Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2

Article abstract of DOI:10.1021/acs.joc.8b03138

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B₂ are presented. We established a mild Suzuki coupling for heavily substituted n

Full text of DOI:10.1021/acs.joc.8b03138

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Article
Synthetic Studies on Enantioselective Total Synthesis of Cyathane
Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2
Guo-Jie Wu, Yuan-He Zhang, Dong-Xing Tan, Long He, Bao-Chen Cao, Yu-peng He, and Fu-She Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03138 • Publication Date (Web): 22 Feb 2019
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Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids:
Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2
a,#
a,b,#
a,b
c
c
c
Guo-Jie Wu, Yuan-He Zhang,
Dong-Xing Tan, Long He, Bao-Chen Cao, Yu-Peng He
a,b
and Fu-She Han*
a
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CAS Key Lab of High-Performance Synthetic Rubber and its Composite Materials, Changchun
Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun,
Jilin 130022, China
b
University of Science and Technology of China, Hefei, Anhui, 230026, China
c
Department of Chemical Engineering and Environment, Liaoning Shihua University, Fushun,
Liaoning 113001, China
Table of Content
Abstract: The details for the synthetic studies on enantioselective total synthesis of cyathane
diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B are presented. We
2
established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates
using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly
regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid
construction of the 5-6-6-tricyclic skeleton. In the middle-stage of the synthesis, a Birch reductive
methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring
expansion were employed as the key reactions to furnish the 5-6-7-tricyclic core bearing two
anti-orientated all-carbon quaternary stereocenters at the C
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and C
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ring junctions. By applying
, and
these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B
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the first total synthesis of cyrneine B and glaucopine C were accomplished through a collective
manner. The late-stage conversions involving a base-mediated double bond migration and a
double bond migration/aerobic -CH oxidation cascade for the stereoselective synthesis of
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cyrneine B and glaucopine C were interesting.
INTRODUCTION
Since the first isolation and structural elucidation of cyathane diterpene natural products by
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Ayer and co-workers in 1972, a rich variety of cyathane diterpenoids of more than 100 members
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1,3
4
have been isolated and categorized different subclasses, such as cyathins, erinacines,
1d,e,5
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7
7c,8
9
10
sarcodonins,
scabronine, glaucopines, cyrneines,
cyanthiwigins, and striatoids, et al.
With only a few exceptions, the majority of cyathane natural products possesses a common 5-6-7
tricyclic carbon core and bears two anti-orientated all-carbon quaternary stereogenic centers at the
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C and C ring junctions. The unique 5-6-7 tricyclic skeleton coupled with the existence of
different degree of oxidation states and various unsaturated double bonds around the ring
periphery gives rise to the structural complexity and diversity of cyathane diterpenoids. In addition
to the intriguing structural features, it is also attractive that almost all of the cyathane diterpenoids
exhibit a wide variety of mild to moderate biological properties such as antibiotics, antimicrobial,
antitumor, antitumor, and anti-inflammatory activities. Most interestingly, some of the molecules
3
g,h
display strong activity for anti-neuroinflammatory
or for stimulating the synthesis of Nerve
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a,c,6b,7c,8a,10
Growth Factor (NGF).
The unique and complex structural feature as well as the wide
biological properties of cyathane natural products has attracted the great interests of synthetic
organic community. Over the past 20 years, numerous syntheses have been reported such as the
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leading contributions from the groups of Nakada, Ward, Trost, Danishefsky, Stoltz,
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Phillips, Reddy, Snider, Cha, and others.
