110
°C, 46%, 2 steps. TBAI = tetrabutylammonium iodide.
With gram scale preparation of 40, we next explored the
second directed 1,4-addition at C8. With similar protocol as
above, addition of 40 with vinyl magnesium bromide
afforded the desired ketone 41 in 43% yield; competitive
1,2-adduct was also formed in 32% yield (SI-17). Other
methods, such as organo-copper or zinc reagents, could also
provide 41, but in lower yields. We reasoned that a bulky
Lewis acid might block C13-carbonyl group to prevent 1,2-
addition and at the same time accelerate 1,4-addition by
reducing LUMO of the enone. Indeed, treatment of 40 with
enol ether from 40 under various conditions (ATPH,
vinylMgCl, then TBSCl or TBSOTf) did not give the desired
product. On the other hand, usual deprotonation and
silylation reaction of 41 with TBSOTf/ Et3N, or
TBSCl/LiHMDS) all led to silylated acetal 42 as the major
product.
Yamamoto’s
aluminum
tris(2,6-diphenylphenoxide)
In order to explore the construction of B-ring (Scheme 5),
ketone 41 was stereoselectively reduced to furnish the
corresponding alcohol (98%), which was subsequently
protected as its benzyl ether 43 (81%). Based on the crystal
structure of 41 (see SI), a chair-like conformation might be
involved in the transition state of this reduction process
(TS-41). Attacking of a small hydride from the axial
direction would lead to movement of the oxygen atom
toward the equatorial position (marked by the bold arrow),
avoiding otherwise overlapping with the two equatorial -
protons. Treatment of 43 with TBAF, then oxidizing diol by
Dess-Martin periodinane provided ketone 44 as the desired
(ATPH)29 before addition of vinylmagnesium chloride led to
conjugate addition product 41 up to 66% along with 22%
SI-17. A single crystal of 41 suitable for X-ray diffraction
confirmed its relative configuration that clearly indicated
the desired 8,11-cis configuration. Attempts to prepare silyl
Scheme 5. Synthesis of tricyclic 46a
Scheme 6. Synthesis of tetracyclic 51 with wrong D-
ringa
ACS Paragon Plus Environment

Page 7 of 29
The Journal of Organic Chemistry
O a) I2, 85%
O
Me
H
Me
metathesis of diene catalyzed by Grubbs' second generation
17
1
H
catalyst in toluene gave the desired tricyclic compound 46
in 46% yield over two steps. These results provided a viable
route to the [5-7-6] skeleton with several desired key
stereocenters.
Me
b) [Pd],
93%
Me
Bpin
14
16
15
2
3
OH
OH
O
O
OTBS
OTBS
O
O
4
5
Me
Me
40
47
c) ATPH
vinylMgCl
Me
Me
In order to further construct the cyclopropane D ring onto
the skeleton, we first wanted to attach isopropenyl group
with C15 to C17 via an iodination/cross-coupling sequence
(scheme 6). Thus, Johnson iodination was used by heating
40 with iodine and pyridine in refluxing methylene
dichloride to furnish α-iodoenone in 85% yield. Palladium-
catalyzed cross-coupling between the α-iodoenone and 2-
isopropenyl boronic acid pinacol ester produced the
desired 47 in excellent yield (93%). Next, we found that
setting a vinyl group at C8 which was cis relationship with
C9 hydroxyl was challenging. Numerous attempts in
substrate-directed 1,4-conjugate addition, such as
organocopper reagents, or rhodium, nickel catalyzed
additions, failed to give the desired product. In most cases,
the starting material was recovered. When vinyl Grignard
reagent and TMSCl were used in the presence of HMPA, 35%
of 1,4-addition product 36 was isolated, in which the
terminal double bond in isopropenyl was isomerized to
internal. We reasoned that the low reactivity was due to the
particularly high steric hindrance around C8. Finally, we
found that the bulky Lewis acid ATPH discussed above
could efficiently enhance reactivity at C8 and 36 could be
isolated in 81% yield as a single diastereomer.
6
7
8
9
81%
OAc
N
O
·
Me
d) N2H4 H2O;
Pb(OAc)4
e) TBAF
Me
13
14
H
N
H
Me
8
8
Me
Me
OH
OTBS
H
OH
OH
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
Me
50%, 2 steps
O
O
O
O
Me
Me
Me
Me
36
48
Me
Me
f) hv
then TPAP
82%
OAc
OAc
Me
H
Me
H
Me
Me
13
14
13
g) ZnCl2,
65%
Me
Me
H
H
H
OH
OH
O
O
O
O
HO
Me
O
50
Me
49
Me
Me
h) Grubbs-II
82%
OAc
Me
H
Me
Me
8
H
H
OH
O
O
HO
51
Me
Me
Inspired by Wenders’ previous work in semi-synthesis of
prostratin,11 we persued a photochemical cyclopropanation
aReagents and conditions. (a) I2, pyridine, CH2Cl2, 50 °C, 85%;
method for
D
ring. Notably, in Wender‘s work,
(b) Pd(PPh3)2Cl2 (5 mol%), AsPh3 (10 mol%), 2-propenylBPin,
Ag2O, THF/H2O (8:1), 93%; (c) Me3Al, 2,6-diphenylphenol,
vinylMgCl, THF, -78 °C to rt, 81%; (d) N2H4H2O, EtOH, 90 °C,
then Pb(OAc)4, CH2Cl2; (e) TBAF, THF, 0 °C, 50%, 2 steps; (f) hv,
EtOAc, rt; then TPAP (20 mol%), NMO, 4ÅMS, 0 °C to rt, 82%;
(g) ZnCl2, 13, THF, -78 °C, 65%; (h) Grubbs second-generation
catalyst (50 mol%), toluene, 110 °C, 82%. 2-propenylBPin = 2-
crotophorbolone (4), as a nonconjugated enone, was used
as the reactant where C14 stereocenter was preset. In our
case, however, 36 was a conjugated enone and selective
formation of C14 stereocenter was the key to correctly build
the D ring.
In event, an ethanolic solution of enone 36 was heated
with an excess of hydrazine hydrate furnished unstable
pyrazoline intermediate, which was immediately oxidized
in the same reaction flask with lead (IV) tetraacetate to
propenyl
boronic
acid
pinacol
perruthenate,
ester,
NMO
TPAP
=
=
tetrapropylammonium
N-
methylmorpholine N-oxide, 4ÅMS = 4Å molecular sieves.
generate
a
cyclic diazene. After treatment with
product (58%) together with a side product which was
identified as spiro-diketone 45 (34%). Formation of 45
could be viewed as an unusual oxidative regio- and
stereoselective semi-pinacol rearrangement. Next,
introduction of 2-methylallyl group to C4 was accomplished
through addition of 2-methylallyl magnesium chloride 13
mediated by LaCl32LiCl, affording the corresponding diene
as single diastereomer. Simple mixing the Grignard reagent
with 44 led to complex mixture and retro-aldol reaction
was observed as a side reaction. Subsequently, ring closing
Scheme 7. Failed B-ring-then-D-ring detours
tetrabutylammonium fluoride (TBAF), the product 48 was
isolated in 50% yield. However, the configurations of the
newly formed C13,C14 stereocenters were initially not clear
based on NMR spectra. Furthermore, photolytic extrusion of
nitrogen (300W UV lamp, 254 nm) of 48 followed by
oxidation gave 49 in 82% yield as single isomer.
Exposure of 49 to methallyl zinc reagent (generated via
ZnCl2 and 13) at -78oC in THF for 30 minutes was found to
effectively yielded diene 50 in good isolated yield (65%). It
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 29
O
Me
H
Me
H
Me
H
O
O
1
14
Me
8
14
14
15
Me
Me
2
Me
Me
OH
15
15
Me
OH
OH
H
H
3
4
5
O
Me
Me
O
O
O
HO
HO
Me
HO
Me
53
Me
OH
OH
14,15-didehydrolangduin A (55)
langduin A (54)
6
7
8
9
d) Li, NH3(l), 50%
O
O
a) TBAF
b) TPAP
62%, 2 steps
c) ZnCl2, , 86%
O
O
Me
H
Me
Me
H
H
Me
Me
Me
14
Me
8
13
15
OH
OH
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
Me
OH
16
O
O
Me
O
OTBS
O
OH
Me
O
Me
Me
O
HO
Me
58
Me
36
Me
Me
h) DDQ
52
Me
i) TsCl, Py.,
65%, 2 steps
j) TPAP, 74%
g) TPAP, NMO
83%
e) NaBH4, 97%
O
OH
Me
H
OH
Me
Me
13
O
H
H
14
f) VO(acac)2
66%
Me
Me
Me
Me
15
2
OH
OH
OH
3
Me
Me
O
O
OH
Me
O
OH
Me
O
HO
Me
O
Me
Me
Me
Me
59
57
56
aReagents and conditions. (a) TBAF, THF, 0 °C to rt; (b) TPAP (10 mol%), NMO, 4ÅMS, 0 °C to rt, 62%, 2 steps; (c) ZnCl2, 13, THF,
-78 °C, 86%; (d) Li, NH3(l), THF, -78 °C, 50%; (e) NaBH4, MeOH/CH2Cl2 (1:1), 0 °C, 97%; (f) VO(acac)2 (5 mol%), TBHP, CH2Cl2, 0 °C
to rt, 66%; (g) TPAP (10 mol%), NMO, 4ÅMS, 0 °C to rt, 83%; (h) DDQ (20 mol%), MeCN/THF/H2O (1:4:1), rt; (i) TsCl, pyridine,
DMAP, CH2Cl2, 0 °C to rt, 65%, 2 steps; (j) TPAP (10 mol%), NMO, 4ÅMS, 0 °C to rt, 74%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone.
ACS Paragon Plus Environment

Page 9 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MeOH/CH2Cl2 (1:1), -78 °C to rt, 56%; (d) MOMCl, DIPEA, CH2Cl2,
0 °C to rt; (e) TBAF, THF, 0 °C to rt; (f) TPAP (10 mol%), NMO,
4ÅMS, 0 °C to rt, 69%, 3 steps; (g) ZnCl2, 13, THF, -78 °C, 67%.
should be mentioned that using direct addition of Grignard
reagent 13 or LaCl32LiCl/13 resulted in mostly retro-aldol
side reaction. Next, formation of B ring from 50 in the
conditions of RCM was achieved and the desired product was
isolated in 82% yield. However, the catalyst loading had to be
With efficient access of 52, we proceeded for B-ring
formation. Success in ring closing metathesis of 52 might pave
a way to langduin A (54),31 14,15-didehydrolangduin A (55)32
as well as 1. However, in sharp contrast to the substrates
discussed above, attempts with various catalysts and
conditions for RCM of compound 52 led to essentially no
reaction (see supporting imformation). We hypothesized that
the rigid and bulky dimethylmethylene group at C14 might
block the approaching of the catalyst, and reducing the C14-
C15 double bond might solve the problem. We found that
dissolving metal reduction with lithium in liquid ammonia
could provide ketone 53 in 50% yield. However, the single
crystal analysis of 53 clearly showed 8,14-cis configuration
that did not match with the structure in natural langduin A.
Alternatively, a three-step sequence was used to epoxidize the
C14-C15 double bond. Thus, reduction of C13-carbonyl group
in 52, followed by hydroxy-directed vanadium-catalysed
epoxidation delivered epoxide 57 in good yield and
diastereoselectivity. 57 was then oxidized to ketone 58 in 83%
yield. The relative configuration of 57 was confirmed by X-ray
crystallography. Disappointedly, all of the three compounds
(56, 57, 58) were found to be not viable in RCM conditions.
1
increased up to 50 mol%. At this stage, we compared the H
NMR spectrum of 51 with the one from reported prostratin 1.
To our surprise, the chemical shift of allylic C8-H in 50 was at
4.05 ppm while it was at 3.38 ppm for 1.11,30 The large
difference led us to consider that the relative configuration of
C8 and C14 was cis rather than the trans stereochemistry in
natural tiglianes. Finally, X-ray analysis of 48 showed that C14
was indeed of the undesired configuration.
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
Failed B-ring-then-D-ring detours
In order to correctly install the C14 thus the D ring
stereochemistry, an attractive alternative approach would
involve reversing the sequence of B-ring and D-ring formation.
We decided to first construct rigid ABC tricyclic structure and
then form the cyclic diazene as a precusor to D ring. This idea
was also encouraged by the success of Wender’s semi-
synthesis. Thus, treatment of enone 36 with TBAF, followed by
oxidation in Ley’s conditions (TPAP, NMO) furnished the
corresponding diketone intermediate in 62% yield over the
two steps (scheme 7). The methallylation with the above-
mentioned zinc reagent-based method again successfully
afforded the desired product 52 in 86% yield. X-ray
crystallographic analysis of a single crystal of 52 revealed its
full structure. Interestingly, this time, retro-aldol reaction was
not observed.
We also tried to release possible steric hindrance of A ring by
a sequence of manipulations. Thus, removal of the acetonide
group by catalytic amount of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone
(DDQ)33
in
mixed
solvent
(acetonitrile/THF/H2O, 1:4:1) followed by selective tosylation
of primary alcohol (TsCl, pyridine, 65% for two steps) and
subsequent cascade oxidation/elimination (TPAP, NMO)
provided diketone 59 in 74% yield. However, diketone 59
again was inert to the RCM conditions.
Scheme 8. synthesis of 62a
O
Me
H
O
Me
H
R1
a) I2, 85%
OH
OH
The failure in ring closing metathesis discussed above
prompted us to reconsider a suitable substituent at C14
(scheme 8). Palladium-catalyzed carbonylation of iodide which
was iodinated from 40 in methanol generated ester 60 in
excellent yield (94%). Treatment of 60 with vinyl copper
reagent (generated from CuCN and vinylMgCl) followed by
reduction using Luche’s method afforded secondary alcohol 61
in 56% yield. Coupling constant of H8 and H14 (3JH8-H14 = 11.2
Hz) indicated 8,14-trans configuration of 61. Protection of
alcohol 61 with MOM group, deprotection of the TBS group
followed by Ley oxidation unveiled ketone 62 in 69% yield for
the three steps. Zinc-mediated methallylation of 62 gave diene
63 in modest yield (67%). Unfortunately, compound 63 was
also immune to various RCM conditions.
b) Pd(PPh3)4,
CO, MeOH
95%
O
O
OTBS
OTBS
O
O
Me
Me
40
R1 = CO2Me
60
Me
Me
c) CuCN, vinylMgCl
then NaBH4, 56%
OR2
R1
Me
H
d) MOMCl
e) TBAF
f) TPAP
OH
R1
Me
H
14
8
OH
O
OH
OTBS
61
69%, 3 steps
O
O
O
O
Me
Me
62
R
2 = MOM
Me
Me
13
g) ZnCl2, , 67%
OR2
OR2
R1
Me
Me
H
H
Successful D ring formation and synthesis of the
tetracyclic scaffold
RCM
R1
OH
O
OH
H
O
O
Me
HO
The initial attempt in building D ring led only to wrong
configuration at C14 (Scheme 6). We reasoned that C14
stereocenter should be formed through protonation of an
enamine-like intermediate during reaction between the enone
substrate and hydrazine. If so, proton source could play an
important role in this step. Because the pyrazoline compound
O
HO
Me
63
Me
Me
Me
Me
64
aReagents and conditions. (a) I2, pyridine, CH2Cl2, 50 °C, 85%;
(b) Pd(PPh3)4 (5 mol%), CO (1 atm), Et3N, MeOH/THF (1:1), 95%;
(c) CuCN, vinylMgCl, THF, -78 °C to rt; then NaBH4, CeCl37H2O,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 29
1
2
3
4
5
derived from condensation of enone 36 and hydrazine hydrate
was unstable to
6
7
8
9
Scheme 9. Revised cyclopropane and trans heptanea
O
Me
H
N
Me
N
Ph
H
14
Me
Me
8
a) PhNHNH2,
TFA, THF
Me
OH
H
OH
OH
65
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
Me
O
O
OTBS
b) TBAF
49%, 2 steps
O
O
Me
Me
36
Me
Me
c) N2H4H2O, TFA
then Pb(OAc)4, 52%
3JH8-H14 = 10.5 Hz
OAc
OAc
Me
Me
OAc
Me
H
Me
N
Me
Me
Me
13
14
H13
H
N
H
14
d) hv, then TBAF
+
H
H
8 H
OH
OH
OH
OH
67
Me
Me
OH
OTBS
66
O
O
O
O
O
O
Me
Me
68
(11%)
(79%)
Me
Me
Me
Me
e) TPAP, NMO
f) 2-MethylallylZnCl
62%, 2 steps
OAc
Me
OAc
Me
Me
Me
H
Me
H
g) Grubbs-II
71%
Me
H
H
OH
O
OH
H
O
O
Me
HO
OH
Me
O
Me
69
Me
35
Me
Me
aReagents and conditions. (a) PhNHNH2, TFA, THF, 90 °C; (b) TBAF, THF, 0 °C, 49%, 2 steps; (c) N2H4H2O, TFA, THF, 90 °C; then
Pb(OAc)4, CH2Cl2, 0 °C, 52%; (d) hv, EtOAc, rt; then TBAF, THF, 0 °C, 79% 67, 11% 68; (e) TPAP (20 mol%), NMO, 4ÅMS, 0 °C to rt; (f)
ZnCl2, 13, THF, -78 °C, 62%, 2 steps; (g) Grubbs second-generation catalyst (40 mol%), toluene, 110 °C, 71%. TFA = trifluoroacetic acid.
acid and oxygen, we decided to firstly investigate the reagent to generated the desired diene 35 in 62% overall as a
condensation of 36 with phenylhydrazine (scheme 9). After single diastereoisomer, along with a small amount of retro-
extensive experiments using different solvents and proton aldol byproducts. It should be noted that the transformation
sources, we found that trifluoroacetic acid (TFA) could was not only highly stereoselective but also rapid (1.1 eq. zinc
o
smoothly promote the condensation in refluxing THF. After reagent, -78 C, <5 min). At this stage, we tried different
deprotection of TBS group, the N-phenyl pyrazoline adduct 65 conditions for the pivotal ring-closing metathesis reaction and
was isolated in 49% overall yield. The key 3J coupling constant found that using 40 mol% of the Grubbs second generation
between H8 and H14 was found to be 11.4 Hz. Furthermore, X- catalyst, the desired product 69 could be formed in 71% yield
ray diffraction analysis of 65 clearly indicated 8,14-trans along with 20% recovered starting material. Consequently, the
configuration.
tetracyclic scaffold of tigliane diterpenoids was successfully
established.
This result encouraged us to test the reaction between enone
36 and hydrazine hydrate in the presence of TFA in THF.
Indeed, this operation furnished the unstable pyrazoline
(observed with NMR) which was oxidized in one-pot to
generate diazene 66 in 52% yield. Photolysis of 66 resulted the
desired cyclopropane intermediate which, upon treatment
with TBAF, was transformed to 67 in good yield (79%). Small
amount (11%) of accompanying stereoisomer with an
unexpected trans-bicyclo[4.1.0]heptane 68 was also isolated.
The unusual highly strained structure of 68 was
unambiguously established to be 13,14-trans configuration by
X-ray diffraction of a crystal. To the best of our knowledge, this
represents the first trans-bicyclo[4.1.0]heptane bicyclic
framework observed by X-ray crystallographic analysis.
Computational studies on the mechanism of solvent- and
acid-controlled stereodivergent protonation
During building the cyclopropane D ring, the completely
inversed stereoselectivity in formation of C14 stereocenter by
using different reaction conditions was intriguing (Scheme 10).
Therefore, DFT calculation was performed to understand the
origin of such selectivity.35 The calculated results indicated the
possible reaction mechanism that correlated with the
experimental results.
In the X-ray structure of 36, intramolecular hydrogen bond
between the tertiary hydroxyl group at C9 and the ethereal
oxygen locked the half-chair conformation of C-ring, which
contained three axial substituents. Under the neutral reaction
conditions, such intramolecular interaction should remain
Next, C4 hydroxyl group was oxidized to an unstable ketone
using Ley oxidation, which was subjected to methallyl zinc
ACS Paragon Plus Environment

Page 11 of 29
The Journal of Organic Chemistry
1
2
3
4
5
unchanged in intermediate A . In this case, (H2O)x bridge was
able to work as proton shuttle to transfer the hydrogen from
6
7
8
9
N1 to C14. Herein, TScis-xH O referred to a transition state which
involved x water molecules and where the H atom was added
to C14 in an anti-position relative to hydroxyl, alkenyl and
2
methyl on the same 6-membered cycle. Via TScis-xH O, an
2
intermediate
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 29
Scheme 10. The caculated results on the stereodivergent protonationa
1
2
3
4
5
6
7
8
OTBS
OTBS
Me
A ring
Me
14
H
O
O
O
N
H
Me
1
N
O
H
EtOH
TFA, THF
2
H
O
n
OH
Me
O
9
O
H
CF3
48
H
66
Me
H
O
H
O
O
Me
Me
8
H
14
O
14
2
Me
Me
H
A
N
N
H
H
N
H
Me
Me
O
1
N
H
Me
F3C
Me
TScis-xH O
TStrans-acid
2
N2H4 H2O
36
TScis-acid
TStrans-acid
TScis-2H O
2
TStrans-2H O
2
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
2.0 kcal/mol
0.0 kcal/mol
0.0 kcal/mol
3.7 kcal/mol
aThe Gibbs free energy of the preferred tansition states were set as 0.0 kcal/mol, and the relative energy of the other transition
states were given for comparation. In the structures of transition states, hydrogen atoms on carbon atoms were omitted for clarity.
with 8,14-cis configuration (Intcis) was obtained, which
would lead to 48 via the following treatment. The calculated
results showed the number of water molecules in (H2O)x
bridge greatly influenced the value of activation energy
relative to the starting materials. However, in the three
groups (x = 2, 3 or 4) of transition states, the transfer of H to
relative configuration were confirmed by X-ray diffraction
analysis. Selective aerobic oxidation of pivalate 70 using
Iwabuchi’s AZADO conditions cleanly provided the desired
ketone with concurrent elimination of the pivalate group.
After protection of C4 alcohol with TMS group, the
corresponding product was isolated in 64% overall yield.
Allylic oxidation of the B ring C20 methyl group to aldehyde
with SeO2 delivered 71 in 81% yield. Next, isomerization of
exo-enone 71 to the endo-enone using rhodium(III) chloride
hydrate as the catalyst was accompanied by solvolytic
C14 via TScis-xH O was always favored, rendering the
2
formation of Intcis. Structurally, as depicted in Scheme 11,
the axial attack of hydrogen would lead to a chair-form
transition state TScis-2H O, which should be more favorable
than the half-chair-form TStrans-2H O according to the Fürst-
2
removal
of
TMS
group,
thus
giving
12-
2
Plattner rule.
deoxyphorbaldehyde-13-acetate (72) in 52% yield. Finally,
reduction of C20 aldehyde group with NaBH4 to the alcohol
was achieved in 86% yield, concluding a total synthesis of
prostratin (1). The NMR spectra and physical properties of
synthetic 72 and 1 were identical to those reported for the
natural products.11,30,34
When CF3COOH was added to the reaction system, we
envisioned that the rigid structure of A, which was
constructed by the intramolecular hydrogen bond, might be
interrupted. Correspondingly, another two transition states
TScis-acid and TStrans-acid were located (Scheme 10). In this
case, pairwise hydrogen bond interaction between A and
CF3COOH was formed. Then, hydrogen migration was
completed with the assistance of another CF3COOH
molecule. From the point view of activation energy, when
the hydrogen atom was added at the same face with the
pendent hydroxyl group (TStrans-acid), the transition state
was highly favored by 3.7 kcal/mol. There might be two
Scheme 11. Completion of the synthesis of prostratin
OAc
Me
Me
OAc
Me
Me
Me
H
Me
H
a) DDQ, then
PivCl, Py.
H
H
O
OH
H
PivO
OH
H
73%
O
HO
HO
Me
HO
69
70
Me
Me
Me
b) AZADO
c) TMSCl
d) SeO2
52%
3 steps
possible causes of this phenomenon. Firstly, in TStrans-acid
,
the H-
OAc
OAc
Me
Me
H
Me
bond interaction between the pendent hydroxyl group and
CF3COOH should stabilize the structure of TStrans-acid and
lower the activation energy relatively. Secondly, when the
intramolecular hydrogen bond was broken, the bulky
substituents on C8, C11 and C9 were all relaxed to be
equatorial, then the axial attack of H atom from the bottom
face would afford a more stable isomer with equatorial
bulky substituent on C14.
Me
Me
H
·
Me e) RhCl3 3H2O
Me
H
H
OH
H
O
OH
H
52%
O
TMSO
O
HO
O
71
12-deoxyphorbaldehyde-
13-acetate (72)
f) NaBH4
86%
OAc
Endgame of total synthesis of prostratin
Me
Me
H
With the tetracyclic advanced intermediate 69 in hand,
the remaining key transformations should include
functional group manipulations at A ring and C20 allylic
oxidation (scheme 11). Based on previous model studies,
removal of the acetonide group by catalytic amount of DDQ
in a solvent mixture (acetonitrile/THF/H2O, 8:2:1) followed
by one-pot selective pivalation of the primary hydroxyl
group furnished 70 in 73% yield. The full structure and
Me
Me
H
H
OH
O
HO
OH
prostratin (1)
aReagents and conditions. (a) 20 mol% DDQ,
MeCN/THF/H2O (8:2:1), rt; then PivCl, pyridine, DMAP, CH2Cl2,
0 °C to rt, 73%; (b) 20 mol% AZADO, DMAP, 30 mol% CuCl, 30
ACS Paragon Plus Environment

Page 13 of 29
The Journal of Organic Chemistry
mol% 2,2’-bpy, MeCN, 0 °C to rt; (c) TMSCl, imidazole, CH2Cl2,
40 °C, 64%, 2 steps; (d) SeO2, PhH, 80 °C, 81%; (e) 30 mol%
RhCl3·3H2O, EtOH, 100 °C, 52%; (f) NaBH4, MeOH, -50 °C, 86%.
and benzene were purified by distillation over
1
2
3
4
5
6
7
8
sodium/benzophenone and stored under N2, MeCN were
purchased from Acros Organics and used directly without
further purification.
CONCLUSIONS
The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd
= doublet of doublet, ddd = doublet of a doublet of a doublet, dt
= doublet of a triplet, td = triplet of a doublet, m = multiplet, br
= broad.
In conclusion, a modular route to [5/7/6] tricyclic core of
tigliane and daphnane diterpenoids has been developed.