While immense achievements have been accomplished in the synthesis of cyathane
diterpenoids, the development of new methods and synthetic strategies toward more practical
synthesis is still interesting. On the other hand, despite of the great advances, there remains a large
3
g
7
7c,8
number of molecules belonging to the subclasses of neocyathins, glaucopines, cyrneines, and
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striatoids, continue to challenge the synthetic chemists. As shown by some representative
structures in Fig. 1A (1−6), the key structural features of these subfamilies that unique to others
1 4
are the presence of extra oxidation at C to C carbons in the five-membered ring periphery. The
increased oxidation states associated with the generation of additional stereocenters increase the
structural complexity of the molecules. As a result, such intricate polycyclic architecture provides
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a good proving ground for the development of new synthetic methods and strategies. In a 2012
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report, Gademann and co-workers furnished an elegant total synthesis of cyrneine A (1) through
a sequence of 24 steps from (-)-(R)-carvone (Fig. 1B) by employing a reductive Knoevenagel
condensation, a Heck cyclization, and a Yamamoto ring expansion as the key transformations. To
our knowledge, this represents the only molecule that has been synthesized among the compounds
of aforementioned subclasses.
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Fig. 1. A) Representative structures of cyrneines (1 and 2), glaucopines (3), neocyathins (4−6), and (+)-allocyathin
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B (7), and B) the key transformations in Gademann’s synthesis of cyrneine A (1)
In addition to the intriguing structures, many molecules within these subclasses exhibit
appealing biological properties. Notably, a number of molecules within the neocyathins, cyrneines,
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g,h
and striatoids possess significant anti-inflammatory activities,
and pronounced neurite
Therefore, it is anticipated that these bioactive compounds
might be used as leading molecules for the development of new agents against Alzheimer disease
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outgrowth-promoting activities.
(
AD) and related neurodegenerative disorder. Driven by the complex structures, the potential
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biological properties, and an in-depth SAR elucidations, we initiated an investigation toward
establishing a strategically new route that is capable of flexibly synthesizing the natural products
as well as potential analogues with structural diversity.
Very recently, we successfully developed a route that could be used for a collective total
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synthesis of cyrneines A (1) and B (2), and glaucopine C (3). As illustrated in Fig. 2, the pivotal
transformations involved in our synthetic route were: (i) an enzyme-catalyzed desymmetric
enantioselective reduction of the readily available diketone 8 for preparing the chiral starting
material 9 in excellent enantioselectivity (99% ee) and diastereoselectivity (ca. 25:1); (ii) a highly
efficient Suzuki-Miyaura cross-coupling of the heavily substituted nonactivated enol triflate 10
catalysed by a phosphinamide-derived palladacyclic catalyst to synthesize the congested
cyclopentene 11; (iii) a chelation-controlled intramolecular cyclization for highly regioselective
construction of 5-6-6 tricyclic carbon scaffold 12; (iv) a Birch reductive methylation for
stereoselective installation of
6
C quaternary carbon of 13; (v) a one-pot Zn carbenoid-mediated
ring expansion for construction the 5-6-7 tricyclic core 14; (vi) a stereoselective reduction of the
carbonyl group at C14 for the synthesis of advanced intermediate 15; (vii) a base-promoted double
bond migration, and (viii) a stereo- and chemoselective double bond migrration/-CH oxidation
cascade. By adopting these key transformations, three polyoxygenated diterpenoids 1−3 were
achieved from 15 through a divergent manner.
On the journey of our synthetic study, we also designed and investigated several other
strategies in addition to the successful one. Although these efforts failed to access our targeted
molecules, some chemistries established in the study would be interesting for practical
applications or, at least, would find important appeal within a wider synthetic community. In
addition, to further exemplify the generality and high efficiency of our synthetic route, we recently
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carried out a synthetic study of (+)-allocyathin B (7) which has been previously synthesized by
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Trost, and Nakada. The details of these results will be presented herein.
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Fig. 2. Key transformations for the synthesis of cyrneines A and B (1 and 2), and glaucopine C (3) developed by
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our group.
RESULTS AND DISCUSSION
Starting from the commercially readily available 2-methyl 1,3-cyclopentanedione 17
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(
Scheme 1), alkylation of 17 with allyl bromide gave the 2,2-disubstituted cyclopentanedione 18.
Desymmetric enantioselective reduction of 18 was firstly carried out by using CBS reduction
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according to the reported literatures. While good enantioselectivity of higher than 90% ee was
observed, the diastereoselectivity was modest (d.r. = ca. 5−6:1). In addition, although the CBS
26a
catalyst derived from L-threonine by Shimizu could afford directly the 3--hydroxy ketone 20
with desired chirality, a stoichiometric amount of catalyst has to be used to gain good
enantioselectivity. As a result, the issues raised from the modest diastereoselectivity and the use of
large amount catalyst made the CBS reduction problematic for large scale preparation of 20.
2
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Alternatively, we examined the baker’s yeast-catalyzed reduction. To compare with CBS
reduction, the enzyme-catalyzed reduction afforded 3--hydroxy ketone 19 with excellent
enantioselectivity of up to 99% ee and a slightly increased diastereoselectivity of up to ca. 7.7:1.
Another added advantage is that the reaction could be more easily performed on multigram scales
albeit the yield was still not sufficiently high (ca. 40% yield over two steps from 17). This was
mainly resulted from the somewhat tedious purification process to remove the diastereoisomers of
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9 by column chromatography for getting pure 19. By employing Mitsunobu conditions, the
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--hydroxy group in 19 was inverted to give the desired 3--hydroxy ketone 20 in 51% yield
over two steps without a careful optimization of the reaction conditions. Transformation of 20 to
enol triflate 22 was carried out smoothly following a three-step procedure involving silylation,
isopropylation, and enolation.
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Scheme 1. Synthesis of enol triflate 22. Reagents and conditions: (a) allyl bromide (2.0 equiv), TBAI (1 mol%), 2
o
N NaOH, H
2
O, 50 C, 8 h. (b) yeast extract (50 wt%), D-glucose (1756 wt%), dry active baker’s yeast (1181 wt%),
o
H O, 35 C, 48 h (40% for 2 steps). (c) p-NO -C H CO H (2.0 equiv), PPh (2.0 equiv), DEAD (2.0 equiv), THF,
2
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2
3
o
o
0
to 50 C, overnight. (d) K CO (2.0 equiv), MeOH/THF (v/v = 1:2), 0 C, 30 min (51% for 2 steps). (e) TBSCl
2 3
(
1.2 equiv), imidazole (1.2 equiv), DMF, rt, overnight (88%). (f) NaH (5.0 equiv), iPrI (10.0 equiv), THF, reflux,
o
overnight; then aq. HCl (2 M), rt, 1.5 h. (g) LiHMDS (1.3 equiv, 1.0 M in THF), PhNTf (1.3 equiv), THF, -78 C
2
to rt, 3 h (56% for 2 steps). TBAI = tetra-n-butylammonium iodide; DEAD = diethyl azodicarboxylate; TBSCl =
t-butyldimethylsilyl chloride; LiHMDS = lithium hexamethyldisilazide; THF = tetrahydrofuran; DMF =
N,N-dimethylformamide.
The Suzuki-Miyaura cross-coupling reaction of the densely substituted enol triflate 22 with
boronic acid 23 was initially carried out by referring to some reported methods relevant to
2
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sterically hindered substrates. Representative data for optimization of reaction conditions were
shown in Table 1. Among an array of conditions being examined, Pd(PPh (entry 2) and the
combination of Pd(OAc) with dppb (entry 7) gave the coupled product 24 in moderately high
3 4
)
2
yields. However, these conditions were problematic for large scale synthesis due to partial
hydrolysis of triflate 22 arising from an elongated reaction time. We then inspected the catalytic
30
efficiency of a palladacycle 26 derived from diaryl phosphinamide in our previous study which
30c
displayed high activity for Suzuki-Miyaura coupling of aryl (pseudo)halides. Delightedly, after
a brief screening of conditions, we found that this catalyst was highly active for the sterically
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hindered enol triflate 22. Rapid and complete conversion was observed at room temperature to
give the product 24 in almost quantitative yield using K
showed that the product was contaminated by a small amount of inseparable by-product.