The key approach involved an oxidative dearomatization of
planar and readily accessible phenol moiety and the
following concise and highly controlled functionalizations,
in order to build the complex and biologically critical six-
membered C ring. Following this strategy, a total synthesis
of prostratin has been accomplished in 23 steps from
commercially available cyclopentadiene. The synthetic
route also features several highly stereoselective reactions
including a bulky Lewis acid promoted stereoselective
9
Preparation
of
(1R,2S)-2-(4-methoxy-2-
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
vinylphenyl)cyclopentan-1-ol (15). A three-necked flask
fitted with a reflux condenser, a nitrogen inlet and an
addition funnel was charged with Mg (3.34 g, 138.97 mmol,
1.50 equiv), several granules of crystalline iodine were
added, 4-methoxy-2-vinylbromobenzene (29.60 g, 138.97
mmol, 1.50 equiv), was added dropwise over ca. 30 min, and
the flask was heated for several minutes with a heat gun to
initiate the reaction. The addition causes the solution to
gently reflux, and once all of the 4-methoxy-2-
vinylbromobenzene had been added, the reaction mixture
was heated with a heating mantle to continue the reflux for
an additional 30 min. To the freshly prepared solution of the
(4-methoxy-2-vinylphenyl) magnesium bromide 12 was
added copper iodide (1.80 g, 9.45 mmol, 0.10 equiv) at 0 °C,
stirred for 30 min. To this reaction mixture was then added
cyclopentene oxide 14 (7.80 g, 92.72 mmol, 1.00 equiv)
dissolved in THF (100 mL) dropwise over a period of 30 min
at 0 °C. The reaction mixture was stirred to room
temperature for 3 h, The reaction was cooled to 0 °C and
quenched with sat. aq. ammonium chloride. Ethyl acetate (5
x 50 mL) was added, and the upper organic layer was
separated. The organic layer was dried with anhydrous
sodium sulfate, the crude was purified by flash
chromatography (petroleum ether/ ethyl acetate 20:1 →
10:1→5:1) to give the secondary alcohol 15 (20 g, 91.67
mmol, 99%) as pale yellow oil. Rf 0.43 (silica gel, 9:1
conjugate addition,
a
solvent- and acid-controlled
stereoselective cyclopropane formation and a late-stage
RCM for B ring formation. DFT investigations of the
mechanism in D ring formation revealed that a switch of
intramolecular hydrogen bond mode led to stereodivergent
protonation. This modular synthetic approach should be
amenable to syntheses of other challenging natural and
unnatural members within the tigliane and daphnane
families.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reactions
were carried out in a flame-dried, septum-sealed flask under an
atmosphere of argon. Analytical thin-layer chromatography
was performed on glass plates coated with 0.25 mm 230–400
mesh silica gel containing a fluorescent indicator. Visualization
was accomplished by exposure to a UV lamp, and/or treatment
with
a solution of p-anisaldehyde or 10% ethanolic
phosphomolybdic acid (PMA) followed by brief heating with a
heating gun. Most of the products were compatible with
standard silica gel chromatography. Column chromatography
was performed on silica gel 60N (spherical and neutral, 200–
300 mesh) using standard methods.
1
petroleum ether/ ethyl acetate, UV, blue, PMA); H NMR
(400 MHz, CDCl3) δ 7.13 (dd, J = 17.3, 10.9 Hz, 2H), 7.01 (d,
J = 2.7 Hz, 1H), 6.84 (dd, J = 8.6, 2.7 Hz, 1H), 5.61 (dd, J = 17.3,
1.2 Hz, 1H), 5.32 (dd, J = 10.9, 1.2 Hz, 1H), 4.22 (dd, J = 13.6,
6.8 Hz, 1H), 3.81 (s, 3H), 3.21 (dd, J = 16.8, 7.9 Hz, 1H), 2.24-
2.02 (m, 2H), 1.95-1.57 (m, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 158.0, 138.9, 135.4, 132.9, 126.9, 116.4, 114.0,
111.5, 80.1, 55.4, 49.2, 33.9, 32.0, 21.9; HRMS (ESI+) m/z
calcd for C14H22NO2 (M+NH4)+: 236.1643, found: 236.1645;
IR (neat) ν 3377, 2953, 1503, 1569, 1493, 1287, 1241, 1029,
987, 856, 815 cm-1.
NMR spectra were measured on a Bruker Avance-400
spectrometer and chemical shifts (δ) are reported in parts per
1
million (ppm). H NMR spectra were recorded at 400 MHz in
NMR solvents (CDCl3) and referenced internally to
corresponding solvent resonance, and 13C NMR spectra were
recorded at 100 MHz, Chemical shift were reported in ppm on
the δ scale relative to CHCl3 (δ = 7.26 for 1H NMR, δ = 77.00 for
13C NMR). All 13C NMR data were obtained with the use of
broadband decoupling (13C{1H}) and reported as proton-
decoupled data. Coupling constants are reported in Hz with
multiplicities denoted as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet) and br (broad). Infrared spectra were
collected on a Thermo Fisher Nicolet 6700 FT-IR spectrometer
using ATR (Attenuated Total Reflectance) method. Absorption
maxima (ν max) are reported in wavenumbers (cm-1). High
resolution mass Spectra (HRMS) were obtained on a Bruker
Apex IV FTMS spectrometer or an Agilent 6224 LC/MS TOF
spectrometer. Single crystal X-ray diffraction analysis were
carried out by Dr. Yousong Ding on Bruker apex duo equipment
at Center for Applied Chemistry Research, Frontier Institute of
Science and Technology, Xi’an Jiaotong University. Melting
points were determined on a Hannon MP300 apparatus and are
not corrected.
Preparation
of
(S)-2-(4-methoxy-2-
vinylphenyl)cyclopentan-1-one (SI-1). To a stirred solution
of secondary alcohol 15 (3.00 g, 13.74 mmol, 1 equiv) in CH2Cl2
(40 mL) at 0 °C was added Dess-Martin periodinane (8.74 g,
20.62 mmol, 1.50 equiv), and the reaction mixture was stirred
at room temperature for 3 h. The resulting mixture was then
quenched with sat. aq. NaHCO3 (10 mL), the biphasic mixture
was extracted with CH2Cl2 (3 x 50 mL), the combined organic
extracts were washed with brine (50 mL), The organic layer
was dried with anhydrous sodium sulfate, the crude was
purified by flash chromatography (petroleum ether/ ethyl
acetate 15:1) to give the ketone SI-1 (2.53 g, 11.71 mmol, 85%)
as pale yellow oil. Rf 0.36 (silica gel, 9:1 petroleum ether/ ethyl
acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J =
2.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.90-6.78 (m, 2H), 5.61 (dd,
J = 17.2, 1.1 Hz, 1H), 5.32 (dd, J = 10.9, 1.1 Hz, 1H), 3.80 (s, 3H),
Commercial reagents were purchased from J&K, Energy,
Sigma-Aldrich, Alfa Aesar, Acros Organics, Strem Chemicals or
TCI and used as received unless otherwise stated. THF, toluene
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 29
3.54 (dd, J = 11.4, 8.6 Hz, 1H), 2.55-2.40 (m, 2H), 2.38-2.26 (m,
temperature for 30 mins. The reaction mixture was
1H), 2.20-2.10 (m, 1H), 2.07-1.87 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 219.0, 158.6, 139.1, 135.0, 128.9, 128.9, 117.1,
114.0, 111.9, 55.4, 52.4, 38.7, 32.5, 21.0; HRMS (ESI+) m/z calcd
for C14H17O2 (M+H)+: 217.1215, found: 217.1223; IR (neat) ν
2950, 2835, 1496, 1290, 1271, 1247, 1036, 856, 812 cm-1.
concentrated to dryness and purified directly by preparative
flash chromatography (9:1 petroleum ether/ ethyl acetate,
twice) to yield the aldehyde SI-4 as pale yellow oil (6 mg, 26
μmol, 26%), the ketone 17 as yellow solid (15 mg, 66 μmol,
66%). 17: Rf 0.62 (silica gel, 9:1 petroleum ether/ ethyl acetate,
UV, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.7 Hz,
1H), 8.04 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.22 (dd, J =
9.2, 2.6 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 3.95 (s, 3H), 3.35 (t, J =
6.1 Hz, 2H), 2.80 – 2.65 (m, 2H), 2.28 (dt, J = 12.8, 6.3 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3); δ 198.3, 159.5, 143.0, 137.6,
128.4, 126.5, 126.4, 125.8, 123.6, 119.0, 107.0, 55.4, 38.3, 25.7,
22.8. SI-4: Rf 0.71 (silica gel, 9:1 petroleum ether/ ethyl acetate,
1
2
3
4
5
6
7
8
Preparation
of
(1R,2S)-1-allyl-2-(4-methoxy-2-
vinylphenyl)cyclopentan-1-ol (SI-2). To a stirred solution of
ketone SI-1 (2.00 g, 9.26 mmol, 1.00 equiv) in Et2O (20.0 mL)
at -78 °C was added allylmagnesium bromide (14.0 mL, 1.0 M
in Et2O, 1.50 equiv) dropwise over ca. 30 min under nitrogen,
and the reaction mixture was stirred at -78 °C for 3 h. The
resulting mixture was then quenched with sat. aq. ammonium
chloride. Ethyl acetate (3 x 10 mL) was added, and the upper
organic layer was separated. The organic layer was dried with
anhydrous sodium sulfate, the crude was purified by flash
chromatography (petroleum ether/ ethyl acetate 20:1) to give
alcohol SI-2 (2.27 g, 8.79 mmol, 95%, d.r. = 10:1, inseparable
mixture) as pale yellow oil. Rf 0.55 (silica gel, 9:1 petroleum
ether/ ethyl acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J = 8.6 Hz, 1H), 7.14-6.99 (m, 2H), 6.86 (dd, J = 8.6, 2.8
Hz, 1H), 5.79 (ddt, J = 17.5, 10.4, 7.3 Hz, 1H), 5.60 (dd, J = 17.2,
2.4 Hz, 1H), 5.32 (dd, J = 10.9, 2.4 Hz, 1H), 5.07-4.98 (m, 2H),
3.83 (s, 3H), 3.19 (dd, J = 10.9, 7.8 Hz, 1H), 2.28-1.57 (m, 10H);
13C{1H} NMR (100 MHz, CDCl3) δ 158.3, 139.8, 136.0, 134.6,
129.7 (two peaks), 118.2, 116.8, 113.4, 112.0, 82.0, 55.4, 48.9,
45.2, 38.4, 31.8, 21.8; HRMS (ESI+) m/z calcd for C17H26NO2
(M+NH4)+: 276.1952, found: 276.1958; IR (neat) ν 3558, 2954,
1492, 1287, 1242, 1030, 990, 910, 874, 856, 815 cm-1.
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
UV, blue, PMA); H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.88
(d, J = 9.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 8.1, 7.1
Hz, 1H), 7.16 – 7.02 (m, 3H), 3.85 (s, 3H), 3.07 – 2.93 (m, 2H),
2.45 (td, J = 7.2, 1.4 Hz, 2H), 2.05 – 1.91 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 202.2, 157.3, 137.4, 135.2, 127.2, 126.1,
125.8, 125.3, 124.1, 118.5, 106.7, 55.3, 43.4, 32.2, 23.1; HRMS
(ESI+) m/z calcd for C15H17O2 (M+H)+: 229.1229, found:
229.1222; IR (neat) ν 2934, 1625, 1255, 1219, 1034, 844, 822,
737 cm-1.
Preparation
of
(((3aR,10bS)-8-methoxy-2,3,4,10b-
tetrahydrobenzo[e]azulen-3a(1H)-yl)oxy)trimethylsilane
(SI-5). To a stirred solution of 16 (1.20 g, 5.21 mmol, 1.00
equiv) and Et3N (1.40 mL, 10.10 mmol, 2.00 equiv) in CH2Cl2
(20 mL) at 0 °C were added TMSOTf (1.40 mL, 7.82 mmol, 1.50
equiv) dropwise over ca. 10 min, and the reaction mixture was
stirred at room temperature for 3 h. The resulting mixture was
then quenched with sat. aq. sodium bicarbonate. CH2Cl2 was
added (3 x 10 mL), the organic layer was dried with anhydrous
sodium sulfate, the crude product was purified by flash
chromatography (petroleum ether) to give SI-5 (1.56 g, 5.16
mmol, 99%) as pale yellow oil. Rf 0.34 (silica gel, petroleum
Preparation
of
(3aR,10bS)-8-methoxy-2,3,4,10b-
tetrahydrobenzo[e]azulen-3a(1H)-ol (16) and (3aS,10bS)-
8-methoxy-2,3,4,10b-tetrahydrobenzo[e]azulen-3a(1H)-
ol (SI-3). To a stirred solution of SI-2 (2.60 g, 10.06 mmol, 1.00
equiv) in toluene (100 mL) was added Grubbs 2nd generation
catalyst (8.5 mg, 0.001 equiv) under nitrogen, and the resultant
mixture was stirred at 80 °C (oil bath) for 3 h. The mixture was
concentrated to dryness and the residue was purified by flash
chromatography (petroleum ether/ ethyl acetate 15:1) to give
16 (1.95 g, 8.47 mmol, 84%) as yellow solid (m.p. 71.4-74.4 °C),
and its diastereoisomer SI-3 (186.5 mg, 0.81 mmol, 8%) as
yellow oil. 16: Rf 0.48 (silica gel, 9:1 petroleum ether/ ethyl
acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J =
8.4 Hz, 1H), 6.86-6.74 (m, 2H), 6.46 (d, J = 12.7 Hz, 1H), 5.78 (dt,
J = 12.7, 4.1 Hz, 1H), 3.81 (s, 3H), 3.00-2.89 (m, 1H), 2.74 (dd, J
= 19.4, 4.7 Hz, 1H), 2.62 (d, J = 19.4 Hz, 1H), 2.20-1.87 (m, 6H),
1.66-1.52 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.5,
136.1, 130.1, 129.7, 129.7, 129.1, 117.1, 113.3, 78.6, 55.6, 53.3,
46.9, 43.0, 30.6, 24.4; HRMS (ESI+) m/z calcd for C15H22NO2
(M+NH4)+: 248.1638, found: 248.1645; IR (neat) ν 3400, 2952,
1602, 1505, 1250, 1162, 1036, 871, 820, 803, 773, 682 cm-1. SI-
3: Rf 0.23 (silica gel, 9:1 petroleum ether/ ethyl acetate, UV,
blue, PMA); 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.4 Hz, 1H),
6.73 (dd, J = 8.4, 2.6 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 6.61 (d, J =
10.5 Hz, 1H), 5.97 (dt, J = 10.5, 7.0 Hz, 1H), 3.79 (s, 3H), 3.01
(dd, J = 10.1, 8.1 Hz, 1H), 2.28 (dd, J = 12.6, 7.8 Hz, 1H), 2.19 (dd,
J = 12.6, 6.2 Hz, 1H), 2.02-1.93 (m, 3H), 1.83-1.70 (m, 3H), 1.65-
1.55 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.0, 137.6,
134.0, 132.5, 131.7, 128.6, 114.7, 112.6, 93.86, 59.9, 55.4, 39.4,
39.0, 36.3, 23.9; HRMS (ESI+) m/z calcd for C15H18O2Na
(M+Na)+: 253.1204, found: 253.1189; IR (neat) ν 3392, 2949,
1603, 1494, 1265, 1242, 1040, 873, 858, 782, 762 cm-1.
1
ether, UV, blue, PMA); H NMR (400 MHz, CDCl3) δ 7.06 (d, J =
8.3 Hz, 1H), 6.77-6.67 (m, 2H), 6.42 (d, J = 12.5 Hz, 1H), 5.70 (dt,
J = 12.5, 4.1 Hz, 1H), 3.80 (s, 3H), 2.81 (dd, J = 11.8, 6.6 Hz, 1H),
2.70 (dd, J = 19.2, 4.5 Hz, 1H), 2.53 (dd, J = 19.2, 2.8 Hz, 1H),
2.19-2.00 (m, 3H), 2.00-1.83 (m, 3H), 1.62-1.43 (m, 1H), -0.17
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.4, 137.1, 132.3,
130.8, 128.8, 127.2, 115.9, 111.5, 81.9, 55.4, 54.2, 46.7, 44.6,
30.1, 24.4, 2.0; HRMS (ESI+) m/z calcd for C18H26O2SiNa
(M+Na)+: 325.1599, found: 325.1581; IR (neat) ν 2952,
1504, 1270, 1247, 1045, 835, 751, 692 cm-1.
Preparation of (3aR,10bS)-3a-((trimethylsilyl)oxy)-
1,2,3,3a,4,10b-hexahydrobenzo[e]azulen-8-ol (18). To a
stirred solution of diphenylphosphine (8.60 mL, 49.60 mmol,
3.00 equiv) in THF (80 mL) at 0 °C was added cold n-
butyllithium solution (22.5 mL, 2.2 M in hexane, 49.60 mmol,
3.00 equiv) by syringe over ca. 20 min under nitrogen. The red
solution was allowed to warm to room temperature over about
30 min before SI-5 (5.00 g, 16.53 mmol, 1.00 equiv) in THF (5
mL) was added. The mixture was stirred at 60 °C (oil bath) for
3 h. Then the resulting mixture was quenched with sat. aq.
ammonium chloride. Ethyl acetate (5 x 10 mL) was added, and
the upper organic layer was separated. The organic layer was
dried with anhydrous sodium sulfate. The crude was purified
by flash chromatography (petroleum ether/ ethyl acetate 20:1)
to give 18 as white solid (m.p. 91.6-92.8 °C) (4.6 g, 15.91 mmol,
96%). Rf 0.60 (silica gel, 9:1 petroleum ether/ ethyl acetate, UV,
blue, PMA); 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.8 Hz, 1H),
6.73-6.60 (m, 2H), 6.38 (d, J = 12.6 Hz, 1H), 5.70 (dt, J = 12.6, 4.1
Hz, 1H), 4.99 (s, 1H), 2.80 (dd, J = 11.5, 6.7 Hz, 1H), 2.76-2.65
(m, 1H), 2.52 (dd, J = 19.3, 2.7 Hz, 1H), 2.16-1.85 (m, 6H), 1.58-
1.47 (m, 1H), -0.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
153.1, 137.3, 132.3, 130.5, 129.0, 127.4, 117.0, 113.2, 81.8, 54.2,
46.7, 44.6, 30.1, 27.1, 24.4, 2.0; HRMS (ESI+) m/z calcd for
Preparation of 7-methoxy-3,4-dihydrophenanthren-
1(2H)-one (17) and 4-(6-methoxynaphthalen-1-yl)butanal
(SI-4). To a stirred solution of 16 (23 mg, 0.10 mmol, 1.00
equiv) in MeCN/H2O (v:v，3:1，2 mL) at room temperature
was added slowly ceric ammonium nitrate (164 mg, 0.30 mmol,
3.00 equiv) and the reaction mixture was stirred at room
ACS Paragon Plus Environment

Page 15 of 29
The Journal of Organic Chemistry
C17H24O2SiNa (M+Na)+: 311.1443, found: 311.1427; IR (neat) ν
Preparation of 4-(6-hydroxynaphthalen-1-yl)butanal
1
2
3
4
5
6
7
8
3277, 2955, 2868, 1502, 1247, 1098, 1045, 860, 834, 752, 698
(22). 21 (22 mg, 0.10 mmol, 1.00 equiv) was dissolved in
MeCN/H2O (v:v, 3:1, 1.3 mL). PhI(OAc)2 (35 mg, 0.11 mmol,
1.10 equiv) was added, and then stirred at room temperature
for 10 min, color of solution changed from yellow to dark red.
The residue was concentrated in vacuo and purified directly by
preparative flash chromatography (2:1 petroleum ether/ ethyl
acetate, twice) to yield 22 as yellow oil (15 mg, 0.07 mmol,
70%). Rf 0.37 (silica gel, 2:1 petroleum ether/ ethyl acetate, UV,
blue, PMA); 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.96 (d, J
= 9.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 – 7.29 (m, 1H), 7.21
– 7.06 (m, 3H), 3.16 – 2.95 (m, 2H), 2.53 (t, J = 7.1 Hz, 2H), 2.16
– 1.95 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 202.5, 153.2,
137.4, 135.3, 127.2, 126.3, 125.7, 125.5, 124.1, 117.7, 110.4,
43.5, 32.2, 23.0; HRMS (ESI+) m/z calcd for C14H15O2 (M+H)+:
215.1072, found: 215.1066; IR (neat) ν 3417, 2925, 2854, 1652,
1046, 806, 757 cm-1.
cm-1.
Preparation of (3aR,10aR,10bR)-1,2,3,10b-tetrahydro-
3a,10a-epoxybenzo[e]azulen-8(4H)-one (19). To a stirred
solution of phenol 18 (11.5 mg, 0.04 mmol, 1.00 equiv) and
NaHCO3 (6.7 mg, 0.08 mmol, 2.00 equiv) in MeCN/H2O (3:1 v/v,
0.5 mL) was added PhI(OAc)2 (13.0 mg, 1.00 mmol, 1.10 equiv)
at 0 °C, the reaction mixture was stirred at room temperature
for 1 h, then the mixture was concentrated to dryness and the
crude product was carefully purified by column
chromatography (petroleum ether/ ethyl acetate 5:1) to give
19 (3.6 mg, 0.017 mmol, 42%) as pale yellow oil. Rf 0.20 (silica
gel, 9:1 petroleum ether/ ethyl acetate, UV, blue, PMA); 1H NMR
(400 MHz, CDCl3) δ 7.03 (d, J = 10.2 Hz, 1H), 6.24-6.18 (m, 2H),
6.08 (dt, J = 11.9, 3.7 Hz, 1H), 5.99 (s, 1H), 2.96 (d, J = 20.1 Hz,
1H), 2.80 (d, J = 8.5 Hz, 1H), 2.54 (dd, J = 20.1, 3.7 Hz, 1H), 2.37-
2.21 (m, 1H), 2.14-1.92 (m, 3H), 1.82-1.65 (m, 1H), 1.53-1.39
(m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.5, 158.2, 144.8,
134.9, 130.0, 127.3, 125.4, 92.7, 76.4, 49.8, 39.3, 37.8, 28.1,
26.0; HRMS (ESI+) m/z calcd for C14H15O2 (M+H)+: 215.1061,
found: 215.1067; IR (neat) ν 2926, 1652, 1601, 1216, 1089,
958, 907, 751 cm-1.
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
Preparation of (Z)-3-hydroxy-12-methoxy-9,10,11,12-
tetrahydrobenzo[10]annulen-8(7H)-one (23). To a stirred
solution of phenol 21 (45 mg, 0.2 mmol, 1.00 equiv) in MeOH
(2 mL) at 0 °C was added slowly PhI(OAc)2 (74 mg, 0.23 mmol,
1.10 equiv). The mixture was allowed to warm to room
temperature over
2 h. Then the reaction mixture was
Preparation of (3aR,10aS,10bS)-10a-(tert-butylperoxy)-
3a-((trimethylsilyl)oxy)-2,3,3a,4,10a,10b-
concentrated to dryness and purified directly by preparative
flash chromatography (2:1 petroleum ether/ ethyl acetate) to
afford 23 (34 mg, 0.14 mmol, 69%) as yellow solid (m.p. 137-
139 °C). Rf 0.58 (silica gel, 2:1 petroleum ether/ ethyl acetate,
hexahydrobenzo[e]azulen-8(1H)-one (20). To a stirred
solution of phenol 18 (288.5 mg, 1.00 mmol, 1.00 equiv) and
RuCl2(PPh3)3 (29.0 mg, 0.03 mmol, 0.03 equiv) in dry benzene
(5.0 mL) at room temperature as added a solution of TBHP
(0.38 mL, 2.6 M in dry benzene, 12.0 mmol, 10.0 equiv)
dropwise under nitrogen. The mixture was stirred at room
temperature for 3 h, then the mixture was concentrated to
dryness and the crude product was purified by flash
chromatography (petroleum ether/ ethyl acetate 20:1) to give
20 (225.0 mg, 0.60 mmol, 49%) as pale yellow oil. Rf 0.33 (silica
gel, 15:1 petroleum ether/ ethyl acetate, UV, blue, PMA); 1H
NMR (400 MHz, CDCl3) δ 6.79 (d, J = 10.2 Hz, 1H), 6.21 (d, J =
12.1 Hz, 1H), 6.17 (d, J = 10.2 Hz, 1H), 6.00 (s, 1H), 5.72 (dd, J =
12.1, 6.2 Hz, 1H), 2.71 (dd, J = 18.7, 6.2 Hz, 1H), 2.38 (d, J = 18.7
Hz, 1H), 1.97 (dd, J = 11.7, 6.7 Hz, 1H), 1.80-1.65 (m, 4H), 1.62-
1.56 (m, 2H), 1.12 (s, 9H), -0.02 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 187.3, 157.9, 150.3, 131.0, 129.6, 127.8, 127.5, 81.8,
81.4, 79.4, 57.6, 41.4, 39.8, 27.2, 26.7, 20.7, 1.6; HRMS (ESI+)
m/z calcd for C21H32O4SiNa (M+Na)+: 399.1967, found:
399.1953; IR (neat) ν 2974, 2876, 1663, 1249, 953, 891, 837,
748 cm-1.
1
UV, blue, PMA); H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),
7.17 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 10.9
Hz, 1H), 6.45 (s, 1H), 6.14 – 5.91 (m, 1H), 4.27 – 4.05 (m, 1H),
3.32 – 3.17 (m, 1H), 2.82 (s, 3H), 2.66 (d, J = 11.8 Hz, 1H), 2.47
– 2.30 (m, 1H), 2.19 (s, 1H), 1.89 (s, 2H), 1.61 (s, 1H), 1.44 (s,
1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 212.0, 157.0, 139.1,
130.8, 129.2, 128.3, 128.1, 116.0, 114.5, 76.9, 55.3, 44.5, 35.7,
21.7; HRMS (ESI+) m/z calcd for C15H19O3 (M+H)+: 247.1334,
found: 247.1330; IR (neat) ν 3238, 2937, 2915, 1601, 1435,
1239, 1215, 1087, 879, 823 cm-1.
Preparation
of
(3aR,10aS,10bS)-10a-hydroxy-3a-
((trimethylsilyl)oxy)-2,3,3a,4,10a,10b-
hexahydrobenzo[e]azulen-8(1H)-one (24). Phenol 18 (2.00
g, 6.93 mmol, 1.00 equiv) was dissolved in chloroform (32 mL)
and tetraphenylporphine (TPP) (213.0 mg, 0.35 mmol, 0.05
equiv) was added. The reaction was kept under oxygen
atmosphere by bubbling with an oxygen balloon. The solution
was irradiated using 400W sodium lamp at 0 °C for 12 h. Then
to the resulting solution was added triphenylphosphine (1.84
g, 7.01 mmol, 1.00 equiv) at 0 °C. After 1 h the reaction mixture
was concentrated to dryness and purified directly by flash
chromatography (petroleum ether/ ethyl acetate 5:1) to give
the desired compound 24 as pale pink solid (m.p. 102.5-103.2
°C) (1.56 g, 5.12 mmol, 74%). Rf 0.28 (silica gel, 2:1 petroleum
ether/ ethyl acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3)
δ 6.89 (d, J = 10.1 Hz, 1H), 6.24 (dd, J = 12.0, 3.2 Hz, 1H), 6.08
(dd, J = 10.1, 1.9 Hz, 1H), 5.92 (s, 1H), 5.88 (ddd, J = 12.0, 6.2,
2.8 Hz, 1H), 2.78 (dd, J = 19.0, 6.2 Hz, 1H), 2.50 (dt, J = 19.0, 2.8
Hz, 1H), 2.27 (dd, J = 12.4, 7.0 Hz, 1H), 2.10 (s, 1H), 1.90-1.79
(m, 1H), 1.74 -1.63 (m, 3H), 1.61-1.49 (m, 2H), -0.02 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.8, 159.5, 150.5, 133.3,
128.7, 125.6, 125.3, 81.7, 72.0, 61.4, 41.9, 40.1, 27.5, 21.1, 1.6;
HRMS (ESI+) m/z calcd for C17H24O3SiNa (M+Na)+: 327.1392,
found: 327.1378; IR (neat) ν 3343, 2955, 1652, 1604, 1247,
952, 929, 837, 772, 757 cm-1.
Preparation
of
(3aR,10bS)-2,3,4,10b-
tetrahydrobenzo[e]azulene-3a,8(1H)-diol (21). To a stirred
solution of 18 (288 mg, 1.00 mmol, 1.00 equiv) in THF (10 mL)
was added TBAF (3 mL, 1 M in THF, 3.00 mmol, 3.00 equiv) at
0 °C. When TLC detected starting material consumption (~1 h),
the mixture was quenched by sat. aq. ammonium chloride,
extracted by ethyl acetate (3 x 10 mL). The organic layer was
dried with anhydrous sodium sulfate. The crude was purified
by flash chromatography (petroleum ether/ ethyl acetate
5:1→2:1) to give 21 as yellow solid (m.p. 169-171 °C) (214 mg,
99 mmol, 99%). Rf 0.19 (silica gel, 5:1 petroleum ether/ ethyl
1
acetate, UV, blue, PMA); H NMR (400 MHz, DMSO-d6) δ 9.04
(s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 9.1 Hz, 1H), 6.56 (s,
1H), 6.27 (d, J = 12.7 Hz, 1H), 5.64 (dt, J = 12.5, 3.9 Hz, 1H), 3.58
(s, 1H), 2.69 (dd, J = 11.5, 6.9 Hz, 1H), 2.57 – 2.43 (m, 2H), 2.10
– 1.69 (m, 5H), 1.58 – 1.34 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 155.4, 136.9, 130.3, 129.8, 129.6, 128.1, 117.8,
113.8, 77.9, 52.6, 46.5, 44.6, 30.4, 23.7; HRMS (ESI+) m/z calcd
for C14H17O2 (M+H)+: 217.1229, found: 217.1230; IR (neat) ν
3254, 2924, 2853, 1504, 1455, 1259, 1185, 1158, 1024, 865,
680 cm-1.
Preparation of (3aR,10R,10aS,10bS)-10a-hydroxy-10-
methyl-3a-((trimethylsilyl)oxy)-2,3,3a,4,9,10,10a,10b-
octahydrobenzo[e]azulen-8(1H)-one (25). To
a stirred
solution of hydroxyl ketone 24 (30.0 mg, 0.099 mmol, 1.00
equiv) in THF (2.0 mL) was added lithium hexamethyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 29
disilazide (0.10 mL, 1.0 M in THF, 0.10 mmol, 1.00 equiv)
Preparation of (3aR,6aR,7R,8R,10R,10aS,10bS)-10-
1
2
3
4
5
6
7
8
dropwise at 0 °C under nitrogen. After being stirred for 10 min,
the reaction mixture was added HMPA (0.17 mL, 10 equiv),
followed by methylmagnesium bromide (0.030 mL, 0.10 mmol,
3.0 M in THF, 1.00 equiv). The mixture was stirred at -78 °C for
1 h. Then the resulting mixture was quenched with sat. aq.
ammonium chloride, extracted by ethyl acetate (3 x 5 mL), and
the upper organic layer was separated. The organic layer was
dried with anhydrous sodium sulfate. The crude product was
purified by flash chromatography (petroleum ether/ ethyl
acetate 5:1) to give 25 as pale pink solid (m.p. 95.1-96.9 °C) (20
mg, 0.062 mmol, 63%). Rf 0.53 (silica gel, 2:1 petroleum ether/
ethyl acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 6.15
(dd, J = 11.9, 3.0 Hz, 1H), 5.82 (ddd, J = 11.9, 6.1, 2.8 Hz, 1H),
5.73 (s, 1H), 2.75-2.57 (m, 3H), 2.51 (dt, J = 18.9, 3.0 Hz, 1H),
2.30 (dd, J = 16.2, 5.4 Hz, 1H), 2.14 (dd, J = 12.7, 6.6 Hz, 1H), 2.05
(s, 1H), 2.01-1.94 (m, 2H), 1.79-1.66 (m, 3H), , 1.55-1.45 (m,
1H), 1.08 (d, J = 6.8 Hz, 3H), -0.01 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 199.4, 159.7, 133.1, 129.0, 125.9, 82.5, 75.8, 64.0,
43.0, 42.1, 40.5, 37.5, 28.2, 21.6, 16.9, 1.6; HRMS (ESI+) m/z
calcd for C18H29O3Si(M+H)+: 321.1876, found: 321.1880; IR
(neat) ν 2974, 1637, 1246, 1089, 976, 933, 836, 749 cm-1.
Preparation of (3aR,6aS,10R,10aS,10bS)-10a-hydroxy-
10-methyl-2,3,9,10,10a,10b-hexahydro-1H,4H-3a,6a-
epoxybenzo[e]azulen-8(7H)-one (27). Camphorsulfonic
acid (14.5 mg, 0.062 mmol, 1.00 equiv) was added into the
solution of 25 (20 mg, 0.063 mmol, 1.00 equiv) in MeOH (1 mL)
at room temperature, then stirred 1 h, the color of reaction
mixture changed from colorless to dark green. The crude
product was concentrated to dryness and purified directly by
preparative flash chromatography (5:1 petroleum ether/ ethyl
acetate) to afford 27 as white solid (m.p. 112-114 °C) (15 mg,
0.06 mmol, 97%). Rf 0.30 (silica gel, 2:1 petroleum ether/ ethyl
acetate, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 5.98 (ddd, J =
9.6, 4.3, 2.3 Hz, 1H), 5.88 – 5.73 (m, 1H), 2.68 – 2.53 (m, 3H),
2.53 – 2.14 (m, 4H), 2.07 – 1.72 (m, 6H), 1.65 – 1.48 (m, 2H),
1.10 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 209.2,
133.0, 128.7, 90.1, 87.8, 85.7, 61.6, 46.3, 44.4, 37.7, 37.2, 34.4,
28.8, 27.0, 17.2; HRMS (ESI+) m/z calcd for C15H21O3 (M+H)+:
249.1491, found: 249.1491; IR (neat) ν 3449, 2964, 2915, 1715,
1206, 1118, 1107, 944, 879, 696 cm-1.
methyl-1,2,3,7,8,9,10,10b-octahydro-4H,10aH-3a,6a-
epoxybenzo[e]azulene-7,8,10a-triol (28). To a solution of
the corresponding diol SI-8 (160.0 mg, 0.50 mmol, 1.00 equiv)
in CH2Cl2 (5.0 mL), NaHCO3 (84.0 mg, 1.00 mmol, 2.00 equiv),
mCPBA (purity 85%, 122.0 mg, 0.60 mmol, 1.20 equiv) were
sequentially added at 0 °C. The reaction mixture was stirred at
room temperature for 1 h, then the mixture was concentrated
to dryness and the crude product was purified by flash
chromatography (petroleum ether/ ethyl acetate 1:1→1:2) to
give triol 28 (92.0 mg, 0.35 mmol, 70%) as a white solid (m.p.
145.7-147.9 °C). Rf 0.17 (silica gel, 1:2 petroleum ether/ ethyl
acetate, UV, blue, PMA); 1H NMR (400 MHz, CDCl3) δ 6.45 (d, J =
9.9 Hz, 1H), 5.98 (dd, J = 9.9, 2.7 Hz, 1H), 4.03-3.96 (m, 1H), 3.83
(s, 1H), 2.59 (d, J = 17.6 Hz, 1H), 2.34-2.28 (m, 1H), 2.02-1.94
(m, 2H), 1.89-1.47 (m, 10H), 1.04 (d, J = 6.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 131.7, 127.4, 91.1, 86.0, 85.8, 72.3,
68.1, 60.5, 38.5, 37.8, 33.2, 32.0, 28.3, 27.8, 17.2; HRMS (ESI+)
m/z calcd for C15H26NO4 (M+NH4)+: 284.1861, found: 284.1856;
IR (neat) ν 3509, 3381, 2963, 2872, 952, 911, 852, 835 cm-1.
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
Preparation
tetrahydro-2H-cyclopenta[b]furan-2-one
(3R,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-
cyclopenta[b]furan-2-one (SI-10). Freshly
of
(3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-
(SI-9)
and
distilled
cyclopentadiene (194 g, 240 mL, 2.94 mol, 1.46 equiv) was
added into the solution of aq. glyoxylic acid (225 mL, 50% in
H2O, 2.01 mol, 1.00 equiv) in H2O (400 mL) at 0 °C, the resultant
bilayer mixture was stirred vigorously at room temperature for
4 d. The aqueous layer was washed with heptane (3 x 300 mL)
and neutralized by NaHCO3 (Caution: large amounts of CO2),
then extracted with ethyl acetate (10 x 500 mL). The organic
layer was dried over anhydrous sodium sulfate. The crude
product was concentrated to dryness to give lactone SI-9 and
SI-10 (183 g, 1.31 mol, 65%) as inseparable mixture (d.r.~2:1)
1
which was sufficiently pure for the next step (detected by H
NMR). Major isomer: 1H NMR (400 MHz, CDCl3) δ 6.32 – 6.14
(m, 1H), 5.89 (dd, J = 5.1, 2.4 Hz, 1H), 5.31 (dt, J = 6.1, 1.9 Hz,
1H), 4.74 (d, J = 9.3 Hz, 1H), 3.19 (tt, J = 9.3, 6.1 Hz, 1H), 2.72 –
2.65 (m, 1H), 2.49 – 2.34 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 177.7, 141.1, 127.5, 86.5, 69.1, 40.5, 30.8. Minor
isomer: 1H NMR (400 MHz, CDCl3) δ 6.10 – 6.01 (m, 1H), 5.86
(dd, J = 5.5, 2.0 Hz, 1H), 5.55 – 5.44 (m, 1H), 4.14 (d, J = 7.2 Hz,
1H), 3.09 – 2.95 (m, 1H), 2.78 – 2.73 (m, 1H), 2.56 – 2.52 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.2, 136.8, 129.2, 87.4,
74.3, 44.1, 36.6.
Preparation of (3aR,8S,10R,10aS,10bS)-10-methyl-3a-
((trimethylsilyl)oxy)-2,3,3a,4,8,9,10,10b-
octahydrobenzo[e]azulene-8,10a(1H)-diol (SI-8). To
a
solution of the ketone 25 (64.0 mg, 0.20 mmol, 1.00 equiv) in
MeOH (2.0 mL), CeCl3·7H2O (74.5 mg, 0.20 mmol, 1.00 equiv)
and NaBH4 (7.6 mg, 0.20 mmol, 1.0 equiv) were sequentially
added at -78 °C. The reaction mixture was stirred for 2 h and
quenched by H2O, extracted by ethyl acetate (3 x 5 mL), the
upper organic layer was separated and the organic layer was
dried with anhydrous sodium sulfate. The crude product was
purified by flash chromatography (petroleum ether/ ethyl
acetate 2:1) to give the diol SI-8 (62.5 mg, 0.19 mmol, 96%) as
a white solid (m.p. 153.1-155.2 °C), and its diastereoisomer
(2.6 mg, 0.008 mmol, 4%) as colorless oil, d.r. = 24:1. Rf 0.23
(silica gel, 2:1 petroleum ether/ ethyl acetate, UV, blue, PMA);
1H NMR (400 MHz, CDCl3) δ 6.02 (d, J = 11.8 Hz, 1H), 5.57 (s,
1H), 5.47 (ddd, J = 11.8, 5.9, 2.9 Hz, 1H), 4.20 (d, J = 4.2 Hz, 1H),
2.59 (dd, J = 18.4, 5.9 Hz, 1H), 2.37 (d, J = 18.4 Hz, 1H), 2.03 (dd,
J = 12.9, 6.1 Hz, 1H), 1.93 (ddd, J = 12.5, 6.5, 3.3 Hz, 1H), 1.82-
1.86 (m, 1H), 1.81-1.60 (m, 7H), 1.48-1.36 (m, 1H), 1.35-1.26
(m, 1H), 1.07 (d, J = 6.6 Hz, 3H), 0.01 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 142.0, 133.3, 131.1, 126.8, 82.2, 75.0, 67.8, 61.4,
42.1, 41.8, 38.0, 34.8, 29.3, 21.5, 17.6, 1.8; HRMS (ESI+) m/z
calcd for C18H30O3SiNa(M+Na)+: 345.1854, found: 345.1856; IR
(neat) ν 3554, 2965, 1245, 1083, 952, 934, 833, 751 cm-1.
Preparation of (S)-1-((1S,2R)-2-hydroxycyclopent-3-en-
1-yl)ethane-1,2-diol
(SI-11)
and
(R)-1-((1S,2R)-2-
hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (SI-12). To the
solution of lactone SI-9/SI-10 (50 g, 357 mmol, 1.00 equiv) in
dry THF (1 L) was carefully added LiAlH4 (15 g, 395 mmol, 1.10
equiv) at 0 °C (Caution: exothermic, large amounts of H2
evolved). After addition, the resultant gray suspension was
carefully warmed up to 90 °C (oil bath) for 18 h (10:1,
DCM/MeOH, Rf = 0.15, blue, PMA). The mixture was cooled to
0 °C and quenched slowly by H2O. The mixture was filtered
through a pad of celite (200 g), washed with THF (6 x 500 mL).
The crude product was concentrated to dryness to give as dark
yellow oil triol SI-11/SI-12 (51 g, 353 mmol, 99%) as
inseparable mixture (d.r.~2:1). SI-11: 1H NMR (400 MHz, D2O)
δ 6.13 – 6.09 (m, 1H), 5.97 – 5.92 (m, 1H), 4.75 (d, J = 5.0 Hz,
1H), 3.88 – 3.82 (m, 1H), 3.79 – 3.76 (m, 1H), 3.57 (dd, J = 12.1,
6.4 Hz, 1H), 2.33 – 2.08 (m, 3H); 13C{1H} NMR (100 MHz, D2O)
δ 136.4, 131.7, 75.4, 71.5, 64.9, 44.4, 32.6. SI-12: 1H NMR (400
MHz, D2O) δ 6.18 – 6.13 (m, 1H), 5.92 – 5.87 (m, 1H), 4.63 (d, J
= 6.2 Hz, 1H), 3.94 –3.88 (m, 1H), 3.84 – 3.80 (m, 1H), 3.64 –
3.59 (m, 1H), 2.41 (d, J = 7.9 Hz, 2H), 2.18 – 2.14 (m, 1H); 13C{1H}
NMR (100 MHz, D2O) δ 136.4, 131.8, 75.5, 72.3, 64.9, 44.0, 33.4.
ACS Paragon Plus Environment

Page 17 of 29
The Journal of Organic Chemistry
Preparation of (1R,5R)-5-(hydroxymethyl)cyclopent-2-
– 4.07 (m, 2H), 4.02 (dd, J = 11.6, 4.3 Hz, 1H), 3.80 (s, 3H), 3.63
(dd, J = 11.7, 3.7 Hz, 1H), 3.35 – 3.16 (m, 1H), 2.53 (d, J = 2.6 Hz,
1H), 2.20 (dd, J = 10.4, 5.3 Hz, 1H), 2.12 – 1.86 (m, 2H), 1.42 (s,
3H), 1.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 138.3,
135.2, 132.4, 128.0, 116.3, 114.0, 111.1, 98.3, 85.4, 78.3, 60.8,
55.2, 47.7, 36.9, 35.0, 28.4, 20.4; HRMS (ESI+) m/z calcd for
C18H25O4 (M+H)+: 305.1753, found: 305.1748; IR (neat) ν 3397,
2989, 2908, 1494, 1196, 1028, 986, 845 cm-1.
1
2
3
4
5
6
7
8
en-1-ol (11). To a solution of triol SI-11/SI-12 (50 g, 347
mmol, 1.00 equiv) in EtOH/H2O (v:v, 1:1, 1 L) was slowly added
sodium periodate (84 g, 392 mmol, 1.13 equiv) at 0 °C, the
resultant mixture was stirred vigorously at room temperature.
When TLC detected starting material consumption (~2 h, 10:1,
DCM/MeOH, Rf = 0.75, blue, PMA), the mixture was filtered.
The filtrate was slowly added NaBH4 (27 g, 711 mmol, 2.00
equiv) at 0 °C (Caution: exothermic). The dark solution was
stirred overnight. Then KHF2 (54 g, 691 mmol, 2.00 equiv) was
added, dark solution changed to clear yellow (20:1,
DCM/MeOH, Rf = 0.25, dark blue, PMA). The resultant mixture
was filtered, washed with EtOH. The crude product was
purified by flash chromatography (20:1, DCM/MeOH) to give
diol 11 as yellow oil (27.7 g, 243 mmol, 70%). 1H NMR (400
MHz, CDCl3) δ 6.07 – 5.99 (m, 1H), 5.85– 5.82 (m, 1H), 4.94 (d,
J = 7.0 Hz, 1H), 3.86 (dd, J = 11.0, 4.5 Hz, 1H), 3.79 (dd, J = 11.0,
8.2 Hz, 1H), 2.50 (ddd, J = 12.9, 7.2, 4.7 Hz, 1H), 2.44 – 2.33 (m,
1H), 2.30 – 2.16 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
135.2, 132.4, 77.7, 62.7, 42.5, 33.6. Diol 11 was prepared
according to reference 36.
Preparation
of
(4aR,6S,7R,7aS)-6-(4-methoxy-2-
vinylphenyl)-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (29).
To the solution of secondary alcohol SI-14 (304 mg, 1.00 mmol,
1.00 equiv) in DCM (10 mL) was sequentially added NaHCO3
(168 mg, 2.00 mmol, 2.00 equiv), Dess-Martin periodinane
(636 mg, 1.50 mmol, 1.50 equiv), then stirred 2 h at room
temperature. The resulting mixture was then quenched with
sat. aq. NaHCO3 (10 mL), the biphasic mixture was extracted
with DCM (3 x 20 mL). The organic layer was dried with
anhydrous sodium sulfate. The resulting yellow oil was used
for the next step without further purification. 2-
Methylmagnesium chloride (3 mL, 0.5 M in THF, 1.5 mmol, 1.50
equiv) was added into the solution of above crude ketone in
THF (10 mL) at 0 °C, then stirred 6 h at room temperature. The
resultant mixture was quenched with sat. aq. ammonium
chloride, extracted by ethyl acetate (3 x 20 mL), and upper
organic layer was separated. The crude product was purified
by flash chromatography (petroleum ether/ ethyl acetate 5:1)
to give 29 as white foam (m.p. 111-113 °C) (580 mg, 0.58 mmol,
58%, 2 steps). Rf 0.69 (silica gel, 2:1 petroleum ether/ ethyl
acetate, UV, purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3)
δ 7.61 (d, J = 8.7 Hz, 1H), 7.07 (dd, J = 17.1, 10.9 Hz, 1H), 6.96 (s,
1H), 6.85 (d, J = 8.7 Hz, 1H), 5.56 (d, J = 17.2 Hz, 1H), 5.28 (d, J =
10.9 Hz, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.12 (d, J = 4.6 Hz, 1H),
4.02 – 3.92 (m, 1H), 3.87 – 3.77 (m, 3H), 3.65 (dd, J = 11.3, 4.6
Hz, 1H), 3.21 (t, J = 8.5 Hz, 1H), 2.98 (s, 1H), 2.30 (d, J = 13.7 Hz,
1H), 2.25 – 2.10 (m, 3H), 1.99 – 1.89 (m, 1H), 1.74 (s, 3H), 1.44
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.0, 143.0, 139.4,
136.0, 130.6, 130.0, 116.4, 114.4, 113.3, 111.4, 99.0, 81.5, 74.7,
62.0, 55.2, 47.6, 47.1, 36.0, 34.0, 27.8, 24.3, 22.0; HRMS (ESI+)
m/z calcd for C22H30O4Na (M+Na)+: 381.2042, found: 381.2043;
IR (neat) ν 3479, 2964, 2936, 2875, 1492, 1247, 1028, 897, 819
cm-1.
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
Preparation
of
(1aS,1bS,5aR,6aS)-3,3-
dimethylhexahydrooxireno[2',3':4,5]cyclopenta[1,2-
d][1,3]dioxine (SI-13). To a stirred solution of diol 11 (11.4 g,
100 mmol, 1.00 equiv) in CH2Cl2 (80 mL) and Me2C(OMe)2 (20
mL), at 0 °C was added PPTs (2.5 g, 9.95 mmol, 0.10 equiv), the
reaction mixture was stirred at room temperature for 18 h.
After TLC detected starting material consumption, NaHCO3 (42
g, 500 mmol, 5.00 equiv), mCPBA (purity 85%, 40.6 g, 200
mmol, 2.00 equiv) were sequentially added at 0 °C. Then the
reaction mixture was stirred at room temperature for 15 h. The
resulting mixture was quenched with sat. aq. Na2S2O3/CH2Cl2
(v/v, 1:2, 500 mL). The organic layer was dried with anhydrous
sodium sulfate. The crude product was purified by flash
chromatography (petroleum ether/ ethyl acetate 20:1) to give
SI-13 as pale yellow oil (12.84 g, 75 mmol, 75%). Rf 0.51 (silica
gel, 10:1 petroleum ether/ ethyl acetate, pale blue, PMA); 1H
NMR (400 MHz, CDCl3) δ 4.39 (d, J = 4.5 Hz, 1H), 4.13 (dd, J =
12.2, 4.5 Hz, 1H), 3.63 (dd, J = 12.2, 1.4 Hz, 1H), 3.52 (s, 1H),
3.45 (d, J = 2.4 Hz, 1H), 2.07 – 1.91 (m, 2H), 1.65 (ddt, J = 10.7,
4.6, 3.0 Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 97.2, 77.3, 77.0, 76.7, 69.9, 59.7, 57.5, 56.4, 30.8,
28.9, 28.8, 19.2; HRMS (ESI+) m/z calcd for C9H14O3Na (M+Na)+:
193.0841, found: 193.0867; IR (neat) ν 2992, 2938, 2883, 1374,
1256, 1196, 1113, 844, 765 cm-1.
Preparation of (7aR,7bS,11aR,12aS)-3-methoxy-6,9,9-
trimethyl-11,11a,12,12a-tetrahydro-7H-
benzo[4,5]azuleno[1,2-d][1,3]dioxin-7a(7bH)-ol
(30).
Preparation
of
(4aR,6S,7S,7aS)-6-(4-methoxy-2-
Under argon, to a stirred solution of 29 (36 mg, 0.10 mmol, 1.00
equiv) in toluene (5 mL) was added Grubbs 2nd generation
catalyst (8.5 mg, 0.01 mmol, 0.10 equiv), and the resultant
mixture was stirred at 110 °C (oil bath) for 12 h. The mixture
was concentrated to dryness and the residue was purified by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
give 30 as pale yellow oil (26 mg, 0.078 mmol, 78%). Rf 0.29
(silica gel, 2:1 petroleum ether/ ethyl acetate, UV, brown, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.3 Hz,
1H), 6.85 – 6.65 (m, 2H), 6.38 (s, 1H), 4.22 (dd, J = 12.1, 3.8 Hz,
1H), 3.97 (d, J = 4.6 Hz, 1H), 3.90 – 3.82 (m, 1H), 3.79 (s, 3H),
3.34 (s, 1H), 2.99 (dd, J = 13.2, 5.0 Hz, 1H), 2.64 – 2.36 (m, 3H),
1.97 (s, 3H), 1.93 (dd, J = 11.9, 5.6 Hz, 2H), 1.51 (s, 3H), 1.41 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.7, 136.9, 135.8,
129.7, 126.9, 126.3, 116.0, 111.4, 98.6, 77.4, 76.5, 60.8, 55.2,
51.4, 50.3, 36.3, 30.1, 28.8, 27.8, 19.8; HRMS (ESI+) m/z calcd
for C20H27O4 (M+H)+: 331.1909, found: 331.1910; IR (neat) ν
3517, 2906, 2877, 1375, 1266, 1156, 904, 771 cm-1.
vinylphenyl)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol (SI-14).
To the freshly prepared solution of the (4-methoxy-2-
vinylphenyl) magnesium bromide 12 (from 4-methoxy-2-
vinylbromobenzene (3.75 g, 17.63 mmol, 1.50 equiv) and Mg
(423 mg, 17.63 mmol, 1.50 equiv)) in THF (20 mL) was added
copper iodide (224 mg, 1.18 mmol, 0.10 equiv.) at 0 °C, stirred
for 30 min. To this reaction mixture was added dropwise a
solution of cyclopentene oxide SI-13 (2.00 g, 11.75 mmol, 1.00
equiv) in THF (20 mL) over a period of 30 min at 0 °C. The
reaction mixture was stirred at room temperature for 3 h. Then
the reaction was re-cooled to 0 °C and quenched with sat. aq.
ammonium chloride, extracted by ethyl acetate (5 x 20 mL).
The organic layer was dried with anhydrous sodium sulfate.
The crude was purified by flash chromatography (petroleum
ether/ ethyl acetate 5:1) to give the secondary alcohol SI-14
(2.65 g, 8.7 mmol, 74%) as pale yellow oil. Rf 0.50 (silica gel, 2:1
petroleum ether/ ethyl acetate, UV, dark green, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz,
1H), 7.13 (dd, J = 17.2, 10.9 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.5
Hz, 1H), 5.59 (d, J = 17.2 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H), 4.24
Preparation of ((2R,3S,3aR,10bS)-3,3a-dihydroxy-8-
methoxy-5-methyl-1,2,3,3a,4,10b-
hexahydrobenzo[e]azulen-2-yl)methyl pivalate (31). To a
stirred solution of 30 (250 mg, 0.76 mmol, 1.00 equiv) in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 29
MeOH/H2O (v:v, 5:1, 12 mL) was added camphorsulfonic acid
calcd for C17H19O3 (M+H)+: 271.1334, found: 271.1332; IR
1
2
3
4
5
6
7
8
(176 mg, 0.76 mmol, 1.00 equiv) at 25 °C, and the resultant
mixture was stirred at 90 °C (oil bath) for 12 h. The mixture
was concentrated to dryness and re-dissolved in DCM (15 mL).