further optimization revealed that K PO was also a suitable base, the side reaction could be
2 3
CO as base (entry 8). NMR analysis
A
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partially suppressed although the yield was somewhat decreased (entry 9). Disappointedly, when
the reaction was performed on large scale, the quantity of the by-product was apparently increased
2 3 3 4
with the presence of either K CO or K PO base.
a
Table 1 Suzuki-Miyaura Cross-Coupling of Enol Triflate 22.
Entry Catalyst
(5 mol%)
Base
Solvent
T
T
Yield of 24
o
b
( C)
85
85
85
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85
85
85
(h)
10
4
(%)
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PdCl
2
(dppf)
K
K
2
CO
CO
3
3
3
3
3
3
3
3
DMSO
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
22
66
trace
44
trace
48
Pd(PPh
3
)
4
2
PdCl /dppe
K CO
10
10
10
10
10
2
2
PdCl /dppb
2
K CO
2
Pd(OAc) /dppe K CO
2
2
Pd(OAc) /dppp K CO
2
2
Pd(OAc) /dppb K CO
67
2
2
c
26
26
2
K CO
DMF/EtOH rt
v/v = 1:1)
2.5 98
(
9
3
K PO
DMF/EtOH rt
(v/v = 1:1)
2.5 82
4
a
Reaction conditions: 22 (0.1 mmol), 23 (0.2 mmol), catalyst (5 mol%), and base (3.0 equiv) in 1 mL solvent
b
c
under nitrogen atmosphere. Isolated yield. Containing a small amount of inseparable by-product 25.
To clarify the details of the by-product, the mixture of the cross-coupled products was
methylated to give a pair of separable compounds whose structures were determined to be 27 and
2
2
8, respectively. Thus, the by-product formed during the cross-coupling reaction was assigned as
5 resulting from the migration of double bond. While the detailed reasons for the migration await
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further investigation, based on the results of various control experiments, it seemed that the
migration reaction was mainly influenced by the electronic nature and position of the substituents
in boronic acids. For instance, when para-methoxylphenyl boronic acid instead of
meta-methoxyphenyl or meta-hydroxyphenyl boronic acids was coupled with 22, only negligible
amount of migrated by-product was detected. In addition, the migration was also affected by other
parameters such as base, reaction time, and solvent. Thus, although extensive efforts aiming at
improving the efficiency of the coupling reaction were attempted, we were unable to establish a
set of reliable conditions to perform the reaction on large scales at current stage.
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Scheme 2. Synthesis of intermediate 32. (a) prenyl bromide (2.0 equiv), K CO (1.5 equiv), acetone, rt,
2
overnight (75%). (b) yeast extract (50 wt%), D-glucose (1500 wt%), dry active baker’s yeast (1333 wt%), H O, rt,
o
3
6 h (67%). (c) p-NO -C H CO H (2.0 equiv), PPh (2.0 equiv), DEAD (2.0 equiv), THF, 0 to 50 C, overnight
2
6
4
2
3
o
(90%). (d) K CO (2.0 equiv), MeOH/THF (v/v = 1:2), 0 C, 30 min (98%). (e) TBSCl (1.2 equiv), imidazole (1.2
2
3
equiv), DMF, rt, overnight (91%). (f) NaH (5.0 equiv), iPrI (10.0 equiv), THF, reflux, overnight; then aq. HCl (2
o
M), rt, 1.5 h (88%). (g) LiHMDS (1.3 equiv, 1.0 M in THF), PhNTf (1.3 equiv), THF, -78 C to rt, 3 h (80%). (h)
2
Boronic acid 23 (2.0 equiv), cat. 26 (5 mol%), K
2
CO
3
(3.0 equiv), DMF/EtOH (v/v = 1:1), rt (93–98%). (i) OsO
4
o
(
4 mol%), NaIO
4
(5.0 equiv), pyridine (3.0 equiv), dioxane/H
2
O (v/v = 5:1), 80 C (80%).