Pyridine (0.3 mL, 3.8 mmol, 5.00 equiv), DMAP (93 mg, 0.76
mmol, 1.00 equiv.), PivCl (0.28 mL, 2.3 mmol, 3.00 equiv) were
sequentially added into reaction solution at 0 °C. The mixture
was allowed to stir at 25 °C for 12 h. The reaction was quenched
by sat. NaHCO3 (3 mL) and extracted with DCM (3 x 20 mL). The
organic layer was concentrated in vacuo and purified by
preparative thin layer chromatography (petroleum ether/
ethyl acetate 5:1) to give 31 (233 mg, 0.61 mmol, 81%, 2 steps)
as white solid (m.p. 141-143 °C). Rf 0.45 (silica gel, 2:1
petroleum ether/ ethyl acetate, UV, brown, p-anisaldehyde); 1H
NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.6
Hz, 2H), 6.37 (s, 1H), 4.46 (dd, J = 10.8, 7.7 Hz, 1H), 4.25 (dd, J =
10.8, 6.6 Hz, 1H), 3.91 – 3.84 (m, 1H), 3.80 (s, 3H), 3.36 (d, J =
3.6 Hz, 1H), 3.03 (t, J = 9.3 Hz, 1H), 2.62 – 2.41 (m, 2H), 2.26 (dt,
J = 13.9, 7.1 Hz, 1H), 2.02 (dd, J = 13.6, 6.5 Hz, 2H), 1.97 (s, 3H),
1.23 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.0, 143.0,
139.4, 136.0, 130.6, 130.0, 116.4, 114.3, 113.3, 111.4, 99.0, 81.5,
74.7, 62.0, 55.2, 47.6, 47.1, 35.9, 34.0, 27.8, 24.2, 22.0; HRMS
(ESI+) m/z calcd for C22H30O5Na (M+Na)+: 397.1991, found:
397.2008; IR (neat) ν 3443, 3347, 2931, 2887, 1729, 1247,
1161, 1101, 1037, 905, 810 cm-1.
(neat) ν 3407, 2955, 2922, 2853, 1722, 1454, 1253, 1049, 897,
880, 772 cm-1.
Preparation of (3aR,10bS)-3a-hydroxy-8-methoxy-2,5-
dimethyl-4,10b-dihydrobenzo[e]azulen-3(3aH)-one (34).
To a solution of 33 (20 mg, 0.074 mmol, 1.00 equiv) and Et3N
(31 µL, 0.22 mmol, 3.00 equiv) in DCM (3 mL) was slowly added
TMSOTf (33 µL, 0.15 mmol, 2.00 equiv) at 0 °C. After 3 h stirring
at room temperature, the residue was concentrated in vacuo.
The resulting oil was dissolved in EtOH/H2O (v:v, 10:1, 3 mL),
followed by addition of RhCl3·3H2O (20 mg, 5.80 µmol, 0.10
equiv) under argon. The reaction mixture was warmed up to
100 °C (oil bath) for 2 h. The residue was concentrated in vacuo
and purified by preparative thin layer chromatography
(petroleum ether/ ethyl acetate 5:1) to give 34 as yellow foam
(16 mg, 0.06 mmol, 82%). Rf 0.38 (silica gel, 2:1 petroleum
ether/ ethyl acetate, UV, yellow, p-anisaldehyde); 1H NMR (400
MHz, CDCl3) δ 7.60 (s, 1H), 7.07 (d, J = 9.1 Hz, 1H), 6.81 (dd, J =
4.4, 1.9 Hz, 2H), 6.41 (s, 1H), 4.01 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H),
2.73 (d, J = 19.3 Hz, 1H), 2.48 (d, J = 19.4 Hz, 1H), 2.02 (s, 3H),
1.94 (dd, J = 2.6, 1.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
206.0, 158.7, 153.4, 140.5, 137.3, 136.7, 126.7, 126.0, 125.5,
116.6, 112.5, 73.8, 55.3, 51.5, 42.3, 27.9, 10.7; HRMS (ESI+) m/z
calcd for C17H19O3 (M+H)+: 271.1334, found: 271.1329; IR
(neat) ν 3416, 2956, 2925, 2853, 1750, 1506, 1250, 1102, 841,
734 cm-1.
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
Preparation of ((5S,7R,8S,9S)-8-hydroxy-2-methoxy-10-
methyl-12-oxo-6,7,8,9-tetrahydro-5H-5,9-
Preparation of (4aR,6S,7S,7aS)-6-(4-methoxyphenyl)-
2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol (SI-
15). To a solution of the 4-Methoxyphenylmagnesium bromide
39 (200 mL, 1.0 M in THF, 200 mmol, 2.00 equiv) was added
copper (I) iodide (1.9 g, 10.0 mmol, 0.10 equiv) at 0 °C, stirred
for 30 min. To this reaction mixture was then added a solution
of cyclopentene oxide SI-13 (17.0 g, 100 mmol, 1.00 equiv) in
THF (200 mL) dropwise over a period of 30 min at 0 °C. The
reaction mixture was stirred to room temperature for 12 h, The
reaction was cooled to 0 °C and quenched with sat. aq.
ammonium chloride. Ethyl acetate (5 x 100 mL) was added, and
the upper organic layer was separated. The organic layer was
dried with anhydrous sodium sulfate, the crude residue was
purified by flash chromatography (petroleum ether/ ethyl
acetate 20:1→10:1→5:1) to give the secondary alcohol SI-15
(21.4 g, 77 mmol, 77%) as yellow oil. Rf 0.20 (silica gel, 2:1
methanobenzo[9]annulen-7-yl)methyl pivalate (32). To a
stirred solution of diol 31 (10 mg, 0.027 mmol, 1.00 equiv) in
DCM (1 mL) was added NaHCO3 (9 mg, 0.11 mmol, 4.00 equiv)
and Dess-Martin periodinane (23 mg, 0.054 mmol, 2.00 equiv)
at 0 °C. After 8 h stirring at room temperature, the residue was
concentrated in vacuo and purified by preparative thin layer
chromatography (petroleum ether/ ethyl acetate 2:1) to give
colorless film 32 as sole product (7 mg, 0.019 mmol, 71%). Rf
0.45 (silica gel, 2:1 petroleum ether/ ethyl acetate, UV, pink, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.3 Hz,
1H), 6.73 (dd, J = 8.3, 2.6 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.28
(s, 1H), 4.28 (dd, J = 11.2, 4.9 Hz, 1H), 4.19 – 4.09 (m, 1H), 4.06
(d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.68 – 3.52 (m, 1H), 3.06 (s, 1H),
2.11 (s, 3H), 2.09 – 1.98 (m, 1H), 1.92 (td, J = 13.5, 10.1 Hz, 1H),
1.73 (tt, J = 8.4, 4.8 Hz, 1H), 1.18 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 208.7, 178.5, 158.8, 133.7, 132.4, 130.5, 128.1, 127.2,
118.0, 113.1, 74.2, 65.7, 65.5, 55.4, 55.3, 40.3, 38.9, 29.6, 27.2,
24.9; HRMS (ESI+) m/z calcd for C22H28O5Na (M+Na)+:
395.1834, found: 395.1839; IR (neat) ν 3454, 2924, 2854, 1709,
1604, 1462, 1271, 1157, 1033, 818 cm-1.
1
petroleum ether/ ethyl acetate, UV, dark blue, PMA); H NMR
(400 MHz, CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 4.16 (dd, J = 5.8, 1.9 Hz, 1H), 4.04 (m, 2H), 3.79 (s, 3H), 3.67
(dd, J = 11.6, 4.8 Hz, 1H), 2.90 (dd, J = 16.7, 9.3 Hz, 1H), 2.25 (m,
1H), 2.14 – 1.98 (m, 3H), 1.45 (s, 3H), 1.41 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 158.3, 134.7, 128.5, 113.9, 98.5, 85.8, 78.3,
61.1, 55.3, 51.9, 36.9, 34.7, 28.2, 20.8; HRMS (ESI+) m/z calcd
for C16H22O4Na (M+Na)+: 301.1416, found: 301.1401; IR (neat)
ν 3392, 2989, 2926, 1512, 1246, 1033, 842, 828 cm-1.
Preparation of (3aR,10bS)-3a-hydroxy-8-methoxy-5-
methyl-2-methylene-1,3a,4,10b-
tetrahydrobenzo[e]azulen-3(2H)-one (33). To a solution of
31 (50 mg, 0.13 mmol, 1.00 equiv) in MeCN (10 mL) was
sequentially added DMAP (16 mg, 0.13 mmol, 1.00 equiv), CuCl
(2.6 mg, 27 μmol, 0.20 equiv), 2,2'-dipyridyl (4.2 mg, 27 μmol,
0.20 equiv) and AZADO (2.0 mg, 13 μmol, 0.10 equiv) at 25 °C.
The solution was stirred at room temperature for 4 h under air.
After the reaction color changed from brown to green, the
reaction was concentrated in vacuo and purified by preparative
thin layer chromatography (petroleum ether/ ethyl acetate
5:1) to give 33 (31 mg, 0.11 mmol, 85%) as yellow oil. Rf 0.70
(silica gel, 2:1 petroleum ether/ ethyl acetate, UV, yellow, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.5 Hz,
1H), 6.80 (dd, J = 8.5, 2.7 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 6.34
(s, 1H), 6.22 (s, 1H), 5.61 (s, 1H), 3.81 (s, 3H), 3.38 – 3.26 (m,
1H), 3.19 – 3.00 (m, 2H), 2.79 (d, J = 19.5 Hz, 1H), 2.48 (d, J =
19.5 Hz, 1H), 1.98 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
203.6, 158.7, 142.5, 136.7, 135.3, 128.7, 126.7, 125.9, 120.3,
117.1, 112.3, 75.6, 55.2, 46.1, 43.3, 31.2, 27.7; HRMS (ESI+) m/z
Preparation
of
4-((4aR,6S,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)phenol
(38). To a stirred solution of SI-15 (27.8 g, 100 mmol, 1.00
equiv) and imidazole (20.4 g, 300 mmol, 3.00 equiv) in CH2Cl2
(300 mL) at 0 °C were added TBSCl (18.1 g, 120 mmol, 1.20
equiv) and the reaction mixture was stirred at room
temperature for 12 h. The resulting mixture was then
quenched with sat. aq. sodium bicarbonate. CH2Cl2 (3 x 100 mL)
was added, the organic layer was dried with anhydrous sodium
sulfate, and filtrated, concentrated to afford the crude residue,
which was used in the next reaction without further
purification. To a stirred solution of diphenylphosphine (52
mL, 300 mmol, 3.00 equiv) in THF (400 mL) at 0 °C was added
n-butyllithium solution (120 mL, 2.5 M in hexane, 300 mmol,
3.00 equiv) by syringe over ca. 30 min under argon. The red
ACS Paragon Plus Environment

Page 19 of 29
The Journal of Organic Chemistry
solution was allowed to warm to room temperature over about
(380 mg, 0.94 mmol, 37%, 75% combined two diastereomers,
1
2
3
4
5
6
7
8
30 min before above crude residue in THF (100 mL) was added.
The mixture was stirred at 80 °C (oil bath) for 12 h. Then the
resulting mixture was quenched with sat. aq. ammonium
chloride at 0 °C. Ethyl acetate (500 mL) was added, and the
upper organic layer was separated. The organic layer was dried
with anhydrous sodium sulfate. The crude was purified by flash
d.r.~1:1). 40: Rf 0.68 (silica gel, 5:1 petroleum ether/ ethyl
acetate, UV, dark blue, p-anisaldehyde); 1H NMR (400 MHz,
CDCl3) δ 6.83 (d, J = 10.2 Hz, 1H), 5.95 (d, J = 10.2 Hz, 1H), 4.17
– 4.06 (m, 2H), 3.99 (s, 1H), 3.66 (d, J = 11.9 Hz, 1H), 3.24 (s,
1H), 2.53 (m, 2H), 2.46 – 2.29 (m, 2H), 2.12 (m, 1H), 1.99 (dd, J
= 22.3, 11.7 Hz, 1H), 1.79 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.10
(d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.8, 153.1, 128.8, 98.3, 79.4, 77.6, 72.9, 60.3,
54.8, 42.4, 37.7, 36.2, 28.9, 26.8, 25.6, 19.3, 17.7, 14.8, -4.4, -4.9;
HRMS (ESI+) m/z calcd for C22H38O5SiNa (M+Na)+: 433.2386,
found: 433.2400; IR (neat) ν 3430, 2954, 2926, 1664, 1381,
1250, 1195, 1065, 834, 777 cm-1. SI-16: Rf 0.43 (silica gel, 5:1
petroleum ether/ ethyl acetate, UV, dark blue, p-anisaldehyde);
1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 10.3 Hz, 1H), 5.93 (d, J
= 10.3 Hz, 1H), 4.18 (dd, J = 12.1, 2.8 Hz, 1H), 3.98 (dd, J = 15.8,
12.8 Hz, 3H), 3.74 (d, J = 12.1 Hz, 1H), 2.66 – 2.45 (m, 2H), 2.38
– 2.22 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 (dt, J = 12.6, 8.8 Hz,
1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.83 (s,
9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
198.4, 155.5, 127.9, 98.4, 79.1, 77.8, 72.9, 60.3, 56.5, 42.7, 37.6,
35.4, 29.0, 26.3, 25.6, 18.8, 17.7, 14.7, -4.5; HRMS (ESI+) m/z
calcd for C22H38O5SiNa (M+Na)+: 433.2386, found: 433.2369; IR
(neat) ν 3391, 2927, 2894, 1664, 1373, 1195, 1070, 832, 778
cm-1.
chromatography
(petroleum
ether/
ethyl
acetate
30:1→20:1→10:1) to give phenol 38 as white solid (m.p. 95-97
°C) (35.9 g, 95 mmol, 95%, over 2 steps). Rf 0.17 (silica gel, 10:1
petroleum ether/ ethyl acetate, UV, dark blue, p-anisaldehyde);
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.5 Hz, 2H), 6.76 (d, J =
8.5 Hz, 2H), 5.33 (s, 1H), 4.11 – 4.01 (m, 2H), 3.89 (dd, J = 6.5,
1.7 Hz, 1H), 3.67 (dd, J = 11.7, 4.7 Hz, 1H), 2.87 (dt, J = 11.9, 7.0
Hz, 1H), 2.24 (td, J = 11.7, 5.9 Hz, 1H), 2.11 – 1.91 (m, 2H), 1.44
(s, 3H), 1.42 (s, 3H), 0.80 (s, 9H), -0.14 (s, 3H), -0.17 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 154.1, 135.3, 128.9, 115.1,
98.5, 87.0, 78.8, 61.3, 52.9, 37.2, 34.3, 28.1, 25.7, 20.6, 18.0, -4.9,
-5.0; HRMS (ESI+) m/z calcd for C21H34O4SiNa (M+Na)+:
401.2124, found: 401.2114; IR (neat) ν 3253, 2954, 2927, 2859,
1515, 1369, 1252, 1144, 1103, 1027, 838, 774 cm-1.
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
Preparation
of
4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxycyclohexa-2,5-dien-1-one (37). Phenol 38 (1.00 g,
2.64 mmol, 1.00 equiv) was dissolved in chloroform/methnol
(v/v, 1:1, 30 mL) and rose bengal (purity 90%, 149 mg, 0.13
mmol, 0.05 equiv) was added. The reaction was kept under
oxygen atmosphere by bubbling with an oxygen balloon. The
solution was irradiated using 400W sodium lamp at room
temperature for 24 h. The reaction mixture was concentrated
to dryness and purified directly by flash chromatography
(petroleum ether/ ethyl acetate 10:1→5:1) to give the desired
cyclohexadienone 37 as pale orange solid (m.p. 79-80 °C) (886
mg, 2.24 mmol, 85%). Rf 0.22 (silica gel, 5:1 petroleum ether/
Preparation of (3R,4R,5R)-4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-3-methyl-5-vinylcyclohexan-1-one (41) and
(1R,2R,4S,6R)-1-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-2-
methyl-4-(prop-1-en-2-yl)-6-vinylcyclohexane-1,4-diol
(SI-17). Me3Al (2.0 M in toluene, 0.85 mL, 1.7 mmol, 2.00 equiv)
was added in a portion to a solution of 2,6-diphenyl phenol
(1.27 g, 5.1 mmol, 6.00 equiv) in toluene (25 mL) at 25°C. The
resultant ATPH yellow-orange solution was stirred at 25 °C for
30 min. Under Argon, to a solution of 40 (349 mg, 0.85 mmol,
1.00 equiv.) in toluene (10 mL) was added ATPH solution
prepared above at -78 °C dropwise over 30 min under argon.
The resultant dark yellow solution was added vinylmagnesium
chloride solution (4.3 mL, 4.25 mmol, 1.0 M in THF, 5.00 equiv)
at -78 °C over 30 min, the bright yellow mixture was warmed
to room temperature over 12h. When TLC detected starting
material consumption, the solution was quenched with sat. aq.
ammonium chloride at 0 °C, filtered. Ethyl acetate (3 x 20 mL)
was added, and the upper organic layer was separated. The
organic layer was dried with anhydrous sodium sulfate, the
crude was purified by flash chromatography (petroleum ether/
ethyl acetate 7:1) to give 1,4-adduct 41 as yellow solid (m.p.
96-98 °C) (245 mg, 0.56 mmol, 66%), 1,2-adduct SI-17 as
yellow solid (m.p. 93-95 °C) (88 mg, 0.19 mmol, 22%). 41: Rf
0.26 (silica gel, 5:1 petroleum ether/ ethyl acetate, blue, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.08 (ddd, J = 17.2,
10.3, 9.0 Hz, 1H), 5.18 – 4.99 (m, 2H), 4.64 (dd, J = 9.3, 3.2 Hz,
1H), 3.90 (dd, J = 7.2, 3.2 Hz, 1H), 3.84 (dd, J = 11.4, 5.7 Hz, 1H),
3.62 (s, 1H), 3.46 (dd, J = 11.4, 7.2 Hz, 1H), 2.87 – 2.72 (m, 1H),
2.69 – 2.50 (m, 2H), 2.30 (ddd, J = 12.9, 9.2, 6.7 Hz, 1H), 2.21 –
2.00 (m, 3H), 1.99 – 1.84 (m, 1H), 1.61 – 1.44 (m, 2H), 1.35 (s,
3H), 1.30 (s, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.92 (s, 9H), 0.17 (s,
3H), 0.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.9, 138.8,
115.5, 98.5, 80.9, 77.2, 73.4, 61.5, 49.6, 49.3, 45.1, 44.7, 40.2,
35.5, 27.5, 25.8, 25.7, 22.1, 17.7, 15.8, -3.9, -5.4; HRMS (ESI+)
m/z calcd for C24H42O5SiNa (M+Na)+: 461.2699, found:
461.2682; IR (neat) ν 3457, 2952, 2929, 1716, 1381, 1370,
1250, 1196, 1101, 834, 778 cm-1. SI-17: Rf 0.22 (silica gel, 5:1
petroleum ether/ ethyl acetate, blue, p-anisaldehyde); 1H NMR
1
ethyl acetate, UV, dark brown, p-anisaldehyde); H NMR (400
MHz, CDCl3) δ 7.04 – 6.88 (m, 2H), 6.19 – 6.13 (m, 2H), 4.09 (dd,
J = 12.0, 3.4 Hz, 2H), 3.98 (d, J = 3.6 Hz, 1H), 3.77 (s, 1H), 3.65
(dd, J = 12.0, 2.1 Hz, 1H), 2.22 – 2.02 (m, 3H), 1.90 – 1.79 (m,
1H), 1.45 (s, 3H), 1.37 (s, 3H), 0.86 (s, 9H), 0.09 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 185.3, 152.0, 151.0, 128.2, 127.6, 98.4,
79.3, 77.5, 70.0, 60.3, 57.3, 35.8, 28.7, 26.6, 25.6, 19.4, 17.7, -4.5,
-4.7; HRMS (ESI+) m/z calcd for C21H34O5SiNa (M+Na)+:
417.2073, found: 417.2056; IR (neat) ν 3369, 2926, 2855, 1664,
1379, 1096, 1072, 833, 773 cm-1.
Preparation of (4R,5R)-4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-5-methylcyclohex-2-en-1-one (40) and (4S,5S)-4-
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-5-methylcyclohex-2-en-1-one (SI-16). To a stirred
solution of 37 (1.00 g, 2.53 mmol, 1.00 equiv) in THF (25 mL)
was added lithium hexamethyl disilazide (2.53 mL, 1.0 M in
THF, 2.53 mmol, 1.00 equiv) dropwise at -60 °C under argon.
After being stirred for 10 min, the reaction mixture was added
DMPU (1.53 mL, 12.65 mmol, 5.00 equiv), followed by
methylmagnesium chloride (2.53 mL, 6.40 mmol, 3.0 M in THF,
3.00 equiv). The mixture was stirred at -78 °C for 1 h and
warmed to -30 °C for 6h. Then the resulting mixture was
quenched with sat. aq. ammonium chloride, extracted by ethyl
acetate (3 x 20 mL), and the upper organic layer was separated.
The organic layer was dried with anhydrous sodium sulfate.
The crude product was purified by flash chromatography
(petroleum ether/ ethyl acetate 20:1→10:1) to give 40 as white
solid (m.p. 123-125 °C) (394 mg, 0.96 mmol, 38%), and the
more polar diastereomer SI-16 as yellow solid (m.p. 89-91 °C)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 29
(400 MHz, CDCl3) δ 5.98 (d, J = 10.2 Hz, 1H), 5.87 (dd, J = 17.4,
added slowly NaH (2.8 g, 60%, 70 mmol, 10.00 equiv) at room
1
2
3
4
5
6
7
8
10.5 Hz, 1H), 5.68 (d, J = 10.2 Hz, 1H), 5.24 – 5.03 (m, 2H), 4.19
(d, J = 5.0 Hz, 1H), 4.00 (dd, J = 11.8, 4.4 Hz, 1H), 3.95 (d, J = 5.0
Hz, 1H), 3.56 (dd, J = 11.8, 3.7 Hz, 1H), 2.35 – 2.20 (m, 2H), 2.08
(dd, J = 10.4, 5.9 Hz, 1H), 1.83 (d, J = 9.6 Hz, 1H), 1.68 – 1.44 (m,
4H), 1.40 (s, 3H), 1.34 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.88 (s,
9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
141.9, 134.7, 131.6, 114.1, 98.0, 80.0, 78.1, 72.6, 72.3, 60.8,
52.9, 40.9, 36.1, 33.3, 28.5, 28.2, 25.8, 20.1, 17.8, 14.5, -4.4, -4.9;
HRMS (ESI+) m/z calcd for C24H42O5SiNa (M+Na)+: 461.2699,
found: 461.2719; IR (neat) ν 3454, 2928, 2856, 1380, 1081,
995, 833, 776 cm-1.
temperature. After stirring 30 min, tetrabutylammonium
iodide (2.58 g, 7 mmol, 1.00 equiv) and benzyl bromide (6 mL,
35 mmol, 5.00 equiv) were sequentially added to the above
solution at 0 °C. The reaction mixture was stirred overnight at
room temperature and quenched by sat. aq. ammonium
chloride, extracted by ethyl acetate (3 x 100 mL). Organic layer
was dried with anhydrous sodium sulfate. The crude product
was purified by flash chromatography (petroleum ether/ ethyl
acetate 100:0→10:1) to give 43 as white solid (3 g, 5.67 mmol,
81%). Rf 0.32 (silica gel, 9:1 petroleum ether/ ethyl acetate,
9
1
blue, PMA); H NMR (400 MHz, CDCl3) δ 7.41 – 7.20 (m, 5H) ,
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
Preparation
of
tert-butyl(((1R,3R,4R,5R)-4-
6.13 (dt, J = 17.5, 9.8 Hz, 1H), 5.12 – 4.96 (m, 2H), 4.65 – 4.49
(m, 3H), 3.85 (ddd, J = 17.1, 9.3, 4.5 Hz, 2H), 3.46 (dd, J = 11.3,
7.1 Hz, 1H), 3.42 – 3.34 (m, 1H), 3.08 (s, 1H), 2.32 – 2.01 (m,
3H), 1.82 (d, J = 11.7 Hz, 1H), 1.76 – 1.58 (m, 3H), 1.48 (dd, J =
14.6, 7.4 Hz, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.95 (d, J = 6.5 Hz,
3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 140.8, 139.3, 128.3, 127.4, 127.2, 114.6, 98.4,
81.0, 77.7, 75.9, 73.5, 69.4, 61.7, 49.9, 47.3, 37.8, 36.2, 35.8,
35.4, 27.5, 26.4, 25.8, 22.1, 17.7, 15.7, -4.0, -5.4; HRMS (ESI+)
m/z calcd for C31H51O5Si (M+H)+: 531.3506, found: 531.3505;
IR (neat) ν 3475, 2933, 2859, 1250, 1101, 1068, 833, 778 cm-1.
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3-
methyl-5-vinyl-7-oxabicyclo[2.2.1]heptan-1-
yl)oxy)dimethylsilane (42). To a solution of ketone 41 (14
mg, 0.032 mmol, 1.00 equiv.) in DCM (0.5 mL) was added Et3N
(0.023 mL, 0.16 mmol, 5.00 equiv.) at 0 °C, after stirring for 15
min, TBSOTf (0.022 mL, 0.096 mmol, 3.00 equiv.) was added to
the reaction mixture at 0 °C, then warmed up to room
temperature and stirred overnight. Then the resulting mixture
was quenched with sat. NaHCO3, extracted by DCM. The crude
product was purified by flash chromatography (petroleum
ether/ ethyl acetate 50:1 with 1% Et3N) to give product 42 (10
mg, 0.018 mmol, 57%) as colorless oil. Rf 0.39 (silica gel, 30:1
petroleum ether/ ethyl acetate, blue, PMA); 1H NMR (400 MHz,
CDCl3) δ 6.14 – 6.05 (m, 1H), 4.97 – 4.91 (m, 2H), 4.29 (d, J = 6.9
Hz, 1H), 4.06 (dd, J = 11.9, 4.5 Hz, 1H), 3.98 (d, J = 4.9 Hz, 1H),
3.62 (dd, J = 11.9, 2.5 Hz, 1H), 2.59 – 2.49 (m, 1H), 2.48 – 2.37
(m, 1H), 2.17 – 1.84 (m, 5H), 1.62 – 1.59 (m, 1H), 1.54 – 1.50 (m,
1H), 1.38 (s, 3H), 1.31 (s, 3H), 1.20 – 1.11 (m, 1H), 1.03 (d, J =
6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.14 (s, 6H), 0.11 (s, 3H),
0.09 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 140.8, 113.5,
106.7, 97.7, 83.9, 80.3, 80.2, 60.9, 51.2, 48.8, 46.1, 43.5, 42.3,
35.7, 29.3, 28.6, 26.0, 25.7, 19.9, 19.5, 18.0, 17.9, -3.0, -4.6, -4.8.
Preparation of (1R,2R,4S,6R)-1-((4aR,6R,7S,7aS)-7-
((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-2-
methyl-6-vinylcyclohexane-1,4-diol (SI-18). To a solution of
the ketone 41 (2.00 g, 4.57 mmol, 1.00 equiv) in MeOH/DCM
(v:v, 1:1, 40 mL), CeCl37H2O (1.7 g, 4.57 mmol, 1.00 equiv) and
NaBH4 (347 mg, 9.14 mmol, 2.00 equiv) were sequentially
added at -78 °C. The reaction mixture was stirred for 2 h and
quenched by H2O, extracted by ethyl acetate (3 x 50 mL), the
upper organic layer was separated and the organic layer was
dried with anhydrous sodium sulfate. The crude product was
purified by flash chromatography (petroleum ether/ ethyl
acetate 5:1) to give the alcohol SI-18 as white foam (1.97 g, 4.48
mmol, 98%). Rf 0.42 (silica gel, 2:1 petroleum ether/ ethyl
acetate, dark brown, p-anisaldehyde); 1H NMR (400 MHz,
CDCl3) δ 6.10 (dt, J = 17.5, 9.8 Hz, 1H), 5.12 – 4.94 (m, 2H), 4.61
(dd, J = 9.7, 3.3 Hz, 1H), 3.84 (ddd, J = 17.1, 9.3, 4.5 Hz, 2H), 3.61
(ddd, J = 15.3, 10.7, 4.5 Hz, 1H), 3.45 (dd, J = 11.3, 7.4 Hz, 1H),
2.28 – 2.17 (m, 2H), 2.11 (qd, J = 14.5, 7.3 Hz, 1H), 1.74 (dd, J =
23.8, 12.1 Hz, 1H), 1.68 – 1.40 (m, 8H), 1.34 (s, 3H), 1.30 (s, 3H),
0.94 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H), 0.16 (s, 3H), 0.10 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 140.5, 114.7, 98.4, 81.0, 77.5,
73.3, 69.5, 61.7, 49.6, 47.4, 39.5, 39.4, 37.8, 35.4, 27.5, 26.3,
25.8, 22.2, 17.7, 15.6, -4.0, -5.4; HRMS (ESI+) m/z calcd for
C24H45O5Si (M+H)+: 441.3036, found:441.3030; IR (neat) ν
3573, 3491, 2948, 2857, 1059, 835, 778 cm-1.
Preparation
of
(4aR,6S,7aS)-6-((1R,2R,4S,6R)-4-
(benzyloxy)-1-hydroxy-2-methyl-6-vinylcyclohexyl)-2,2-
dimethyltetrahydrocyclopenta[d][1,3]dioxin-7(4H)-one
(44) and (1S,3R,4a'R,5R,7R,7a'S)-5-(benzyloxy)-2',2',3-
trimethyl-7-vinyldihydro-4'H-spiro[cycloheptane-1,6'-
cyclopenta[d][1,3]dioxine]-2,7'(5'H)-dione (45). To
a
stirred solution of 43 (1.27 g, 2.40 mmol, 1.00 equiv) in THF
(50 mL) was added TBAF (3.6 mL, 1 M in THF, 3.60 mmol, 1.50
equiv) at room temperature. After stirring overnight, TLC
detected starting material consumption. The solution was
quenched with sat. aq. ammonium chloride at 0 °C, extracted by
ethyl acetate (3 x 50 mL). The crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate
2:1→1:1) to afford colorless oil (1 g). To the solution of above
secondary alcohol (1 g, 2.40 mmol, 1.00 equiv) in DCM (40 mL)
was sequentially added tert-butanol (0.88 mL, 9.60 mmol, 4.00
equiv), NaHCO3 (1.6 g, 19.20 mmol, 8.00 equiv), Dess-Martin
periodinane (4.1 g, 9.60 mmol, 4.00 equiv), then stirred
overnight at room temperature. The reaction mixture was
concentrated to dryness and purified directly by flash
chromatography (petroleum ether/ ethyl acetate 5:1) to give
44 as white foam (580 mg, 1.39 mmol, 58%) and 45 as white
solid (m.p. 107-109 °C) (364 mg, 0.82 mmol, 34%). 44: Rf 0.51
(silica gel, 2:1 petroleum ether/ ethyl acetate, pink, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.22 (m, 5H),
5.83 (ddd, J = 17.2, 10.2, 8.7 Hz, 1H), 5.13 – 4.95 (m, 2H), 4.64 –
4.48 (m, 2H), 4.22 (dd, J = 12.3, 3.9 Hz, 1H), 4.06 (d, J = 5.4 Hz,
1H), 3.70 (dd, J = 12.2, 1.2 Hz, 1H), 3.49 – 3.33 (m, 1H), 2.63 (dd,
J = 13.3, 7.3 Hz, 1H), 2.43 – 2.25 (m, 2H), 1.94 – 1.72 (m, 4H),
1.66 (dd, J = 23.4, 12.2 Hz, 1H), 1.55 – 1.49 (m, 1H), 1.46 (s, 3H),
1.37 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 139.1, 137.8, 128.3, 127.5, 127.3, 117.1, 98.4, 75.8,
75.8, 71.6, 69.6, 59.9, 54.4, 47.2, 37.6, 35.5, 33.6, 32.6, 28.5,
25.9, 19.0, 16.0; HRMS (ESI+) m/z calcd for C25H35O5 (M+H)+:
415.2485, found: 415.2475; IR (neat) ν 2936, 2858, 1752, 1686,
1375, 1087, 970, 936, 714 cm-1. 45: Rf 0.29 (silica gel, 2:1
petroleum ether/ ethyl acetate, pink, p-anisaldehyde); 1H NMR
(400 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H), 5.66 (dt, J = 16.8, 9.7
Hz, 1H), 5.15 – 5.00 (m, 2H), 4.58 (d, J = 11.9 Hz, 1H), 4.49 (d, J
= 11.9 Hz, 1H), 4.17 (dd, J = 12.3, 3.9 Hz, 1H), 4.07 (d, J = 4.7 Hz,
1H), 3.65 – 3.57 (m, 1H), 3.57 – 3.44 (m, 1H), 2.91 (dd, J = 10.8,
6.4 Hz, 1H), 2.63 (t, J = 12.8 Hz, 1H), 2.43 (t, J = 9.7 Hz, 1H), 2.39
– 2.23 (m, 1H), 2.07 (dd, J = 14.4, 3.2 Hz, 2H), 2.02 – 1.92 (m,
1H), 1.78 (dd, J = 13.0, 6.4 Hz, 1H), 1.48 (d, J = 3.7 Hz, 1H), 1.43
Preparation
of
(1R,2R,4S,6R)-4-(benzyloxy)-1-
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-2-
methyl-6-vinylcyclohexan-1-ol (43). To a stirred solution of
alcohol SI-18 (3.08 g, 7 mmol, 1.00 equiv) in THF (100 mL) was
ACS Paragon Plus Environment

Page 21 of 29
The Journal of Organic Chemistry
(s, 3H), 1.33 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 215.3, 211.5, 138.5, 138.2, 128.4, 127.5, 127.5,
116.8, 98.1, 78.7, 72.2, 70.2, 68.6, 59.4, 44.0, 41.6, 38.3, 37.0,
32.7, 30.6, 28.6, 19.1, 17.6; HRMS (ESI+) m/z calcd for C25H33O5
(M+H)+: 413.2328, found: 413.2339; IR (neat) ν 3374, 2986,
2935, 1634, 1370, 1223, 1101, 1038, 967, 895, 729, 696 cm-1.
Preparation of (1R,3S,4aR,7aR,7bS,11aR,12aS,12bR)-3-
(benzyloxy)-1,6,9,9-tetramethyl-
hydroxy-5-methyl-2-(prop-1-en-2-yl)cyclohex-2-en-1-one
(47). To a stirred solution of SI-20 (260 mg, 0.48 mmol, 1.00
equiv) in THF (8 mL) was added Pd(PPh3)2Cl2 (17 mg, 0.024
mmol, 0.05 equiv), AsPPh3 (15 mg, 0.048 mmol, 0.10 equiv),
Ag2O (111 mg, 0.768 mmol, 1.6 equiv) at room temperature
under argon. After 30 min, the dark mixture was added 2-
isopropenyl boronic acid pinacol ester (0.18 mL, 0.96 mmol,
2.00 equiv) and H2O (1 mL). The resultant solution was stirred
at 80 °C (oil bath) for 12 h. The mixture was concentrated to
dryness and the residue was purified by flash chromatography
(petroleum ether/ ethyl acetate 10:1) to give 47 as yellow solid
(m.p. 126-128 °C) (203 mg, 0.45 mmol, 93%). Rf 0.51 (silica gel,
5:1 petroleum ether/ ethyl acetate, UV, dark brown, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.67 (d, J = 0.8 Hz,
1H), 5.16 (d, J = 1.0 Hz, 1H), 5.06 (s, 1H), 4.20 – 4.08 (m, 2H),
4.00 (d, J = 3.2 Hz, 1H), 3.68 (d, J = 11.9 Hz, 1H), 3.30 (s, 1H),
2.64 – 2.40 (m, 3H), 2.34 (dd, J = 12.3, 6.6 Hz, 1H), 2.16 – 1.97
(m, 2H), 1.91 (s, 3H), 1.84 – 1.76 (m, 1H), 1.46 (s, 3H), 1.39 (s,
3H), 1.11 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 197.5, 148.1, 140.7, 140.6, 116.5, 98.3,
79.3, 77.6, 73.2, 60.3, 55.0, 43.4, 37.7, 36.2, 28.9, 26.9, 25.6,
22.4, 19.2, 17.7, 14.8, -4.4, -4.9; HRMS (ESI+) m/z calcd for
C25H43O5 Si (M+H)+: 451.2880, found: 451.2862; IR (neat) ν
3495, 2955, 2930, 2910, 1665, 1197, 1107, 1081, 836, 777 cm-
1,2,3,4,4a,7,11,11a,12,12a-decahydro-12bH-
benzo[4,5]azuleno[1,2-d][1,3]dioxine-7a,12b(7bH)-diol
(46). To a solution of 44 (8 mg, 0.019 mmol, 1.00 equiv) in THF
(2 mL) was added freshly prepared 2-methylallyllanthanum
chloride (58 μL, 0.5 M in THF, 0.029 mmol, 1.50 equiv) at -78
°C, stirred 1 h at the same temperature, then warmed to 0 °C,
quenched with sat. aq. ammonium chloride. The reaction
mixture was concentrated to dryness and purified directly by
flash chromatography (petroleum ether/ ethyl acetate 10:1) to
give yellow oil (9 mg) which was used to next step. Under
argon, the solution of above secondary alcohol (9 mg, 0.019
mmol, 1.00 equiv) in toluene (2 mL) was added Grubbs 2nd
generation catalyst (8 mg, 9.5 µmol, 0.50 equiv). The solution
was warmed up to 110 °C (oil bath) for 12 h. The reaction
mixture was concentrated to dryness and purified directly by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
give 46 as dark brown oil (3.9 mg, 8.8 μmol, 46%, 2 steps). Rf
0.35 (silica gel, 5:1 petroleum ether/ ethyl acetate, pink, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3); δ 7.46 – 7.20 (m, 5H),
5.03 (s, 1H), 4.56 (s, 2H), 3.82 – 3.66 (m, 2H), 3.56 – 3.44 (m,
1H), 3.37 (tt, J = 11.0, 3.9 Hz, 1H), 3.12 (s, 1H), 3.05 (d, J = 13.0
Hz, 1H), 2.48 (d, J = 17.6 Hz, 1H), 2.33 – 2.09 (m, 3H), 2.07 – 1.95
(m, 1H), 1.86 (dd, J = 13.5, 5.1 Hz, 1H), 1.83 – 1.68 (m, 5H), 1.63
(dd, J = 11.9, 4.6 Hz, 1H), 1.54 – 1.43 (m, 1H), 1.40 (s, 3H), 1.36
(s, 3H), 1.33 – 1.29 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 139.1, 134.9, 128.3, 127.9, 127.5, 127.4,
99.3, 78.3, 75.8, 75.5, 74.9, 69.6, 62.6, 56.4, 43.9, 40.6, 37.2,
36.9, 36.7, 35.5, 29.4, 27.2, 26.5, 24.6, 17.3; HRMS (ESI+) m/z
calcd for C27H38O5Na (M+Na)+: 465.2617, found: 465.2616; IR
(neat) ν 3539, 2956, 2919, 2849, 1455, 1377, 1261, 1095, 807,
697 cm-1.
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
.
Preparation of (3S,4R,5R)-4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-5-methyl-2-(propan-2-ylidene)-3-
vinylcyclohexan-1-one
(36)
and
(2R,3S,4R,5R)-4-
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-5-methyl-2-(prop-1-en-2-yl)-3-vinylcyclohexan-
1-one (SI-21). Me3Al (2.0 M in toluene, 0.44 mL, 0.88 mmol,
2.00 equiv) was added in a portion to a solution of 2,6-diphenyl
phenol (655 mg, 2.64 mmol, 6.00 equiv) in toluene (10 mL) at
25 °C. The resultant ATPH yellow-orange solution was stirred
at 25 °C for 30 min. To a stirred solution of 47 (200 mg, 0.44
mmol, 1.00 equiv) in toluene (5 mL) was added ATPH solution
prepared above at -78 °C dropwise over 30 min under argon.
The resultant dark yellow solution was added vinylmagnesium
chloride solution (2.2 mL, 2.2 mmol, 1.0 M in THF, 5.00 equiv)
at -78 °C for 1 h, the bright yellow mixture was warmed to room
temperature over 12h. The resulting mixture was then
quenched with sat. aq. ammonium chloride, filtered. Ethyl
acetate (3 x 20 mL) was added, and the upper organic layer was
separated. The organic layer was dried with anhydrous sodium
sulfate, the crude was purified by flash chromatography
(petroleum ether/ ethyl acetate 20:1→10:1) to give enone 36
(171 mg, 0.36 mmol, 81%) as white solid (m.p. 100-103 °C), SI-
21 as yellow solid (m.p. 114-115 °C) (8.4 mg, 0.018 mmol, 4%).
36: Rf 0.47 (silica gel, 10:1 petroleum ether/ ethyl acetate, UV,
purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.28 (ddd,
J = 17.5, 10.4, 4.9 Hz, 1H), 5.03 (dt, J = 10.4, 1.9 Hz, 1H), 4.89 (dt,
J = 17.5, 1.9 Hz, 1H), 4.14 (dd, J = 12.0, 3.0 Hz, 1H), 4.09 (d, J =
2.6 Hz, 1H), 3.96 (d, J = 3.2 Hz, 1H), 3.69 (d, J = 12.0 Hz, 1H), 3.59
– 3.50 (m, 1H), 2.99 (s, 1H), 2.42 (qd, J = 15.8, 7.0 Hz, 2H), 2.35
– 2.28 (m, 1H), 2.21 (dd, J = 14.2, 7.2 Hz, 1H), 2.16 – 2.10 (m,
1H), 2.09 (s, 3H), 2.07 – 2.00 (m, 1H), 1.78 (s, 3H), 1.72 – 1.61
(m, 2H), 1.45 (s, 3H), 1.40 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H), 0.85
(s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 203.5, 145.7, 137.4, 131.7, 114.6, 98.2, 79.4, 77.7, 74.6, 60.4,
57.1, 50.5, 46.3, 37.7, 35.8, 29.2, 26.7, 25.7, 23.1, 22.0, 19.0,
17.7, 17.1, -4.3, -4.9; HRMS (ESI+) m/z calcd for C27H47O5 Si
(M+H)+: 479.3193, found: 479.3189; IR (neat) ν 3491, 2950,
2926, 2855, 1682, 1382, 1253, 1069, 830, 773 cm-1. SI-21: Rf
Preparation of (4S,5R)-4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-4-
hydroxy-2-iodo-5-methylcyclohex-2-en-1-one (SI-20). To a
stirred solution of hydroxyl ketone 40 (2.00 g, 4.87 mmol, 1.00
equiv) and pyridine (3.92 mL, 48.7 mmol, 10.00 equiv) in
CH2Cl2 (50 mL) at room temperature was added I2 (6.18 g, 24.3
mmol, 5.00 equiv). The dark solution was stirred at 50 °C (oil
bath) for 18 h. The resulting mixture was quenched with sat.
aq. Na2S2O3/CH2Cl2 (v/v, 1:2, 200 mL). The organic layer was
dried with anhydrous sodium sulfate. The crude product was
purified by flash chromatography (petroleum ether/ ethyl
acetate 10:1) to give iodide SI-20 as yellow solid (m.p. 155-159
°C) (2.22 g, 4.14 mmol, 85%). Rf 0.60 (silica gel, 5:1 petroleum
ether/ ethyl acetate, UV, purple, p-anisaldehyde); 1H NMR (400
MHz, CDCl3) δ 7.67 (s, 1H), 4.12 (dd, J = 12.2, 3.2 Hz, 2H), 3.99
(d, J = 3.6 Hz, 1H), 3.67 (dd, J = 12.2, 1.7 Hz, 1H), 3.19 (s, 1H),
2.67 (qd, J = 17.0, 5.8 Hz, 2H), 2.49 (td, J = 9.7, 2.7 Hz, 1H), 2.40
– 2.32 (m, 1H), 2.17 – 2.06 (m, 1H), 2.03 – 1.90 (m, 1H), 1.86 –
1.78 (m, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.09 (d, J = 6.9 Hz, 3H),
0.87 (s, 9H), 0.10 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
191.6, 161.6, 104.6, 98.4, 79.4, 77.6, 76.1, 60.2, 54.7, 40.7, 37.9,
36.2, 29.2, 27.1, 25.6, 19.2, 17.7, 14.6, -4.4, -4.9; HRMS (ESI+)
m/z calcd for C22H37IO5SiNa (M+Na)+: 559.1353, found:
559.1349; IR (neat) ν 3469, 2954, 2927, 2855, 1677, 1093,
1072, 968, 833, 775 cm-1.
Preparation of (4R,5R)-4-((4aR,6R,7S,7aS)-7-((tert-
butyldimethylsilyl)oxy)-2,2-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 29
0.12 (silica gel, 10:1 petroleum ether/ ethyl acetate, UV, purple,
to dryness and the crude product was purified by flash
p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 5.85 (dt, J = 17.5,
10.1 Hz, 1H), 5.10 (dd, J = 17.5, 8.6 Hz, 2H), 4.91 (s, 1H), 4.81
(dd, J = 9.6, 2.9 Hz, 1H), 4.68 (s, 1H), 3.87 (ddd, J = 17.2, 9.3, 4.4
Hz, 1H), 3.67 (s, 1H), 3.47 (dd, J = 11.4, 7.0 Hz, 1H), 3.41 (d, J =
11.9 Hz, 1H), 2.68 (t, J = 13.7 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.31
(ddd, J = 12.7, 9.6, 7.2 Hz, 1H), 2.19 – 2.08 (m, 1H), 1.94 (ddd, J
= 13.2, 6.6, 4.3 Hz, 1H), 1.63 (s, 3H), 1.61 – 1.51 (m, 1H), 1.34 (s,
3H), 1.29 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.17 (s,
3H), 0.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 209.5, 141.2,
137.0, 117.0, 116.0, 98.4, 80.7, 77.4, 73.8, 61.4, 58.7, 52.3, 49.7,
45.3, 40.1, 35.4, 27.4, 26.0, 25.8, 21.9, 19.4, 17.7, 16.0, -4.0, -5.4;
HRMS (ESI+) m/z calcd for C27H46O5SiNa (M+Na)+: 501.3012,
found: 501.3015; IR (neat) ν 3514, 2928, 2855, 1713, 1369,
1250, 1059, 835, 779 cm-1.
chromatography (petroleum ether/ ethyl acetate 5:1) to give
ketone 49 (77 mg, 0.19 mmol, 82%) as colorless solid (m.p.
149-151 °C). Rf 0.32 (silica gel, 2:1 petroleum ether/ ethyl
1
2
3
4
5
6
7
8
1
acetate, purple, p-anisaldehyde); H NMR (400 MHz, CDCl3) δ
5.81 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H), 5.09 (dd, J = 17.1, 1.3 Hz,
1H), 4.99 (dd, J = 10.2, 1.9 Hz, 1H), 4.24 (dd, J = 12.2, 3.6 Hz, 1H),
4.04 (d, J = 4.4 Hz, 1H), 3.82 (s, 1H), 3.72 (d, J = 12.2 Hz, 1H),
3.07 (t, J = 8.6 Hz, 1H), 2.60 (dd, J = 12.8, 8.1 Hz, 1H), 2.54 – 2.35
(m, 1H), 2.09 – 1.89 (m, 5H), 1.87 – 1.77 (m, 2H), 1.61 (dd, J =
15.7, 3.9 Hz, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.04 (s,
3H), 0.98 – 0.89 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ
216.4, 171.5, 136.3, 117.5, 98.2, 75.5, 72.0, 65.84, 59.6, 56.0,
43.0, 35.2, 33.1, 32.2, 30.6, 29.0, 26.5, 25.6, 23.9, 21.1, 18.6,
18.0, 14.8; HRMS (ESI+) m/z calcd for C23H34O6Na (M+Na)+:
429.2253, found: 429.2257; IR (neat) ν 3478, 2923, 2875, 1730,
1723, 1372, 1237, 1081, 1034, 972, 919, 827 cm-1.
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
Preparation
of
(3aS,4S,5R,6R,7aR)-5-hydroxy-5-
((4aR,6R,7S,7aS)-7-hydroxy-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,3,6-
trimethyl-4-vinyl-3,3a,4,5,6,7-hexahydro-7aH-indazol-7a-
yl acetate (48). To a stirred solution of 36 (560 mg, 1.17 mmol,
1.00 equiv) in EtOH (10 mL) was added hydrazine hydrate (344
µL, 85% in H2O, 5.85 mmol, 5.00 equiv) at 0 °C dropwise over
10 min. The resultant pale yellow solution was heated at 90 °C
(oil bath) for 12 h. Upon complete consumption of starting
material (by TLC), the solvent was removed in vacuo, and the
flask was backfilled with argon. A solution of Pb(OAc)4 (2.59 g,
5.85 mmol, 5.00 equiv.) in CH2Cl2 (10 mL) was added to the
above residue in CH2Cl2 (10 mL) at 0 °C dropwise by syringe
over 30 min, and allowed to stir for 3 h. The reaction was
quenched by addition of sat. aq. sodium bicarbonate (5 mL) at
0 °C, filtered and extracted with CH2Cl2 (5 x 10 mL). The
reaction mixture was concentrated under reduced pressure. To
a solution of the resulting residue in THF (10 mL) was added
TBAF (5.85 mL, 1.0 M in THF, 5.85 mmol, 5.00 equiv) and the
reaction mixture was stirred at 0 °C for 2 h. The resulting
mixture was then quenched with sat. aq. ammonium chloride
(10 mL). Ethyl acetate (5 x 10 mL) was added, and the upper
organic layer was separated. The organic layer was dried with
anhydrous sodium sulfate, the crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate
5:1→2:1) to give 48 (255 mg, 0.58 mmol, 50%, 2 steps) as
colorless solid (m.p. 161-163 °C). Rf 0.32 (silica gel, 1:1
petroleum ether/ ethyl acetate, brown, p-anisaldehyde); 1H
NMR (400 MHz, CDCl3) δ 6.34 – 6.16 (m, 1H), 5.24 – 5.15 (m,
2H), 4.58 (d, J = 8.5 Hz, 1H), 4.08 – 3.90 (m, 2H), 3.56 (dd, J =
11.8, 4.5 Hz, 1H), 2.96 (s, 1H), 2.74 (t, J = 9.1 Hz, 1H), 2.50 (d, J
= 8.6 Hz, 1H), 2.30 – 2.17 (m, 1H), 2.12 (s, 3H), 2.09 – 1.98 (m,
2H), 1.87 (ddd, J = 12.8, 6.6, 2.5 Hz, 1H), 1.72 (dt, J = 9.7, 9.3 Hz,
1H), 1.66 – 1.56 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H),
1.30 (s, 3H), 0.99 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 169.3, 136.4, 118.1, 116.0, 98.3, 89.4, 79.6, 78.7, 72.7,
61.0, 51.7, 49.0, 45.2, 35.7, 35.3, 33.8, 30.4, 28.1, 28.0, 23.7,
22.0, 20.8, 15.1; HRMS (ESI+) m/z calcd for C23H37N2O6 (M+H)+:
437.2652, found: 437.2703; IR (neat) ν 3382, 2953, 2924, 1712,
1369, 1271, 1243, 1215, 1112, 1056, 968, 916 cm-1.
Preparation
of
(1R,3R,4R,5S,6S)-4-hydroxy-4-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-
3,7,7-trimethyl-5-vinylbicyclo[4.1.0]heptan-1-yl acetate
(50). To a stirred solution of 49 (41 mg, 0.1 mmol, 1.00 equiv)
in THF (3 mL) was added freshly prepared 2-methylallylzinc
chloride (0.24 mL, 0.5 M in THF, 0.12 mmol, 1.20 equiv) at -78
°C. After 30 minutes, the reaction was quenched by addition of
sat. aq. ammonium chloride at 0°C. Ethyl acetate (3 x 5 mL) was
added, and the upper organic layer was separated. The organic
layer was dried with anhydrous sodium sulfate. The crude was
purified by flash chromatography (petroleum ether/ ethyl
acetate 10:1) to give 50 (30 mg, 0.065 mmol, 65%) as colorless
foam. Rf 0.33 (silica gel, 10:1 petroleum ether/ ethyl acetate,
purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.07 (dt, J
= 17.4, 10.1 Hz, 1H), 5.21 (dd, J = 17.4, 2.0 Hz, 1H), 5.06 (dd, J =
10.1, 2.1 Hz, 1H), 4.87 (dd, J = 2.1, 1.4 Hz, 1H), 4.69 (s, 1H), 4.15
(dd, J = 12.1, 3.2 Hz, 1H), 4.01 (d, J = 3.3 Hz, 1H), 3.89 (d, J = 1.4
Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.30 (d, J = 1.5 Hz, 1H), 3.22 (t,
J = 9.4 Hz, 1H), 2.52 (d, J = 14.3 Hz, 1H), 2.45 (dd, J = 12.4, 8.0
Hz, 1H), 2.23 (q, J = 12.1 Hz, 1H), 2.12 – 1.92 (m, 5H), 1.79 (s,
3H), 1.77 – 1.61 (m, 3H), 1.58 – 1.48 (m, 1H), 1.45 (s, 3H), 1.44
(s, 3H), 1.33 (s, 3H), 1.01 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.96
(d, J = 9.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.4,
143.1, 140.1, 114.7, 114.4, 98.7, 82.8, 75.5, 73.7, 66.4, 60.5,
53.2, 50.1, 41.7, 36.1, 34.5, 34.1, 31.2, 29.8, 29.0, 25.8, 24.8,
23.7, 21.1, 18.9, 18.7, 16.2; HRMS (ESI+) m/z calcd for
C27H42O6Na (M+Na)+: 485.2879, found: 485.2880; IR (neat) ν
3499, 2923, 1736, 1456, 1373, 1236, 1099, 969, 907, 889 cm-1.