Owing to the relatively low efficiency for large scale synthesis of 19 resulting from the
modest diastereoselectivity for desymmetric reduction of 18 and the problematic Suzuki-Miyaura
cross-coupling of 22, we had to renew our synthetic route. Accordingly, 1,3-cyclopentanedione 29
bearing a bulkier prenyl group was prepared (Scheme 2). We assumed that by replacing the allyl
group in 18 with a sterically more hindered prenyl group, the diastereoselectivity of desymmetric
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reduction might be improved and the migration might be suppressed. As expected, the
enzyme-catalyzed desymmetrization of 29 afforded the 3--hydroxy ketone 9 with up to 99% ee
and ca. 25:1 diastereoselectivity. Subsequently, 9 was smoothly converted into the enol triflate 10
in five steps by implementing the similar procedure for the synthesis of 22. More importantly, the
coupling reaction of 10 with boronic acid 23 catalyzed by the palladacycle 26 proceeded
uneventfully to give the desired product 11 in excellent yield on decagram level without the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
observation of any migrated by-product. Notably, as shown in our previous report, the
palladacycle 26 exhibited a broad compatibility to a rich range of heavily substituted enol triflates.
Oxidative cleavage of the trisubstituted alkene in 11 proceeded selectively to afforded the
aldehyde 32. Since all the transformations from 17 to 32 could be reliably performed on
multigram scales, the modified route provided a practical way for supplying sufficient
intermediate 32 for late-stage synthetic study.
Scheme 3. Unsuccessful Friedel-Crafts cyclization mediated by acids: A) the results using our substrates; and B)
the reported results in literature (ref 29b and 31)
For the Friedel-Crafts cyclization of 32, we first examined the acid-mediated reactions
(
3 2
Scheme 3A). Among an array of Lewis and Brønsted acids being screened, BF ·Et O could
promote the cyclization of 32. However, the desired product was not obtained due to the poor
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
regioselectivity of ortho vs. para to phenolic OH and the subsequent dehydration of the central
six-membered ring. As a result, a ca. 1:2.5 mixture of dehydrated regioisomers 34 and 35 was
afforded in ca. 83% yield. Under the same conditions, the methyl protected substrate 33 gave the
dehydrated product 36 with exclusive para selectivity in 76% yield. In fact, similar results
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
concerning the acid-mediated cyclization have been reported in prior literature in the synthesis of
29b
hamigeran B (Scheme 3B). For instances, Trost and co-workers
demonstrated that in the
presence of various acids, the cyclization of the nitrile compound 37 was ineffective; alternatively,
the acyl chloride 38 afforded only the tetracyclic by-product 39 with para selectivity to MeO
31
group. Recently, Jiang and co-workers showed that with the presence of BF
3
·Et
2
O, the
cyclization of aldehyde 40 could proceed to produce the dehydrated products. However, a poor
regioselectivity of 41:42 = ca. 3:2 was observed.
The unsuccessful efforts on acid-promoted cyclization encouraged us to redesign and develop
an alternative strategy. After extensive exploration, we established a chelation-controlled protocol
that could achieve the cyclization reaction in high regioselectivity at the position ortho to phenolic
OH. As illustrated in Scheme 4, treatment of 32 with EtMgBr generated a magnesium phenolate.
The Mg(II) salt thus generated may serve as a weak Lewis acid which may coordinate with the
32
aldehyde functionality, forming a closed transition state 43. Due to the fixed transition state, the
followed Friedel-Crafts reaction proceeds exclusively at the ortho position to phenolic OH, and
ultimately delivering the cyclized magnesium salt 44. As a result, a couple of C
7
epimers 45 and
4
6 with ca. 1:3 ratio were formed. The major isomer 46 could be isolated in 48% yield. For the
introduction of C
6
methyl group, we initially examined a ring-opening/methylation cascade of
33
34
epoxide. Accordingly, oxidative cyclization of 46 afforded the epoxide 47 in 47% yield.