Preparation
of
(1R,2aR,3aS,3bS,6aR,6bS,10aR,11aS,11bR)-6a,11b-
dihydroxy-1,3,3,5,8,8-hexamethyl-
1,3,3a,3b,6,6a,6b,10,10a,11,11a,11b-
dodecahydrocyclopropa[3',4']benzo[1',2':4,5]azuleno[1,2
-d][1,3]dioxin-2a(2H)-yl acetate (51). To a stirred solution
of 50 (50 mg, 0.11 mmol, 1.00 equiv) in toluene (3 mL) was
added Grubbs 2nd generation catalyst (46 mg, 0.054 mmol,
0.50 equiv) under Ar, and the resultant mixture was stirred at
110 °C (oil bath) for 12 h. The mixture was concentrated to
dryness and the residue was purified by flash chromatography
(petroleum ether/ ethyl acetate 5:1) to give 51 (39 mg, 0.09
mmol, 82%) as yellow oil. Rf 0.18 (silica gel, 10:1 petroleum
ether/ ethyl acetate, purple, p-anisaldehyde); 1H NMR (400
MHz, CDCl3) δ 5.24 (s, 1H), 4.06 (d, J = 8.3 Hz, 1H), 3.72 (d, J =
9.0 Hz, 1H), 3.67 (dd, J = 10.8, 6.6 Hz, 1H), 3.48 (t, J = 11.2 Hz,
1H), 3.08 (s, 1H), 2.73 (s, 1H), 2.50 (d, J = 17.9 Hz, 1H), 2.39 –
2.16 (m, 2H), 2.01 (s, 3H), 1.83 (s, 3H), 1.81 – 1.74 (m, 3H), 1.70
– 1.60 (m, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.18 (s, 3H), 1.09 (s,
4H), 0.96 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
171.4, 135.5, 127.7, 99.4, 78.9, 74.6, 73.4, 65.9, 63.0, 57.4, 42.4,
Preparation of (1R,3R,4R,5S,6S)-4-((4aR,6S,7aS)-2,2-
dimethyl-7-oxohexahydrocyclopenta[d][1,3]dioxin-6-yl)-
4-hydroxy-3,7,7-trimethyl-5-vinylbicyclo[4.1.0]heptan-1-
yl acetate (49). To a stirred solution of secondary alcohol 48
(100 mg, 0.23 mmol, 1.00 equiv) in ethyl acetate (6 mL), was
irradiated using 300W mercury lamp at 25 °C. After 12 h, the
reaction mixture was concentrated under reduced pressure. To
a solution of the resulting residue in CH2Cl2 (10 mL) was added
4Å MS (100 mg), 4-Methylmorpholine N-oxide monohydrate
(93 mg, 0.69 mmol, 3.00 equiv) and TPAP (16 mg, 0.046 mmol,
0.20 equiv) at 0 °C, and the reaction mixture was stirred at
room temperature for 8 h. Then the mixture was concentrated
ACS Paragon Plus Environment

Page 23 of 29
The Journal of Organic Chemistry
36.4, 35.8, 34.6, 31.7, 30.6, 27.6, 26.9, 26.7, 25.8, 24.8, 23.8,
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-2-
isopropyl-5-methyl-3-vinylcyclohexan-1-one (53). To
21.1, 17.2, 15.8; HRMS (ESI+) m/z calcd for C25H38O6Na
(M+Na)+: 457.2566, found: 457.2557; IR (neat) ν 3439, 2962,
1722, 1371, 1259, 1098, 1016, 869, 798 cm-1.
a
1
2
3
4
5
6
7
8
Schlenk flask equipped with liquid ammonia (~5 mL) was
added lithium wire (4.6 mg, 0.66 mmol, 5.00 equiv) at -78 °C
under Ar. After 15 minutes, a solution of 52 (55 mg, 0.13 mmol,
1.00 equiv) in THF (1.5 mL) was dropped into the dark blue
ammonia solution at -78 °C. The reaction was allowed to stir for
2 h at the same temperature, and then warmed up to 0 °C. The
reaction was quenched with solid NH4Cl, followed by addition
sat. aq. NH4Cl. After warming to room temperature, the
aqueous layer was extracted with EtOAc, and the combined
organic layer was washed with brine, dried over MgSO4 and
concentrated in vacuo. The crude oil was purified by flash
chromatography (petroleum ether/ ethyl acetate 20:1→10:1)
to give 53 (27 mg, 0.065 mmol, 50%) as colorless solid (m.p.
158-160 °C). Rf 0.66 (silica gel, 5:1 petroleum ether/ ethyl
Preparation of (4aR,6S,7aS)-6-((1R,2S,6R)-1-hydroxy-6-
methyl-4-oxo-3-(propan-2-ylidene)-2-vinylcyclohexyl)-
2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxin-7(4H)-
one (SI-22). TBAF (0.31 mL, 1.0 M in THF, 0.31 mmol, 1.50
equiv) was slowly added into a solution of 36 (100 mg, 0.21
mmol, 1.00 equiv) was dissolved in THF (5 mL) at 0 °C. After
addition, the reaction was allowed to stir for 3 h at 25 °C. The
resulting mixture was then quenched with sat. aq. ammonium
chloride (1 mL), extracted with EtOAc. The organic layer was
dried with anhydrous sodium sulfate and concentrated in
vacuo to afford yellow oil which was sufficiently pure for the
next step. The above product dissolved in DCM (10 mL),
followed by sequential addition of powdered 4Å MS (100 mg),
NMO (86 mg, 0.63 mmol, 3.00 equiv), TPAP (7.4 mg, 0.021
mmol, 0.10 equiv) at 0 °C, and the reaction mixture was stirred
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
acetate, purple, p-anisaldehyde); H NMR (400 MHz, CDCl3) δ
5.40 (dt, J = 16.8, 10.4 Hz, 1H), 5.18 – 5.10 (m, 1H), 5.04 (d, J =
16.8 Hz, 1H), 4.89 (s, 1H), 4.72 (s, 1H), 4.25 – 4.08 (m, 2H), 3.72
(d, J = 12.1 Hz, 1H), 3.58 (s, 1H), 3.50 (s, 1H), 3.22 (dd, J = 10.7,
4.5 Hz, 1H), 2.56 (d, J = 14.3 Hz, 1H), 2.53 – 2.21 (m, 6H), 2.15
(d, J = 14.3 Hz, 1H), 1.89 – 1.73 (m, 4H), 1.68 (dd, J = 11.4, 6.9
Hz, 1H), 1.49 (s, 3H), 1.45 (s, 3H), 1.01 (d, J = 6.7 Hz, 3H), 0.96
(d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 212.6, 143.1, 135.1, 118.8, 114.9, 98.8, 83.5, 75.6,
73.9, 60.4, 56.8, 53.3, 50.4, 50.1, 44.2, 36.2, 34.4, 29.4, 28.1,
24.8, 22.6, 19.7, 19.0, 15.3; HRMS (ESI+) m/z calcd for
C25H40O5Na (M+Na)+: 443.2773, found: 443.2775; IR (neat) ν
3523, 3489, 2961, 2877, 1705, 1379, 1261, 1086, 864, 798 cm-
at room temperature for
8 h. Then the mixture was
concentrated to dryness and the crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
give ketone SI-22 (47 mg, 0.13 mmol, 62%, 2 steps) as yellow
solid (m.p. 103-105°C). Rf 0.53 (silica gel, 1:1 petroleum ether/
1
ethyl acetate, UV, purple, p-anisaldehyde); H NMR (400 MHz,
CDCl3) δ 5.70 (ddd, J = 17.1, 10.2, 8.4 Hz, 1H), 5.01 (dd, J = 10.2,
1.1 Hz, 1H), 4.94 (d, J = 17.1 Hz, 1H), 4.35 – 4.25 (m, 1H), 4.15
(d, J = 4.4 Hz, 1H), 3.76 (d, J = 1.1 Hz, 1H), 3.75 – 3.70 (m, 1H),
2.72 (dd, J = 12.4, 8.2 Hz, 1H), 2.57 (dd, J = 18.1, 12.8 Hz, 1H),
2.39 – 2.26 (m, 1H), 2.16 (dd, J = 18.1, 4.2 Hz, 1H), 2.05 – 1.90
(m, 6H), 1.85 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 1.01 (d, J = 6.8
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 215.7, 204.7, 144.0,
136.0, 133.0, 116.8, 98.5, 77.3, 75.6, 71.9, 59.8, 56.8, 49.9, 42.9,
35.2, 32.2, 29.0, 26.3, 23.1, 22.2, 18.8, 14.5; HRMS (ESI+) m/z
calcd for C21H30O5Na (M+Na)+: 385.1990, found: 385.1991; IR
(neat) ν 3493, 2923, 1735, 1685, 1377, 1225, 1159, 1081, 980,
922, 822, 759 cm-1.
1
.
Preparation of (1R,2S,4S,6R)-1-((4aR,6S,7R,7aS)-7-
hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-6-
methyl-3-(propan-2-ylidene)-2-vinylcyclohexane-1,4-diol
(56). NaBH4 (18 mg, 0.48 mmol, 2.00 equiv) was added into a
solution of 52 (100 mg, 0.24 mmol, 1.00 equiv) in MeOH/DCM
(v:v, 1:1, 10 mL) at 0 °C. After stirring 6 h at the same
temperature, the reaction was quenched by H2O (0.5 mL),
concentrated to dryness. The crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
give 56 (97 mg, 0.46 mmol, 97%) as yellow solid (m.p. 134-136
°C). Rf 0.65 (silica gel, 2:1 petroleum ether/ ethyl acetate,
purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.34 –
6.15 (m, 1H), 5.00 – 4.90 (m, 1H), 4.87 (s, 1H), 4.69 (s, 1H), 4.62
(dd, J = 12.2, 7.5 Hz, 1H), 4.23 – 4.07 (m, 2H), 3.78 (s, 1H), 3.70
(d, J = 8.6 Hz, 1H), 3.65 (d, J = 12.2 Hz, 1H), 3.46 (s, 1H), 2.60 (d,
J = 14.3 Hz, 1H), 2.22 – 1.98 (m, 3H), 1.91 – 1.76 (m, 11H), 1.75
– 1.62 (m, 3H), 1.54 (dd, J = 13.1, 7.3 Hz, 1H), 1.48 (s, 3H), 1.45
(s, 3H), 1.39 (dd, J = 12.8, 6.8 Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 143.3, 139.8, 134.0, 132.2,
114.5, 114.0, 98.8, 83.2, 76.8, 73.8, 67.5, 60.7, 54.3, 50.4, 50.3,
36.1, 34.9, 34.4, 29.2, 28.2, 24.8, 21.0, 20.9, 19.2, 16.1; HRMS
(ESI+) m/z calcd for C25H40O5Na (M+Na)+: 443.2773, found:
443.2775; IR (neat) ν 3511, 3440, 2973, 2928, 2874, 1371,
1196, 1155, 984, 968, 894, 863, 819 cm-1.
Preparation
of
(3S,4R,5R)-4-hydroxy-4-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-5-
methyl-2-(propan-2-ylidene)-3-vinylcyclohexan-1-one
(52). To a stirred solution of SI-22 (100 mg, 0.28 mmol, 1.00
equiv) in THF (3 mL) was added freshly prepared 2-
methylallylzinc chloride (0.66 mL, 0.5 M in THF, 0.33 mmol,
1.20 equiv) at -78 °C. After 30 minutes, the reaction was
quenched by addition of sat. aq. ammonium chloride (0.5 mL)
at 0 °C. Ethyl acetate (3 x 5 mL) was added, and the upper
organic layer was separated. The organic layer was dried with
anhydrous sodium sulfate. The crude was purified by flash
chromatography (petroleum ether/ ethyl acetate 10:1) to give
52 (86 mg, 0.24 mmol, 86%) as colorless foam (m.p. 156-159
°C). Rf 0.54 (silica gel, 5:1 petroleum ether/ ethyl acetate, UV,
purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.27 –
6.07 (m, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.91 (d, J = 15.3 Hz, 2H),
4.67 (s, 1H), 4.15 (dd, J = 12.1, 3.3 Hz, 1H), 4.05 (d, J = 3.3 Hz,
1H), 3.69 – 3.63 (m, 3H), 3.52 (s, 1H), 2.55 (dd, J = 15.3, 10.1 Hz,
1H), 2.49 – 2.34 (m, 2H), 2.34 – 2.18 (m, 2H), 2.18 – 2.07 (m,
5H), 1.84 (s, 3H), 1.82 (s, 3H), 1.78 – 1.68 (m, 1H), 1.53 – 1.43
(m, 7H), 1.07 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 203.7, 146.3, 142.5, 136.9, 131.6, 115.1, 114.8, 98.8, 83.8,
76.4, 74.8, 60.5, 53.5, 51.4, 49.9, 45.6, 36.4, 33.5, 29.4, 27.5,
24.8, 23.2, 22.7, 19.0, 16.7; HRMS (ESI+) m/z calcd for
C25H38O5Na (M+Na)+: 441.2617, found: 441.2620; IR (neat) ν
3534, 3491, 2989, 2929, 2853, 1679, 1380, 1251, 1190, 1083,
968, 900, 850 cm-1.
Preparation of (3R,4S,6R,7S,8R)-7-((4aR,6S,7R,7aS)-7-
hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-
2,2,6-trimethyl-8-vinyl-1-oxaspiro[2.5]octane-4,7-diol
(57). To a stirred solution of 56 (82 mg, 0.19 mmol, 1.00 equiv)
and VO(acac)2 (2.5 mg, 9.5 μmol, 0.05 equiv) in DCM (3 mL) was
added TBHP (32 μL, 6 M in decane, 0.19 mmol, 1.00 equiv) at 0
°C, and then slowly warmed up to 25 °C for 1 h. The mixture
was quenched by sat. aq. NaS2O3, extracted with EtOAc. The
organic layer was dried with anhydrous sodium sulfate, the
crude was purified by flash chromatography (petroleum ether/
ethyl acetate 5:1→2:1→1:1) to give 57 (56 mg, 0.12 mmol,
Preparation
of
(2R,3S,4R,5R)-4-hydroxy-4-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 29
66%) as colorless solid (m.p. 149-151°C). Rf 0.42 (silica gel, 2:1
ether/ ethyl acetate, UV, purple, p-anisaldehyde); 1H NMR (400
petroleum ether/ ethyl acetate, purple, p-anisaldehyde); 1H
NMR (400 MHz, CDCl3) δ 6.33 (dt, J = 17.2, 10.1 Hz, 1H), 5.24
(dd, J = 10.1, 2.1 Hz, 1H), 5.13 (dd, J = 17.2, 1.9 Hz, 1H), 4.96 –
4.87 (m, 1H), 4.72 (s, 1H), 4.30 (s, 1H), 4.14 (dd, J = 12.1, 3.2 Hz,
1H), 3.98 (d, J = 3.2 Hz, 1H), 3.84 (d, J = 8.9 Hz, 1H), 3.70 (t, J =
7.7 Hz, 1H), 3.62 (d, J = 12.1 Hz, 1H), 3.37 (d, J = 0.8 Hz, 1H), 2.86
(d, J = 9.6 Hz, 1H), 2.41 (dd, J = 12.2, 8.7 Hz, 2H), 2.24 – 1.99 (m,
3H), 1.83 (s, 3H), 1.80 – 1.51 (m, 5H), 1.46 (s, 3H), 1.44 (s, 3H),
1.43 (s, 3H), 1.40 – 1.36 (m, 1H), 1.35 (s, 3H), 1.03 (d, J = 6.3 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.7, 136.6, 118.2,
115.3, 98.9, 83.6, 78.2, 74.2, 69.0, 68.3, 63.5, 60.4, 53.1, 50.3,
46.2, 37.6, 34.2, 34.1, 30.0, 28.1, 24.8, 22.5, 20.7, 18.9, 16.5;
HRMS (ESI+) m/z calcd for C25H40O6Na (M+Na)+: 459.2723,
found: 459.2715; IR (neat) ν 3473, 2974, 2935, 2907, 1373,
1085, 966, 927, 862, cm-1.
MHz, CDCl3) δ 6.24 (t, J = 2.2 Hz, 1H), 5.79 (ddd, J = 17.3, 10.2,
8.2 Hz, 1H), 5.52 (t, J = 2.2 Hz, 1H), 4.98 (d, J = 10.7 Hz, 2H), 4.80
– 4.72 (m, 2H), 4.06 (s, 1H), 3.29 (s, 1H), 3.27 (d, J = 8.1 Hz, 1H),
2.75 – 2.65 (m, 2H), 2.65 – 2.53 (m, 2H), 2.37 (d, J = 13.9 Hz,
1H), 2.24 (d, J = 13.9 Hz, 1H), 2.17 (dt, J = 7.3, 4.4 Hz, 2H), 2.02
(s, 3H), 1.74 (s, 3H), 1.63 (s, 3H), 1.02 (d, J = 6.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 206.7, 203.7, 145.8, 140.8, 140.2,
136.6, 132.2, 121.4, 116.5, 115.6, 83.3, 76.5, 49.5, 47.8, 46.7,
44.0, 35.7, 26.7, 23.9, 23.3, 22.2, 15.0; HRMS (ESI+) m/z calcd
for C22H30O4Na (M+Na)+: 381.2042, found: 381.2040; IR (neat)
ν 3454, 2953, 2923, 2852, 1751, 1682, 1606, 1376, 1184, 1065,
984, 911, 731 cm-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
Preparation of methyl (3R,4R)-3-((4aR,6R,7S,7aS)-7-
((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3-
hydroxy-4-methyl-6-oxocyclohex-1-ene-1-carboxylate
(60). To a solution of SI-20 (110 mg, 0.2 mmol, 1.00 equiv) in
MeOH/THF (v:v, 1:1, 4 mL) was sequentially added Et3N (138
µL, 1.0 mmol, 5.00 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.05
equiv) at room temperature. Then the mixture was transferred
into autoclave, backfilled CO for 3 times. Then the reaction was
heated at 55 °C (oil bath) under CO (1 atm.) for 12 h. After
cooling to room temperature, the reaction mixture was filtered
through a pad of celite, concentrated in vacuo, and purified by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
afford 60 (89 mg, 0.19 mmol, 95%) as yellow oil. Rf 0.19 (silica
gel, 5:1 petroleum ether/ ethyl acetate, purple, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 1.1 Hz,
1H), 4.19 – 4.05 (m, 2H), 4.00 (d, J = 3.6 Hz, 1H), 3.79 (s, 3H),
3.67 (dd, J = 12.0, 1.6 Hz, 1H), 3.43 (s, 1H), 2.62 (dd, J = 17.1, 4.7
Hz, 1H), 2.57 – 2.44 (m, 2H), 2.37 (dd, J = 12.5, 6.2 Hz, 1H), 2.18
– 2.08 (m, 1H), 2.08 – 1.93 (m, 1H), 1.82 (dt, J = 12.5, 8.1 Hz,
1H), 1.46 (s, 3H), 1.39 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.87 (s,
9H), 0.10 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7, 164.6,
158.0, 131.5, 98.4, 79.3, 77.4, 73.2, 60.2, 54.7, 52.2, 43.1, 37.5,
36.3, 28.9, 26.7, 25.6, 19.2, 17.7, 14.7, -4.4, -4.9; HRMS (ESI+)
m/z calcd for C24H41O7Si (M+H)+: 469.2622, found: 469.2618;
IR (neat) ν 3490, 2927, 2876, 2854, 1742, 1682, 1282, 1095,
832, 775 cm-1.
Preparation
of
(3S,6R,7S,8R)-7-hydroxy-7-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-
2,2,6-trimethyl-8-vinyl-1-oxaspiro[2.5]octan-4-one (58).
57 (12 mg, 0.027 mmol, 1.00 equiv) dissolved in DCM (1 mL),
followed by sequential addition of powdered 4Å MS (15 mg),
NMO (3.7 mg, 0.027 mmol, 3.00 equiv), TPAP (1 mg, 2.7 μmol,
0.10 equiv) at 0 °C, and the reaction mixture was stirred at
room temperature for 8 h. Then the mixture was concentrated
to dryness and the crude product was purified by flash
chromatography (petroleum ether/ ethyl acetate 5:1) to give
ketone 58 (10 mg, 0.022 mmol, 83%) as colorless solid (m.p.
210-212 °C). Rf 0.42 (silica gel, 2:1 petroleum ether/ ethyl
1
acetate, purple, p-anisaldehyde); H NMR (400 MHz, CDCl3) δ
5.89 (dt, J = 17.0, 10.1 Hz, 1H), 5.31 – 5.07 (m, 2H), 4.91 (s, 1H),
4.70 (s, 1H), 4.17 (dd, J = 12.1, 3.3 Hz, 1H), 4.01 (d, J = 3.0 Hz,
2H), 3.62 (d, J = 12.2 Hz, 1H), 3.18 (d, J = 9.8 Hz, 1H), 3.04 (s,
1H), 2.73 (dd, J = 20.2, 13.8 Hz, 1H), 2.57 – 2.44 (m, 1H), 2.38
(d, J = 14.1 Hz, 1H), 2.24 – 2.06 (m, 4H), 1.92 – 1.83 (m, 1H),
1.82 (s, 3H), 1.75 – 1.66 (m, 1H), 1.63 (s, 3H), 1.49 (s, 3H), 1.48
(s, 3H), 1.19 (s, 3H), 1.08 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 208.4, 142.5, 135.0, 118.7, 115.4, 99.0, 84.4, 77.7,
77.3, 77.01, 76.7, 74.1, 72.1, 66.1, 60.6, 53.0, 50.4, 47.8, 42.9,
35.2, 33.8, 30.0, 27.6, 24.7, 21.4, 20.3, 18.93, 14.9; HRMS (ESI+)
m/z calcd for C25H38O6Na (M+Na)+: 457.2566, found: 457.2570;
IR (neat) ν 3510, 3489, 2978, 2909, 2879, 1726, 1377, 1196,
1159, 1082, 970, 931, 870 cm-1.
Preparation
of
methyl
(1S,2S,3R,4R,6S)-3-
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,6-
dihydroxy-4-methyl-2-vinylcyclohexane-1-carboxylate
(61). Vinylmagnesium chloride (0.5 mL, 2 M in THF, 1.00 mmol,
2.00 equiv) was added into a suspension of CuCN (45 mg, 0.50
mmol, 1.00 equiv) in THF (5 mL) at 0 °C and stirred for 10 min.
To the solution of 60 (234 mg, 0.50 mmol, 1.00 equiv) in THF
(5 mL) was slowly added above prepared cooper reagent at -
78°C, and warmed up to room temperature with stirring for 12
h. The mixture was quenched with sat. aq. ammonium chloride
(0.5 mL), extracted with EtOAc (3 x 5 mL). The organic layer
was dried with anhydrous sodium sulfate, concentrated in
vacuo, and re-dissolved in DCM/MeOH (v:v, 1:1, 10 mL). The
yellow solution was added CeCl37H2O (186 mg, 0.50 mmol,
1.00 equiv), cooled to -78°C, followed by portion-wise addition
of NaBH4 (95 mg, 2.50 mmol, 5.00 equiv), and warmed up to
room temperature for 6 h. The mixture was quenched by
adding H2O (0.5 mL), then concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum
ether/ ethyl acetate 5:1→2:1) to give 61 (140 mg, 0.56 mmol,
56%) as yellow oil. Rf 0.21 (silica gel, 2:1 petroleum ether/
ethyl acetate, purple, p-anisaldehyde); 1H NMR (400 MHz,
CDCl3) δ 6.06 – 5.86 (m, 1H), 5.11 – 4.96 (m, 2H), 4.64 (dd, J =
9.9, 3.4 Hz, 1H), 3.85 (d, J = 3.5 Hz, 3H), 3.62 (s, 3H), 3.49 (s, 1H),
3.46 – 3.36 (m, 1H), 2.80 – 2.67 (m, 1H), 2.45 – 2.33 (m, 1H),
2.26 – 2.07 (m, 2H), 2.04 (s, 1H), 1.77 – 1.35 (m, 8H), 1.32 (s,
Preparation of (3S,4R,5R)-4-hydroxy-4-((1S,2R)-2-
hydroxy-2-(2-methylallyl)-4-methylene-3-
oxocyclopentyl)-5-methyl-2-(propan-2-ylidene)-3-
vinylcyclohexan-1-one (59). 52 (89 mg, 0.21 mmol, 1.00
equiv) was dissolved in THF/MeCN/H2O (v/v/v, 1 mL/ 4mL/
1mL), followed by addition of DDQ (4.8 mg, 0.021 mmol, 0.20
equiv) at 25 °C. The dark red solution was allowed to stir at the
same temperature for 18 h, concentrated to dryness, and then
re-dissolved in DCM (5 mL). To the yellow solution was
sequentially added DMAP (26 mg, 0.21 mmol, 1.00 equiv),
pyridine (83 µL, 1.05 mmol, 5.00 equiv), TsCl (80 mg, 0.42
mmol, 2.00 equiv) at 0 °C. After stirring at room temperature
for 8 h, the mixture was concentrated to dryness and the crude
product was purified by flash chromatography (petroleum
ether/ ethyl acetate 10:1→5:1) to give yellow oil (73 mg, 0.14
mmol, 65%, 2 steps). To a solution of the above compound (73
mg, 0.14 mmol, 1.00 equiv) in DCM (5 mL) was sequentially
added powdered 4Å MS (100 mg), NMO (56 mg, 0.41 mmol,
3.00 equiv), TPAP (4.8 mg, 0.014 mmol, 0.10 equiv) at 0 °C, and
the reaction mixture was stirred at room temperature for 8 h.
Then the mixture was concentrated to dryness and the crude
product was purified by flash chromatography (petroleum
ether/ ethyl acetate 5:1) to give 59 (36 mg, 0.1 mmol, 74%) as
yellow solid (m.p. 94-96 °C). Rf 0.57 (silica gel, 5:1 petroleum
ACS Paragon Plus Environment

Page 25 of 29
The Journal of Organic Chemistry
3H), 1.27 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.90 (s, 9H), 0.15 (s,
(s, 3H), 1.35 (s, 3H), 1.08 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100
3H), 0.10 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.7, 137.1,
117.0, 98.5, 80.9, 77.3, 73.2, 70.9, 61.6, 54.5, 51.3, 50.6, 48.9,
38.2, 37.5, 35.4, 27.3, 25.9, 25.8, 22.4, 17.7, 15.5, -4.0, -5.5;
HRMS (ESI+) m/z calcd for C26H47O7Si (M+H)+: 499.3091,
found: 499.3092; IR (neat) ν 3469, 2929, 2857, 1741, 1371,
1068, 833, 775 cm-1.
MHz, CDCl3) δ 174.7, 143.3, 136.7, 117.5, 114.2, 98.6, 94.9, 81.9,
76.0, 74.9, 72.6, 60.3, 55.3, 52.9, 52.2, 51.4, 51.2, 49.5, 38.6,
35.4, 35.3, 29.2, 28.5, 24.6, 18.9, 17.1; HRMS (ESI+) m/z calcd
for C26H43O8 (M+H)+: 483.2958, found: 483.2955; IR (neat) ν
3462, 3070, 2945, 1733, 1373, 1250, 1102, 1042, 973 cm-1.
Preparation of (3aR,4S,5R,6R)-5-((4aR,6R,7S,7aS)-7-
hydroxy-2,2-
1
2
3
4
5
6
7
8
Preparation of methyl (1S,2S,3R,4R,6S)-3-((4aR,6S,7aS)-
2,2-dimethyl-7-oxohexahydrocyclopenta[d][1,3]dioxin-6-
yl)-3-hydroxy-6-(methoxymethoxy)-4-methyl-2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,3,6-
trimethyl-2-phenyl-4-vinyl-3,3a,4,5,6,7-hexahydro-2H-
indazol-5-ol (65). Phenylhydrazine (62 µL, 0.63 mmol, 1.00
equiv) was added into a stirred solution of 36 (300 mg, 0.63
mmol, 1.00 equiv) and TFA (47 µL, 0.63 mmol, 1.00 equiv) in
THF (5 mL) at room temperature. The reaction was heated to
90 °C (oil bath) for 16 h, then concentrated in vacuo. The crude
residue was purified by flash chromatography (petroleum
ether/ ethyl acetate 5:1) to give yellow oil. The yellow oil was
dissolved in THF (5 mL), followed by addition of TBAF (1.26
mL, 1 M in THF, 1.26 mmol, 1.00 equiv) at 0 °C. After stirring at
0°C for 2 h, the reaction was quenched with sat. aq. ammonium
chloride (0.5 mL) at 0 °C. Ethyl acetate (3 x 5 mL) was added,
and the upper organic layer was separated. The organic layer
was dried with anhydrous sodium sulfate. The crude was
purified by flash chromatography (petroleum ether/ ethyl
acetate 5:1) to give 65 (140 mg, 0.31 mmol, 49%, 2 steps) as
yellow solid (m.p. 232-234°C). Rf 0.29 (silica gel, 1:1 petroleum
ether/ ethyl acetate, dark purple, p-anisaldehyde); 1H NMR
(400 MHz, CDCl3) δ 7.29 – 7.18 (m, 4H), 6.99 (t, J = 6.7 Hz, 1H),
6.07 – 5.88 (m, 1H), 5.28 (d, J = 10.4 Hz, 1H), 5.20 (d, J = 17.6 Hz,
1H), 4.80 (d, J = 8.5 Hz, 1H), 4.08 – 3.92 (m, 2H), 3.57 (dd, J =
11.9, 4.3 Hz, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.96 (s, 1H), 2.55 –
2.44 (m, 3H), 2.40 – 2.26 (m, 1H), 2.04 (td, J = 10.7, 5.4 Hz, 1H),
1.82 (ddt, J = 18.6, 12.8, 9.2 Hz, 2H), 1.65 – 1.58 (m, 1H), 1.58 (s,
3H), 1.40 (s, 3H), 1.31 (s, 3H), 1.05 (d, J = 6.5 Hz, 3H), 0.81 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.8, 145.9, 137.6,
128.4, 122.3, 120.9, 118.8, 98.2, 79.5, 78.9, 75.1, 70.1, 61.0,
55.1, 51.4, 48.7, 38.9, 35.5, 31.2, 29.5, 28.1, 27.3, 20.7, 17.1,
16.4; HRMS (ESI+) m/z calcd for C27H39N2O4 (M+H)+: 455.2910,
found: 455.2905; IR (neat) ν 3156, 2979, 2933, 2855, 1491,
1364, 1032, 918, 764, 700 cm-1.
vinylcyclohexane-1-carboxylate (62). MOMCl (0.23 mL, 3.00
mmol, 2.00 equiv) was added into a stirred solution of 61 (760
mg, 1.52 mmol, 1.00 equiv) and DIPEA (0.75 mL, 4.56 mmol,
3.00 equiv) in DCM (20 mL) at 0 °C. After addition, the reaction
was allowed to room temperature for 12 h. The mixture was
quenched with sat. aq. NaHCO3 (2 mL), extracted with DCM (3
x 10 mL). The organic layer was dried with anhydrous sodium
sulfate and concentrated in vacuo to yield crude yellow oil
which was used directly to the next step. To the above residue
solution in THF (30 mL) was added TBAF (4.6 mL, 1 M in THF,
4.56 mmol, 3.00 equiv) at 0 °C. After stirring at room
temperature for 3 h, the reaction was quenched with sat. aq.
NH4Cl (2 mL), extracted with EtOAc (3 x 15 mL). The organic
layer was concentrated in vacuo and purified by flash
chromatography (petroleum ether/ ethyl acetate 5:1→2:1) to
give yellow oil (586 mg). The above product dissolved in DCM
(10 mL), followed by sequential addition of powdered 4Å MS
(600 mg), NMO (558 mg, 4.1 mmol, 3.00 equiv), TPAP (48 mg,
0.14 mmol, 0.10 equiv) at 0 °C, and the reaction mixture was
stirred at room temperature for 8 h. Then the mixture was
concentrated to dryness and the crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate 5:1) to
give ketone 62 (448 mg, 1.05 mmol, 69%, 3 steps) as yellow oil.
Rf 0.34 (silica gel, 5:1 petroleum ether/ ethyl acetate, purple, p-
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
anisaldehyde); H NMR (400 MHz, CDCl3) δ 5.59 (dt, J = 17.4,
10.1 Hz, 1H), 5.12 – 4.99 (m, 2H), 4.68 (d, J = 7.0 Hz, 1H), 4.56
(d, J = 7.0 Hz, 1H), 4.20 (dd, J = 12.2, 4.1 Hz, 1H), 4.04 (d, J = 5.2
Hz, 1H), 3.80 (td, J = 10.8, 4.6 Hz, 1H), 3.72 – 3.64 (m, 1H), 3.59
(s, 3H), 3.31 (s, 3H), 2.93 (t, J = 11.1 Hz, 1H), 2.62 – 2.44 (m, 2H),
1.94 – 1.77 (m, 3H), 1.69 (d, J = 11.6 Hz, 1H), 1.43 (s, 3H), 1.33
(s, 3H), 0.98 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 174.5, 133.9, 119.9, 98.5, 95.0, 76.1, 75.7, 71.3, 59.9, 55.3,
54.1, 51.4, 51.3, 37.2, 34.2, 32.7, 28.2, 25.6, 19.1, 15.9; HRMS
(ESI+) m/z calcd for C22H34O8Na (M+Na)+: 449.2151, found:
449.2155; IR (neat) ν 3456, 2949, 1728, 1142, 1028, 919, 733
cm-1.
Preparation of (3aR,4S,5R,6R,7aS)-5-((4aR,6R,7S,7aS)-
7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-5-
hydroxy-3,3,6-trimethyl-4-vinyl-3,3a,4,5,6,7-hexahydro-
7aH-indazol-7a-yl acetate (66) and (4S,5R,6R)-5-
((4aR,6R,7S,7aS)-7-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,3,6-
trimethyl-4-vinyl-4,5,6,7-tetrahydro-3H-indazol-5-ol (SI-
23). To a stirred solution of 36 (200 mg, 0.42 mmol, 1.00 equiv)
and TFA (0.93 mL, 1.26 mmol, 3.00 equiv) in THF (10 mL) was
added hydrazine hydrate (72 µL, 85% in H2O, 1.26 mmol, 3.00
equiv) at 0 °C dropwise over 10 min. The resultant pale yellow
solution was heated at 90 °C (oil bath) for 12 h. Upon complete
consumption of starting material (by TLC), the solvent was
removed in vacuo, and the flask was backfilled with argon. A
solution of Pb(OAc)4 (931 mg, 2.10 mmol, 5.00 equiv) in CH2Cl2
(10 mL) was added to the above residue in CH2Cl2 (10 mL) at 0
°C dropwise by syringe over 30 min, and allowed to stir for 3 h.
The reaction was quenched by addition of sat. aq. sodium
bicarbonate (3 mL) at 0 °C, filtered and extracted with CH2Cl2
(5 x 10 mL). The combined organic layers were dried with
anhydrous sodium sulfate, the crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate
10:1→5:1) to give diazene 66 (120 mg, 0.22 mmol, 52%) as
white foam, SI-23 as yellow foam (56 mg, 0.11 mmol, 27%). 66:
Rf 0.36 (silica gel, 2:1 petroleum ether/ ethyl acetate, brown, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.00 – 5.85 (m, 1H),
Preparation of methyl (1S,2S,3R,4R,6S)-3-hydroxy-3-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-6-
(methoxymethoxy)-4-methyl-2-vinylcyclohexane-1-
carboxylate (63). To a stirred solution of 62 (43 mg, 0.10
mmol, 1.00 equiv) in THF (5 mL) was added freshly prepared
2-methylallylzinc chloride (300 μL, 0.5 M in THF, 0.15 mmol,
1.50 equiv) at -78°C under Ar. After 5 minutes, the reaction was
quenched with sat. aq. NH4Cl (0.5 mL) at 0 °C, extracted with
EtOAc (3 x 5 mL). The organic layer was dried with anhydrous
Na2SO4 and concentrated in vacuo. The crude product was
purified by flash chromatography (petroleum ether/ ethyl
acetate 10:1) to yield 63 (32 mg, 0.067 mmol, 67%) as colorless
oil. Rf 0.65 (silica gel, 10:1 petroleum ether/ ethyl acetate,
purple, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 5.90 (dt, J
= 17.5, 10.2 Hz, 1H), 5.21 – 5.09 (m, 2H), 4.84 (s, 1H), 4.79 (s,
1H), 4.69 (d, J = 6.9 Hz, 2H), 4.55 (d, J = 6.9 Hz, 1H), 4.17 – 4.10
(m, 2H), 3.77 (td, J = 10.8, 4.2 Hz, 1H), 3.72 – 3.66 (m, 1H), 3.60
(s, 3H), 3.50 (d, J = 1.6 Hz, 1H), 3.31 (s, 3H), 2.86 – 2.76 (m, 2H),
2.55 – 2.36 (m, 2H), 2.23 – 2.12 (m, 1H), 1.94 (d, J = 14.2 Hz,
1H), 1.90 – 1.81 (m, 2H), 1.77 (s, 3H), 1.59 – 1.48 (m, 3H), 1.42
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 29
5.31 – 5.11 (m, 2H), 4.38 (d, J = 8.1 Hz, 1H), 3.98 – 3.85 (m, 2H),
– 1.95 (m, 6H), 1.74 – 1.52 (m, 3H), 1.44 (s, 3H), 1.37 (s, 3H),
1
2
3
4
5
6
7
8
3.51 (dd, J = 11.6, 4.9 Hz, 1H), 2.81 (s, 1H), 2.43 (d, J = 10.5 Hz,
1H), 2.21 (d, J = 14.2 Hz, 1H), 2.16 – 2.10 (m, 1H), 2.09 – 2.06
(m, 1H), 2.05 (s, 3H), 2.01 – 1.95 (m, 1H), 1.94 – 1.85 (m, 2H),
1.56 (dd, J = 11.7, 5.4 Hz, 1H), 1.51 (s, 3H), 1.35 (s, 3H), 1.30 (s,
3H), 1.29 – 1.27 (m, 1H) 1.26 (s, 3H), 1.21 (d, J = 7.1 Hz, 3H),
0.87 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 169.3, 138.4, 118.1, 117.8, 98.1, 92.1, 80.6, 78.0, 75.1,
61.1, 54.2, 45.7, 42.5, 35.6, 35.4, 35.1, 27.8, 27.4, 25.7, 22.2,
21.8, 20.8, 17.6, 16.6, -4.1, -5.4; HRMS (ESI+) m/z calcd for
C29H50N2O6SiNa (M+Na)+: 573.3336, found: 573.3331; IR (neat)
ν 3565, 2933, 2857, 1739, 1367, 1244, 1053, 835, 777 cm-1. SI-
23: Rf 0.30 (silica gel, 2:1 petroleum ether/ ethyl acetate, UV,
pink, p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 5.72 (dt, J =
16.4, 10.0 Hz, 1H), 5.36 – 5.16 (m, 2H), 4.18 (d, J = 2.2 Hz, 1H),
4.10 (dd, J = 12.0, 3.5 Hz, 1H), 3.94 (d, J = 3.8 Hz, 1H), 3.66 (dd,
J = 12.0, 1.8 Hz, 1H), 3.16 (d, J = 9.6 Hz, 1H), 3.00 (ddd, J = 17.5,
6.1, 2.5 Hz, 1H), 2.85 (s, 1H), 2.73 (dd, J = 17.5, 1.7 Hz, 1H), 2.32
– 2.23 (m, 1H), 2.22 – 2.07 (m, 2H), 2.01 – 1.92 (m, 1H), 1.63 –
1.54 (m, 1H), 1.42 (s, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H),
1.11 (d, J = 7.1 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 150.4, 149.2, 135.3, 120.0,
98.1, 92.1, 79.4, 77.8, 75.2, 60.4, 54.0, 47.3, 36.0, 35.6, 29.1,
28.4, 26.9, 25.7, 21.4, 20.5, 19.1, 17.7, 16.3, -4.3, -4.9; HRMS
(ESI+) m/z calcd for C27H47N2O4Si (M+H)+: 491.3305, found:
491.3297; IR (neat) ν 3501, 2930, 2859, 1379, 1194, 1089,
1075, 966, 833, 778 cm-1.
1.30 (s, 3H), 1.05 (d, J = 6.9 Hz, 6H), 0.24 (d, J = 12.1 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 138.1, 117.5, 98.1, 80.1,
79.0, 77.9, 64.1, 60.9, 54.5, 44.9, 41.8, 39.8, 36.4, 36.1, 32.7,
29.0, 28.7, 25.2, 21.2, 19.9, 17.3, 15.9; HRMS (ESI+) m/z calcd
for C23H37O6 (M+H)+: 409.2590, found: 409.2588; IR (neat) ν
3534, 3384, 2957, 2935, 2871, 1733, 1373, 1221, 1194, 967,
912, 836 cm-1.
Preparation
of
(1S,3R,4R,5S,6R)-4-hydroxy-4-
((4aR,6S,7R,7aS)-7-hydroxy-2,2-dimethyl-7-(2-
methylallyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl)-
3,7,7-trimethyl-5-vinylbicyclo[4.1.0]heptan-1-yl acetate
(35). To a stirred solution of secondary alcohol 67 (204 mg,
0.50 mmol, 1.00 equiv), 4Å MS (200 mg), 4-Methylmorpholine
N-oxide monohydrate (203 mg, 1.50 mmol, 3.00 equiv) in
CH2Cl2 (40 mL) at 0 °C was added TPAP (35 mg, 0.10 mmol, 0.20
equiv), and the reaction mixture was stirred at room
temperature for 5 h. The resulting mixture filtered through a
short pad of Florisil®, elution with CH2Cl2 (20 mL) and
concentrated in vacuo. The resulting oil was dissolved in THF
(10 mL), at -78 °C was added a solution of 2-Methylallylzinc
chloride (0.55 mmol, 1.10 equiv, prepared from 0.55 mL zinc
chloride (1.0 M in THF) and 1.10 mL 2-Methylallylmagnesium
chloride (0.5 M in THF)), and the reaction mixture was stirred
at -78 °C for 5 min. Then warmed to 0 °C, the resulting mixture
was quenched with sat. aq. ammonium chloride. Ethyl acetate
(3 x 10 mL) was added, and the upper organic layer was
separated. The organic layer was dried with anhydrous sodium
sulfate, the crude was purified by flash chromatography
(petroleum ether/ ethyl acetate 10:1) to give diene 35 (143 mg,
0.31 mmol, 62%, over 2 steps) as colorless oil. Rf 0.32 (silica
gel, 5:1 petroleum ether/ ethyl acetate, purple, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 6.29 (ddd, J = 17.1,
10.4, 9.2 Hz, 1H), 5.12 (dd, J = 10.4, 8.7 Hz, 2H), 4.83 (s, 1H),
4.66 (s, 1H), 4.22 – 4.04 (m, 3H), 3.65 (d, J = 12.0 Hz, 1H), 3.40
(s, 1H), 2.75 (d, J = 14.3 Hz, 1H), 2.44 – 2.34 (m, 1H), 2.30 – 2.18
(m, 2H), 2.12 (dd, J = 8.7, 5.1 Hz, 1H), 2.01 (s, 3H), 1.97 (d, J =
14.3 Hz, 1H), 1.79 (s, 3H), 1.77 – 1.68 (m, 2H), 1.64 – 1.57 (m,
1H), 1.48 – 1.44 (m, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.11 (s, 3H),
1.09 (s, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.74 (d, J = 5.1 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 143.7, 141.0, 115.2,
114.2, 98.6, 82.0, 75.4, 73.3, 64.3, 60.6, 53.1, 49.6, 44.5, 36.7,
34.9, 31.5, 30.7, 29.2, 28.5, 24.8, 23.8, 23.0, 21.1, 19.1, 18.3,
15.8; HRMS (ESI+) m/z calcd for C27H42O6Na (M+Na)+:
485.2879, found: 485.2873; IR (neat) ν 3443, 2926, 1723, 1371,
1232, 1197, 1135, 969, 871 cm-1.
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
Preparation
of
(1S,3R,4R,5S,6R)-4-hydroxy-4-
((4aR,6R,7S,7aS)-7-hydroxy-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,7,7-
trimethyl-5-vinylbicyclo[4.1.0]heptan-1-yl acetate (67)
and
(1R,3R,4R,5S,6R)-4-hydroxy-4-((4aR,6R,7S,7aS)-7-
hydroxy-2,2-
dimethylhexahydrocyclopenta[d][1,3]dioxin-6-yl)-3,7,7-
trimethyl-5-vinylbicyclo[4.1.0]heptan-1-yl acetate (68).
To a stirred solution of diazene 66 (100 mg, 0.18 mmol, 1.00
equiv) in ethyl acetate (20 mL), was irradiated using 300W
mercury lamp at 25 °C. After 12 h, the reaction mixture was
concentrated under reduced pressure. To a solution of the
resulting residue in THF (20 mL) was added TBAF (0.36 mL, 1.0
M in THF, 0.36 mmol, 2.00 equiv) and the reaction mixture was
stirred at 0 °C for 2 h. The resulting mixture was then quenched
with sat. aq. ammonium chloride. Ethyl acetate (5 x 10 mL) was
added, and the upper organic layer was separated. The organic
layer was dried with anhydrous sodium sulfate, the crude
product was purified by flash chromatography (petroleum
ether/ ethyl acetate 2:1) to give alcohol 67 (58 mg, 0.14 mmol,
79%) as colorless foam and trans isomer 68 (8 mg, 0.019 mmol,
11%) as white solid (m.p. 130-133 °C). 67: Rf 0.78 (silica gel,
1:1 petroleum ether/ ethyl acetate, dark blue, p-anisaldehyde);
1H NMR (400 MHz, CDCl3) δ 6.29 (dt, J = 17.2, 9.9 Hz, 1H), 5.23
(s, 1H), 5.11 – 4.98 (m, 2H), 4.62 (dd, J = 8.8, 2.0 Hz, 1H), 4.04
(dd, J = 6.4, 2.0 Hz, 1H), 3.92 (dd, J = 11.6, 5.4 Hz, 1H), 3.52 (dd,
J = 11.6, 5.4 Hz, 1H), 3.31 (s, 1H), 2.28 – 2.16 (m, 1H), 2.13 – 1.98
(m, 3H), 2.04 (s, 3H), 1.72 – 1.56 (m, 2H), 1.44 – 1.40 (m, 1H),
1.38 (s, 3H), 1.35 – 1.31 (m, 1H), 1.30 (s, 3H), 1.15 (s, 3H), 1.08
(s, 3H), 0.89 (d, J = 6.2 Hz, 3H), 0.62 (d, J = 3.9 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 173.3, 140.0, 115.1, 98.2, 79.3, 77.5,
73.6, 62.9, 61.4, 50.7, 44.8, 36.5, 35.9, 32.5, 30.6, 27.9, 27.3,
23.6, 22.3, 21.2, 21.1, 16.5, 15.3; HRMS (ESI+) m/z calcd for
C23H36O6Na (M+Na)+: 431.2410, found: 431.2401; IR (neat) ν
3396, 2935, 2243, 1719, 1369, 1248, 1049, 994, 913, 849, 730
cm-1. 68: Rf 0.66 (silica gel, 1:1 petroleum ether/ ethyl acetate,
Preparation
of
(1R,2aS,3aR,3bS,6aR,6bS,10aR,11aS,11bR)-6a,11b-
dihydroxy-1,3,3,5,8,8-hexamethyl-
1,3,3a,3b,6,6a,6b,10,10a,11,11a,11b-
dodecahydrocyclopropa[3',4']benzo[1',2':4,5]azuleno[1,2
-d][1,3]dioxin-2a(2H)-yl acetate (69). To a stirred solution
of 35 (50 mg, 0.11 mmol, 1.00 equiv) in toluene (5 mL) was
added Grubbs 2nd generation catalyst (37.4 mg, 0.043 mmol,
0.4 equiv) under argon, and the resultant mixture was stirred
at 110 °C (oil bath) for 12 h. The mixture was concentrated to
dryness and the residue was purified by flash chromatography
(petroleum ether/ ethyl acetate 5:1) to give 69 (34 mg, 0.078
mmol, 71%) as pale yellow solid (m.p. 138-141 °C), and
recovered starting material 35 (10 mg, 0.022 mmol, 20%). Rf
0.15 (silica gel, 5:1 petroleum ether/ ethyl acetate, brown, p-
anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 5.43 – 5.31 (m, 1H),
3.96 (dd, J = 11.6, 4.5 Hz, 1H), 3.70 (d, J = 6.1 Hz, 1H), 3.61 (dd,
J = 11.6, 5.1 Hz, 1H), 3.42 (s, 1H), 2.50 (t, J = 6.1 Hz, 1H), 2.45 (d,
J = 17.0 Hz, 1H), 2.13 (d, J = 17.0 Hz, 1H), 2.10 – 2.05 (m, 1H),
2.03 (s, 3H), 2.02 – 1.88 (m, 3H), 1.89 – 1.79 (m, 2H), 1.73 (s,
3H), 1.58 (dd, J = 15.7, 5.3 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3H),
1
dark blue, p-anisaldehyde); H NMR (400 MHz, CDCl3) δ 6.44
(ddd, J = 16.7, 10.5, 6.0 Hz, 1H), 5.32 – 5.18 (m, 2H), 4.28 (d, J =
7.5 Hz, 1H), 4.10 (dd, J = 11.6, 4.4 Hz, 2H), 3.67 (dd, J = 12.0, 2.5
Hz, 1H), 3.23 (dd, J = 12.0, 6.0 Hz, 1H), 2.39 – 2.24 (m, 3H), 2.17
ACS Paragon Plus Environment

Page 27 of 29
The Journal of Organic Chemistry
1.12 (s, 3H), 1.09 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.5
concentrated in vacuo. The residue was used in the next
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 134.8, 127.8,
98.8, 77.6, 77.4, 75.8, 65.0, 61.7, 54.3, 48.0, 39.6, 35.7, 34.9,
31.3, 31.2, 28.8, 28.2, 25.6, 23.8, 22.7, 21.7, 21.3, 19.0, 15.9;
HRMS (ESI+) m/z calcd for C25H38O6Na (M+Na)+: 457.2566,
found: 457.2562; IR (neat) ν 3513, 2973, 2943, 2869, 1742,
1368, 1226, 1120, 1056, 1011, 875 cm-1.
reaction without further purification. Imidazole (63 mg, 0.92
mmol, 20 equiv), TMSCl (40 µL, 0.46 mmol, 10 equiv), were
successively added to a solution of the above crude in CH2Cl2 (5
mL) at room temperature. The reaction mixture was warmed
to 40 °C (oil bath) and stirred for 5 h. Then the mixture was
concentrated to dryness and the crude product was purified by
flash chromatography (petroleum ether/ ethyl acetate
20:1→10:1) to give SI-25 (10.8 mg, 0.029 mmol, 64%, over 2
steps) as a colorless oil. Rf 0.52 (silica gel, 5:1 petroleum ether/
1
2
3
4
5
6
7
8
Preparation of ((1aR,1bS,4aR,5S,6R,7aS,7bR,8R,9aS)-
9a-acetoxy-4a,5,7b-trihydroxy-1,1,3,8-tetramethyl-
1a,1b,4,4a,5,6,7,7a,7b,8,9,9a-dodecahydro-1H-
1
cyclopropa[3,4]benzo[1,2-e]azulen-6-yl)methyl pivalate
(70) and ((1aR,4aR,5S,6R,7aS,8R,9aS)-9a-acetoxy-4a,5-
dihydroxy-1,1,3,8-tetramethyl-1a,4,4a,5,6,7,7a,8,9,9a-
decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-6-
yl)methyl pivalate (SI-24). To a stirred solution of 69 (32 mg,
0.074 mmol, 1.00 equiv) in THF/MeCN/H2O (v/v/v, 2 mL/
8mL/ 1mL) was added DDQ (3.4 mg, 0.015 mmol, 0.20 equiv).
The dark solution was stirred at room temperature for 18 h.
Upon complete consumption of starting material (by TLC), the
solvent was removed in vacuo, then the residue was
redissolved in CH2Cl2 (5 mL), at 0 °C was added DMAP (9 mg,
0.074 mmol, 1.00 equiv), pyridine (29 µL, 0.37 mmol, 5.00
equiv), pivaloyl chloride (28 µL, 0.22 mmol, 3.00 equiv) in
sequence. The yellow solution was stirred at room temperature
for 8 h. Then the mixture was concentrated to dryness and the
crude product was purified by flash chromatography
(petroleum ether/ ethyl acetate 10:1→5:1) to give 70 (26 mg,
0.054 mmol, 73%) as a yellow solid (m.p. 163-165 °C) and SI-
24 (2.7 mg, 5.9 µmol, 8%) as a yellow solid (m.p. 101-105 °C).