Unfortunately, attempted ring-opening/methylation toward synthesizing 50 by means of capturing
-
the possible species 48 with an appropriate Me source was proved to be futile. A complex mixture
was obtained under various conditions.
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TBSO
Me
TBSO
Me
Me
Me
Me
Me
TBSO
Me
O
Me
Me
O
Mg(II)
O
O
Mg(II)
a
OH
O
3
2
43
chelation-control)
44
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TBSO
Me
TBSO
Me
TBSO
Me
Me
Me
7
OH
OH
OH
OH
O
b
O
6
+
47%
Me
Me
Me
Me
4
7
46
45
4
(
8% yield for 46
45:46 = ca. 1:3)
Lewis acid;
-
[
Me ] source
TBSO
Me
Me
Me
TBSO
Me
TBSO
Me
Me
OLA
O
OLA
OH
Me
O
Me
O
Me
Me
Me
50
4
8
49
Scheme 4. Successful cyclization and attempted introduction of
C
6
methyl group through the
o
ring-opening/methylation cascade of epoxide. (a) EtMgBr (1.1 eqiuv, 1.0 M in THF), -78 to 40 C, overnight (64%
o
total). (b) NaIO (2.0 equiv), MeCN/H O (v/v =3:1), 0 C to rt, 2 h (47%).
4
2
We then inspected the Birch reductive alkylation although a literature survey showed that
such transformation has been rarely investigated in a fused-ring system presumably due to the
concerns of annular strain, steric hindrance, and stereoselectivity. Accordingly, treatment of 32
with EtMgBr followed by in situ selective methylation of the phenolic OH furnished the
construction of the tricyclic compound 51 in 64−72% yield (Scheme 5). PCC oxidation of the
alcohol in 51 gave ketone 12. After an exhaustive optimization of reaction conditions, we could
22
successfully introduce the C
6
angular methyl by means of Birch reductive methylation, affording
1
3 with exclusive -stereoselectivity in 72−75% yield without the detection of epi-13. The
stereochemistry was determined by NOESY spectroscopic analysis and was further demonstrated
by the single X-ray crystallographic analysis of cyrneine A (1) after completion of its total
synthesis (See Scheme 6). The exclusively high stereoselectivity is presumably due to the sterical
9
repulsion between the C methyl and MeI electrophile. As a result, the nucleophilic attack of
carbon anion form the si-face via TS-1 rather than the re-face via TS-2 is preferred. Notably, these
transformations could be reliably implemented on gram scale. Deoxygenation of carbonyl in the
central ring of 13 was carried out by employing the Wolff-Kishner-Huang reaction. Our extensive
experiments showed that the use of semicarbazide 52 to form a semicarbazone and the use of
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
KOtAm in degassed xylene for the following reduction of semicarbazone was crucial. Under the
optimized conditions, the desired 54 was obtained in ca. 36% yield accompanied by the formation
of a small amount of desilylated 53, which could be resilylated to give 54. Consequently, 54 was
afforded in ca. 53% total yield. Next, our attention was shifted to the construction of the
seven-membered ring. Thus, 54 was converted into dienone 55 by means of selective bromination
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
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0
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3
4
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7
8
9
0
35
of electron-riched double bond of enol ether with NBS followed by base-mediated elimination.
Attempted cyclopropanation of 55 with bromoform aimed at synthesizing the
dibromocyclopropane 56 was carried out under various conditions according to the reported
29e,36
literature.
However, the desired cyclopropanation did not proceed. The reaction was
terminated at the 1,4-addition stage to give the Michael addition product 57 as the sole product.