70: Rf 0.38 (silica gel, 2:1 petroleum ether/ ethyl acetate, blue,
p-anisaldehyde); 1H NMR (400 MHz, CDCl3) δ 5.36 (d, J = 4.1 Hz,
1H), 4.32 (dd, J = 11.2, 7.9 Hz, 1H), 4.01 (dd, J = 11.2, 5.3 Hz, 1H),
3.61 (t, J = 6.6 Hz, 1H), 3.21 (d, J = 5.9 Hz, 1H), 3.08 (s, 1H), 2.48
– 2.43 (m, 1H), 2.39 (d, J = 16.6 Hz, 1H), 2.28 (d, J = 16.6 Hz, 1H),
2.20 – 2.10 (m, 1H), 2.03 (s, 3H), 2.00 – 1.81 (m, 4H), 1.76 (s,
3H), 1.70 – 1.65 (m, 1H), 1.56 (dd, J = 14.0, 5.0 Hz, 1H), 1.19 (s,
9H), 1.13 (s, 3H), 1.07 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.83 (d, J
= 6.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.2, 172.3,
135.0, 128.6, 77.9, 77.5, 74.9, 64.6, 53.3, 45.3, 39.6, 39.4, 38.8,
35.0, 31.8, 30.8, 28.8, 27.2, 25.9, 23.4, 22.9, 21.3, 18.7, 15.7;
HRMS (ESI+) m/z calcd for C27H42O7Na (M+Na)+: 501.2828,
found: 501.2826; IR (neat) ν 3352, 2959, 2924, 1717, 1374,
1246, 1154, 1050, 997, 888 cm-1. SI-24: Rf 0.58 (silica gel, 2:1
petroleum ether/ ethyl acetate, UV, dark blue, p-anisaldehyde);
1H NMR (400 MHz, CDCl3) δ 5.71 (s, 1H), 4.38 (dd, J = 10.8, 7.5
Hz, 1H), 4.16 (dd, J = 10.8, 6.6 Hz, 1H), 3.80 (t, J = 5.0 Hz, 1H),
3.21 (d, J = 4.7 Hz, 1H), 2.63 – 2.55 (m, 1H), 2.48 – 2.25 (m, 4H),
2.22 – 2.07 (m, 2H), 2.04 (s, 3H), 1.92 – 1.66 (m, 6H), 1.34 (s,
1H), 1.20 (s, 9H), 1.15 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.97 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.7, 171.2, 139.0,
136.2, 126.0, 125.3, 77.2, 77.0, 64.3, 63.8, 51.2, 48.7, 42.2, 38.8,
33.7, 33.2, 31.4, 29.3, 29.3, 27.4, 27.2, 21.5, 21.0, 20.7, 16.5;
HRMS (ESI+) m/z calcd for C27H40O6Na (M+Na)+: 483.2723,
found: 483.2720; IR (neat) ν 3496, 2956, 2925, 2870, 1722,
1361, 1280, 1233, 1158, 981, 890 cm-1.
ethyl acetate, UV, purple, p-anisaldehyde); H NMR (400 MHz,
9
CDCl3) δ 6.06 (s, 1H), 5.42 (s, 2H), 2.96 – 2.65 (m, 3H), 2.40 (d,
J = 15.8 Hz, 1H), 2.22 – 2.15 (m, 1H), 2.05 (s, 3H), 2.04 – 1.86
(m, 3H), 1.68 (s, 3H), 1.67 – 1.59 (m, 1H), 1.15 (s, 3H), 1.10 (s,
3H), 1.05 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 1H), 0.03 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 203.0, 172.4, 142.9, 136.4,
128.6, 119.1, 78.3, 73.7, 64.5, 53.0, 41.8, 40.6, 35.6, 31.7, 30.7,
28.6, 24.3, 23.6, 22.8, 21.2, 18.9, 15.6, 1.4; HRMS (ESI+) m/z
calcd for C25H38O5SiNa (M+Na)+: 469.2386, found: 469.2380; IR
(neat) ν 3431, 2956, 1728, 1642, 1375, 1250, 1106, 1085, 991,
842, 736 cm-1
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
Preparation of (1aR,1bS,4aR,7aS,7bR,8R,9aS)-3-formyl-
7b-hydroxy-1,1,8-trimethyl-6-methylene-5-oxo-4a-
((trimethylsilyl)oxy)-1,1a,1b,4,4a,5,6,7,7a,7b,8,9-
dodecahydro-9aH-cyclopropa[3,4]benzo[1,2-e]azulen-9a-
yl acetate (71). To a stirred solution of ketone SI-25 (7.2 mg,
0.016 mmol, 1.00 equiv) in benzene (6 mL) was added
selenium dioxide (8.9 mg, 0.08 mmol, 5.00 equiv). The yellow
solution was stirred at 80 °C (oil bath) for 30 min. Then the
mixture was concentrated to dryness and the crude product
was purified by flash chromatography (petroleum ether/ ethyl
acetate 5:1→2:1) to give aldehyde 71 (6.1 mg, 0.013 mmol,
81%) as a colorless foam. Rf 0.12 (silica gel, 5:1 petroleum
ether/ ethyl acetate, UV, purple, p-anisaldehyde); 1H NMR (400
MHz, CDCl3) δ 9.42 (s, 1H), 6.74 (dd, J = 6.5, 2.1 Hz, 1H), 6.08 (s,
1H), 5.43 (s, 1H), 3.58 (d, J = 17.1 Hz, 1H), 2.83 – 2.66 (m, 2H),
2.48 (t, J = 6.5 Hz, 1H), 2.36 – 2.16 (m, 2H), 2.09 (s, 3H), 1.95
(dd, J = 15.9, 7.9 Hz, 1H), 1.85 (dd, J = 12.0, 7.7 Hz, 1H), 1.69 (dd,
J = 15.9, 5.6 Hz, 1H), 1.20 (s, 3H), 1.17 (d, J = 7.2 Hz, 1H), 1.10
(s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.05 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 201.8, 192.1, 172.4, 157.9, 142.3, 141.8, 119.8,
77.8, 74.7, 63.9, 52.6, 42.6, 35.2, 31.5, 31.1, 30.5, 28.8, 23.8,
22.7, 21.3, 18.8, 15.5, 1.3; HRMS (ESI+) m/z calcd for
C25H36O6SiNa (M+Na)+: 483.2179, found: 483.2189; IR (neat) ν
3400, 2957, 2921, 2850, 1730, 1684, 1370, 1249, 1072, 976,
845 cm-1.
Preparation of 12-deoxyphorbaldehyde-13-acetate
(72). A flame-dried 10 mL vial was charged with 71 (12 mg,
0.026 mmol, 1.00 equiv) and RhCl33H2O (2.1 mg, 7.8 µmol,
0.30 equiv), EtOH (3 mL) at room temperature. The reaction
mixture was heated to 100 °C (oil bath) and stirred for 30 min.
After being cooled to room temperature, the reaction mixture
was filtrated through a short pad of Celite with CH2Cl2, the
mixture was concentrated to dryness and the crude product
was purified by preparative thin layer chromatography (2:1
CH2Cl2/ Et2O) to yield 12-deoxyphorbaldehyde-13-acetate 72
(5.3 mg, 0.014 mmol, 52%) as a colorless foam. Rf 0.42 (silica
Preparation
of
(1aR,1bS,4aR,7aS,7bR,8R,9aS)-7b-
hydroxy-1,1,3,8-tetramethyl-6-methylene-5-oxo-4a-
((trimethylsilyl)oxy)-1,1a,1b,4,4a,5,6,7,7a,7b,8,9-
1
gel, 2:1 CH2Cl2/ Et2O, UV, dark blue, p-anisaldehyde); H NMR
dodecahydro-9aH-cyclopropa[3,4]benzo[1,2-e]azulen-9a-
yl acetate (SI-25). To a stirred solution of 70 (22 mg, 0.046
mmol, 1.00 equiv), DMAP (5.6 mg, 0.046 mmol, 1.00 equiv) in
MeCN (10 mL) was added Cuprous chloride (1.4 mg, 0.014
mmol, 0.3 equiv), 2,2'-dipyridyl (2.2 mg, 0.014 mmol, 0.30
equiv), 2-azaadamantane-N-oxyl (1.4 mg, 9.2 µmol, 0.2 equiv)
at 0 °C. The dark solution was stirred at room temperature for
18 h under air. The resulting green mixture filtered through a
short pad of Florisil®, elution with CH2Cl2 (10 mL) and
(600 MHz, CDCl3) δ 9.43 (s, 1H), 7.55 (s, 1H), 6.71 (dd, J = 5.6,
1.8 Hz, 1H), 5.65 (s, 1H), 3.37 (t, J = 5.3 Hz, 1H), 3.08 (s, 1H),
2.88 (d, J = 19.5 Hz, 1H), 2.44 (d, J = 19.5 Hz, 1H), 2.15 – 2.07 (m,
1H), 2.07 (s, 3H), 2.06 – 1.99 (m, 1H), 1.78 (d, J = 1.4 Hz, 3H),
1.60 (dd, J = 14.7, 11.2 Hz, 1H), 1.24 (s, 3H), 1.08 (s, 3H), 1.02
(d, J = 5.3 Hz, 1H), 0.90 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 208.2, 193.7, 173.4, 160.4, 158.1, 142.8, 133.4,
76.7, 72.8, 63.2, 55.7, 41.4, 36.5, 34.5, 31.9, 31.6, 23.1, 22.9,
21.2, 18.5, 15.2, 10.1; HRMS (ESI+) m/z calcd for C22H28O6Na
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 29
(M+Na)+: 411.1784, found: 411.1778; IR (neat) ν 3396, 2927,
(FIST), Mr. G. Chang and Ms. A. Lu at the Instrument Analysis
2874, 1712, 1630, 1379, 1262, 1193, 1014, 911, 736 cm-1.
Preparation of prostratin (1). A flame-dried 10 mL vial
was charged with 72 (3.7 mg, 9.5 µmol, 1.00 equiv) and MeOH
(2 mL). The reaction flask was cooled to –50 °C, NaBH4 (0.4 mg,
10.5 µmol, 1.10 equiv) was added slowly. Upon complete
consumption of starting material (ca 15 min), the reaction
mixture was quenched by the addition of 100 µL H2O. Then the
mixture was concentrated to dryness and the crude product
was purified by preparative thin layer chromatography (1:1
CH2Cl2/ Et2O, twice) to yield prostratin 1 (3.2 mg, 8.2 µmol,
86%) as a colorless film. Rf 0.13 (silica gel, 1:1 CH2Cl2/ Et2O,
twice, UV, dark blue, p-anisaldehyde); 1H NMR (600 MHz,
CDCl3) δ 7.58 (s, 1H), 5.68 (d, J = 5.1 Hz, 1H), 5.38 (s, 1H), 4.03
(d, J = 12.8 Hz, 1H), 3.98 (d, J = 12.8 Hz, 1H), 3.26 (s, 1H), 2.99
(t, J = 5.1 Hz, 1H), 2.53 (d, J = 19.0 Hz, 1H), 2.48 (d, J = 19.0 Hz,
1H), 2.31 (s, 1H), 2.14 – 2.02 (m, 1H), 2.07 (m, 3H), 2.03 – 1.92
(m, 1H), 1.83 – 1.71 (m, 3H), 1.57 (dd, J = 14.7, 11.3 Hz, 1H),
1.19 (s, 3H), 1.06 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 5.3
Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 209.1, 173.2, 161.2,
139.9, 132.8, 130.2, 76.0, 73.7, 68.2, 63.6, 55.7, 39.1, 38.6, 36.2,
32.4, 31.7, 23.3, 22.7, 21.2, 18.5, 15.3, 10.1; 1H NMR (600 MHz,
C6D6) δ 7.48 (s, 1H), 5.69 (d, J = 5.3 Hz, 1H), 3.74 (d, J = 12.8 Hz,
1H), 3.69 (d, J = 12.8 Hz, 1H), 3.47 (s, 1H), 3.12 (t, J = 4.4 Hz, 1H),
2.46 (d, J = 19.0 Hz, 1H), 2.38 (d, J = 19.0 Hz, 1H), 2.11 – 2.07 (m,
1H), 2.02 (dd, J = 14.5, 6.9 Hz, 1H), 1.72 (dd, J = 14.5, 11.4 Hz,
1H), 1.60 – 1.59 (m, 3H), 1.55 (s, 3H), 1.10 (s, 3H), 1.01 (s, 3H),
0.98 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 5.3 Hz, 1H); 13C{1H} NMR
(150 MHz, C6D6) δ 208.7, 172.9, 160.9, 140.7, 133.1, 130.0, 76.3,
74.1, 68.2, 64.0, 56.4, 39.7, 39.0, 36.8, 33.1, 32.5, 23.5, 22.9,
20.8, 19.1, 15.6, 10.2; HRMS (ESI+) m/z calcd for C22H30O6Na
(M+Na)+: 413.1940, found: 413.1934; IR (neat) ν 3379, 2985,
2923, 2874, 1705, 1628, 1378, 1329, 1262, 1016, 911, 735 cm-
Center of XJTU for their assistance with 400-MHz, 600-MHz
NMR and high-resolution mass spectrometry analysis, Drs. Y.
Ding and W. Chen at FIST for X-ray diffraction analysis. P.L. is a
“Chung Ying Scholar” of Xi’an Jiaotong University.
1
2
3
4
5
6
7
8
REFERENCES
[1]
Liao, S.-G.; Chen, H.-D.; Yue, J.-M. Plant Orthoesters. Chem.
Rev. 2009, 109, 1092-1140.
[2]
Wang, H.-B.; Wang, X.-Y.; Liu, L.-P.; Qin, G.-W.; Kang, T.-G.
9
Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae
Families. Chem. Rev. 2015, 115, 2975-3011.
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]
a) Hergenhahn, M.; Adolf, W.; Hecker, E. Resiniferatoxin
and other esters of novel polyfunctional diterpenes from
Euphorbia resinifera and unispina. Tetrahedron Lett. 1975, 16,
1595-1598. b) Kissin, I.; Szallasi, A. Therapeutic Targeting of
TRPV1 by Resiniferatoxin, from Preclinical Studies to Clinical
Trials. Curr. Top. Med. Chem. 2011, 11, 2159-2170.
[4]
a) Cashmore, A. R.; Seelye, R. N.; Cain, B. F.; Mack, H.;
Schmidt, R.; Hecker, E. The structure of prostratin: a toxic
tetracyclic diterpene ester from Pimelea Prostrata. Tetrahedron
Lett. 1976, 17, 1737-1738. b) McCormick, I. R. N.; Nixon, P. E.;
Waters, T. N. Waters, On the structure of prostratin: An X-ray study.
Tetrahedron Lett. 1976, 17, 1735-1736.
[5]
Gustafson, K. R.; Cardellina, J. H.; McMahon, J. B.;
Gulakowski, R. J.; Ishitoya, J.; Szallasi, Z.; Lewin, N. E.; Blumberg, P.
M.; Weislow, O. S. A nonpromoting phorbol from the Samoan
medicinal plant Homalanthus nutans inhibits cell killing by HIV-1.
J. Med. Chem. 1992, 35, 1978-1986.
[6]
a) Kulkosky, J.; Culnan, D. M.; Roman, J.; Dornadula, G.;
Schnell, M.; Boyd, M. R.; Pomerantz, R. J. Prostratin: Activation of
latent HIV-1 expression suggests a potential inductive adjuvant
therapy for HAART. Blood 2001, 98, 3006-3015. b) Hezareh, M.;
Moukil, M. A.; Szanto, I.; Pondarzewski, M.; Mouche, S.; Cherix, N.;
Brown, S. J.; Carpentier, J. L.; Foti, M. Mechanisms of HIV receptor
and co-receptor down-regulation by prostratin: role of
conventional and novel PKC isoforms. Antivir. Chem. Chemother.
2004, 15, 207–222.
1
.
ASSOCIATED CONTENT
[7]
Gulakowski, J.; McMahon, J. B.; Buckheit, R. W.; Gustafson,
Supporting Information
K. R.; Boyd, M. R. A non-tumor-promoting phorbol ester, against
human immunodeficiency virus (HIV). Antivir. Res. 1997, 33, 87-97.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxx.
[8]
Wang, M.-T.; Holderfield, M.; Galeas, J.; Delrosario, R.; To,
List of SI-compounds
M. D.; Balmain, A.; McCormick, F. K-Ras Promotes Tumorigenicity
through Suppression of Non-canonical Wnt Signaling. Cell 2015,
163, 1237-1251.
Tables for optimization of key reactions
DFT calculation details
1H NMR and 13C NMR spectra for all new compounds (PDF)
[9]
Shen, X.; Xiong, G.-L.; Jing, Y.; Xiao, H.; Cui, Y.; Zhang, Y.-F.;
Shan, Y.-J.; Xing, S.; Yang, M.; Liu, X.-L.; Dong, B.; Wang, L.-S.; Luo, Q.-
L.; Yu, Z.-Y.; Cong, Y.-W. The protein kinase C agonist prostratin
induces differentiation of human myeloid leukemia cells and
enhances cellular differentiation by chemotherapeutic agents.
Cancer Lett. 2015, 356, 686-696.
[10] Alotaibi, S. A. D.; Johnson, T. L.; Tiriveedhi, V. Potential
anticancer effect of prostratin through SIK3 inhibition. Oncol. Lett.
2018, 15, 3252-3258.
[11] a) Wender, P. A.; Kee, J.-M.; Warrington, J. M. Practical
Synthesis of Prostratin, DPP, and Their Analogs, Adjuvant Leads
Against Latent HIV. Science 2008, 320, 649-652. b) Beans, E. J.;
Fournogerakis, D.; Gauntlett, C.; Heumann, L. V.; Kramer, R.;
Marsden, M. D.; Murray, D.; Chun, T.-W.; Zack, J. A.; Wender, P. A.
Highly potent, synthetically accessible prostratin analogs induce
latent HIV expression in vitro and ex vivo. Proc. Natl. Acad. Sci. USA
2013, 110, 11698-11703.
The X-ray crystallographic data of compds. 23, 27, 29, 41,
47, 52, 53, 57, 65, 68, 70, SI-9, SI-11, SI-21 (CIF)
AUTHOR INFORMATION
Corresponding Author
* lipengfei@xjtu.edu.cn; xuliang4423@shzu.edu.cn
Author Contributions
§These authors contributed equally.
Notes
A pending patent has been applied for by Xi’an Jiaotong
University on the synthetic route of prostratin.
[12]
For a full list of 47 references on synthetic studies of
ACKNOWLEDGMENT
Generous support by the National Natural Science Foundation
of China (Nos. 21971202, 21672168, 21963010 and
81673564), Key Laboratory Construction Program of Xi'an
tigliane and daphnane diterpenoids, please see the supporting
information.
[13] a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D.
Studies on tumor promoters. 7. The synthesis of a potentially
general precursor of the tiglianes, daphnanes, and ingenanes. J. Am.
Chem. Soc. 1989, 111, 8954-8957. b) Wender, P. A.; Kogen, H.; Lee,
H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D. Studies on tumor
Municipal
Bureau
of
Science
and
Technology
(201805056ZD7CG40) is acknowledged. The authors thank Ms.
C. Feng at the Frontier Institute of Science and Technology
ACS Paragon Plus Environment

Page 29 of 29
The Journal of Organic Chemistry
promoters. 8. The synthesis of phorbol. J. Am. Chem. Soc. 1989, 111,
amino alcohols into amino carbonyl compounds. Angew. Chem. Int.
Ed. 2014, 53, 3236-3240. b) Li, X.; Zhu, M.; Wang, Z.; Liu, X.; Song,
H.; Zhang, D.; Wang, F.; Qin, Y. Synthesis of atisine, ajaconine,
denudatine, and hetidine diterpenoid alkaloids by a bioinspired
approach. Angew. Chem. Int. Ed. 2016, 55, 15667-15671. c) Li, Y.;
Zhu, S.; Li, J.; Li, A. Asymmetric total syntheses of
aspidodasycarpine, lonicerine, and the proposed structure of
lanciferine. J. Am. Chem. Soc. 2016, 138, 3982-3985.
8957-8958. c) Wender, P. A.; McDonald, F. E. Studies on tumor
promoters. 9. A second-generation synthesis of phorbol. J. Am.
Chem. Soc. 1990, 112, 4956-4958. d) Wender, P. A.; Rice, K. D.;
Schnute, M. E. The First Formal Asymmetric Synthesis of Phorbol.
J. Am. Chem. Soc. 1997, 119, 7897-7898.
[14] Lee, K.; Cha, J. K. Formal Synthesis of (+)-Phorbol. J. Am.
Chem. Soc. 2001, 123, 5590-5591.
1
2
3
4
5
6
7
8
9
[15] For more [5+2] cycloaddition approach to build related
ring systems, also see: Liu, X.; Liu, J. Y.; Zhao, J.; Li, S.; Li, C.-C.
Toward the Total Synthesis of Eurifoloid A. Org. Lett. 2017, 19,
2742-2745.
[16] Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.;
Tebbe, A. L.; Ueno, Y. The First Synthesis of a Daphnane Diterpene:ꢀ
The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin. J. Am.
Chem. Soc. 1997, 119, 12976-12977.
[17] Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.;
Kan, C.; Kee, J.-M.; Kowalski, J. A.; Longcore, K. E. Gateway Synthesis
of Daphnane Congeners and Their PKC Affinities and Cell-Growth
Activities. Nat. Chem. 2011, 3, 615-619.
[18] Asaba, T.; Katoh, Y.; Urabe, D.; Inoue, M. Total Synthesis
of Crotophorbolone. Angew. Chem. Int. Ed. 2015, 54, 14457-14461.
[19] Hashimoto, S.; Katoh, S.-i.; Kato, T.; Urabe, D.; Inoue, M.
Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated
Three-Component Coupling and 7-endo Cyclization. J. Am. Chem.
Soc. 2017, 139, 16420-16429.
[27]
Tojo,
G.;
Fernandez, M. I.; A Guide to Current Common Practice. In Oxidatio
n of Alcohols to Aldehydes and Ketones; Springer US: 2006.
[28] a) Disanayaka, B. W.; Weedon, A. C. A convenient
synthesis of 2-methyl-2-cyclopenten-1-one. Synthesis 1983, 952. b)
Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff,
N.; Wood, J. L. Total synthesis of ingenol. J. Am. Chem. Soc. 2004,
126, 16300-16301. c) Zhang, P.; Yan, Z.; Li, Y.; Gong, J.; Yang, Z.
Enantioselective total synthesis of (-)-pavidolide B. J. Am. Chem. Soc.
2017, 139, 13989-13992. d) Bi, X.; Xu, W.; Yao, Y.; Zhou, L.; Liang,
G. Total syntheses of a family of cadinane sesquiterpenes. J. Org.
Chem. 2018, 83, 5825-5828.
[29] Maruoka, K.; Shimada, I.; Imoto, H.; Yamamoto, H.
Conjugate addition of reactive carbanions to α,β-unsaturated
ketones in the presence of ATPH. Synlett 1994, 519-520.
[30] Tang, Q.; Su, Z.; Han, Z.; Ma, X.; Xu, D.; Liang, Y.; Cao, H.;
Wang, X.; Qu, X.; Hoffman, A.; Liu, H.; Gu, D.; Qiu, D. LC-MS method
for detecting prostratin in plant extracts and identification of a
high-yielding population of Euphorbia fischeriana. Phytochemistry
Lett. 2012, 5, 214-218.
[31] Ma, Q. G.; Liu, W. Z.; Wu, X. Y.; Zhou, T. X.; Qin, G. W.
Diterpenoids from Euphorbia fischeriana. Phytochemistry, 1997,
44, 663-666.
[32] Wang, H. B.; Chu, W. J.; Wang, Y.; Ji, P.; Wang, Y. B.; Yu, Q.;
Qin, G. W. Diterpenoids from the roots of Euphorbia fischeriana. J.
Asian Nat. Prod. Res. 2010, 12, 1038-1043.
[33] a) Tanemura, K.; Suzuki, T.; Horaguchi, T. 2,3-Dichloro-
5,6 dicyano-pbenzoquinone as a mild and efficient catalyst for the
deprotection of acetals. J. Chem. Soc., Chem. Commun. 1992, 14,
979−980. b) Fernández, J. G.; Mellet, C. O.; Marín, A. M.; Fuentes, J.
A mild and efficient procedure to remove acetal and dithioacetal
protecting groups in carbohydrate derivatives using 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone. Carbohydrate Res. 1995, 274, 263-
268.
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
[20] Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nineteen-
step total synthesis of (+)-phorbol. Nature 2016, 532, 90.
[21]
a) Tong, G.; Liu, Z.; Li, P. Stereocontrolled Construction
of the Tricyclic Framework of Tiglianes and Daphnanes by an
Oxidative Dearomatization Approach. Org. Lett. 2014, 16, 2288-
2291. b) Tong, G.; Liu, Z.; Li, P. Total synthesis of (±)-prostratin.
Chem 2018, 4, 2944-2954.
[22] a) Roche, S. P.; Porco, J. A. Dearomatization Strategies in
the Synthesis of Complex Natural Products, Angew. Chem. Int. Ed.
2011, 50, 4068-4093. b) Magdziak, D.; Meek, S. J.; Pettus, T. R. R.
Cyclohexadienone Ketals and Quinols: Four Building Blocks
Potentially Useful for Enantioselective Synthesis, Chem. Rev. 2004,
104, 1383-1429.
[23] a) Ireland, R. E.; Walba, D. M. Demethylation of Methyl
Aryl Ethers: 4-Ethoxy-3-hydroxybenzaldehyde. Org. Synth. 1977,
56, 44-48. b) Wipf, P.; Jung, J. K. Formal Total Synthesis of (+)-
Diepoxin σ. J. Org. Chem. 2000, 65, 6319-6337.
[24] a) Matsuura, T.; Omura, K.; Nakashima, R. Photo-induced
reaction. II. Photo-sensitized oxidation of hindered phenols. Bull.
Chem. Soc. Jpn. 1965, 38, 1358-1362. b) Wasserman, H. H.; Ives, J.
L. Singlet oxygen in organic synthesis. Tetrahedron 1981, 37, 1825-
1852. c) Prein, M.; Maurer, M.; Peters, E. M.; Peters, K.; Schnering,
H. G.; Adam, W. Diastereoselective synthesis of 4-hydroxyperoxy-
3,5-cyclohexadienones in the photooxygenation of hydroxyethyl-
substituted phenols. Chem-Eur. J. 1995, 1, 89-94. d) Jones, K. M.;
Hillringhaus, T.; Klussmann, M. A singlet oxygen approach to
oxaspirocycles. Tetrahedron Lett. 2013, 54, 3294-3297. e) Wang,
H.; Wang, L.; Li, Y.; Zhang, X.; Tang, P. Collective Synthesis of
Schilancidilactones A, B and Schilancitrilactones A, B, C, 20-epi-
Schilancitrilactone A. Chinese J. Chem. 2019, 37, 255-268. f) Yi, J.-C.;
Wu, Z.-J.; You, S.-L. Copper-Catalyzed Oxidative Dearomatization of
2-Naphthols via Etherification. Chinese J. Chem. 2019, 37, 903-908.
[25] a) Solomon, M.; Jamison, W. C. L.; McCormick, M.; Liotta,
D. Ligand-assisted nucleophilic additions. Control of site and face
attack of nucleophiles on 4-oxido enones. J. Am. Chem. Soc. 1988,
110, 3702-3704. b) Brocksom, T. J.; Coelho, F.; Depres, J.-P.; Greene,
A. E.; Lima, M. E. F.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.;
Wang, Y. First Comprehensive Bakkane Approach: Stereoselective
and Efficient Dichloroketene-Based Total Syntheses of (±)- and (-)
-9-Acetoxyfukinanolide, (±)-and (+)-Bakkenolide A, (-)-
Bakkenolides III, B, C, H, L, V, and X, (±)- and (-)-Homogynolide A,
(±)-Homogynolide B, and (±)-Palmosalide C. J. Am. Chem. Soc. 2002,
124, 15313-15325.
[34] Wang, Y.; Huang, R.; Wang, H.; Jin, Z.; Lou, L.; Qin, G.
Diterpenoids from the Roots of Euphorbia fischeriana. J. Nat. Prod.
2006, 69, 967-970.
[35] For details of computational software, methods and
results, and the corresponding references, see supporting
information.
[36] An, G.-i.; Rhee, H. A facile synthesis of cis-4-amino-2-
cyclopentene-1-methanol, a key intermediate for the synthesis of
carbocyclic nucleosides. Nucleosides Nucleotides Nucleic Acids,
2002, 21, 65–72.
[26] a) Sasano, Y.; Nagasawa, S.; Yamazaki, M.; Shibuya, M.;
Park, J.; Iwabuchi, Y. Highly chemoselective aerobic oxidation of
ACS Paragon Plus Environment