The structure of 57 was deduced from the structural proof of compound 58 since the structure of
5
7 cannot be definitely assigned by NMR and MS analyses due to the complexity of the product
raising from the formation of a pair of epimeric 57 and the easy of debromination.
Scheme 5. Successful introduction of C
6
methyl group by Birch reductive methylation and attempted ring
o
expansion reaction. (a) EtMgBr (1.1 eqiuv, 1.0 M in THF), -78 to 40 C, overnight, then K
2
CO
3
(2.0 equiv), MeI
o
(
5.0 equiv), and DMF were charged in situ, 55 C, 10 h (64–72%). (b) PCC (4.0 equiv), NaOAc (4.0 equiv), celite
o
(ca. 130 wt%), rt, 6 h (82%). (c) Liq. NH , tBuOH (1.0 equiv), K (2.5 equiv), Et O, -78 C, 10 min; then LiBr (2.5
3
2
o
equiv), MeI (5.0 equiv), and THF were charged in situ, -78 C, 1 h, then warmed to rt over a period of 1 h (72%).
o
o
(
d) 52 (5.0 equiv), NaOAc (5.0 equiv), EtOH, 35 C, 3 h. (e) KOtAm (5.0 equiv), degassed xylene, 140 C, 1.8 h
(36% for 54; 18% for 53). (f) TBSCl (1.2 equiv), imidazole (1.2 equiv), DMF, rt, overnight (93%). (g) NBS (1.1
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o
o
equiv), H
2
O (2.0 equiv), THF, 0 C to rt, 15 min; then DBU (2.0 equiv), 45 C, 3.5 h (67%). (h) LiHMDS (1.0 M
o
in THF, 1.5 equiv), CHBr ((5.0 equiv), Et2O, -78 C, 2 h (68%). (i) DBU (2.0 equiv), THF, rt, 15 min (84%). PCC
3
=
pyridinium chlorochromate; tAm
=
tert-amyl; NBS
=
N-bromosuccinimide; DBU
=
1
,8-diazabicyclo[5.4.0]undec-7-ene.
We then tried the Zn carbenoid-mediated ring expansion based on a protocol reported by
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37
Zercher (Scheme 6). Accordingly, Wolff-Kishner-Huang reduction of 13 afforded a mixture of
5
3 and 54. Without purification, the mixture was hydrolysed under acid conditions to give a
mixture of ketone 59 and 60. The mixture was subjected to resilylation to convert 59 into 60. As a
result, 60 could be efficiently synthesized in 62% overall yield through a four-step sequence from
1
3. The -acylation of 60 afforded a mixture of 61 and its enol tautomer, which was smoothly
transformed to the 5-6-7-tricyclic compound 14 by a one-pot Zn carbenoid-mediated ring
expansion following a iodination and DBU-promoted elimination. Finally, removal of TBS with
2
4
TMSOTf, reduction of ketone and ester groups with LiAlH
4
,
and selective oxidation of the
allylic primary alcohol to aldehyde with MnO accomplished the total synthesis of cyrneine A (1)
2
in 20 linear steps from commercially available 2-methyl 1,3-cyclopentanedione 17. The structure
1
of 1 was unambiguously confirmed by a combination of multiple analyses including H- and
1
3
38
C-NMR, HRMS, specific rotation, and single crystal X-ray diffraction (CCDC 1830226).
Scheme 6. Successful construction of the seven-membered ring and the completion of the synthesis of cyrneine A.
o
(
(
a) 5% aq. HCl, THF, 15 to 20 C, 40 min (89%). (b) TBSCl (1.2 equiv), imidazole (1.2 equiv), DMF, rt, overnight
o
62%, 4 steps from 13). (c) LiHMDS (1.0 M in THF, 3.5 equiv), CNCO
2
Me (3.0 equiv), THF, -78 C, 1 h. (d)
ZnEt
2
(1.0 M in hexane, 6.0 equiv), CH (6.0 equiv), CH Cl , rt, 2 h; then I
2
I
2
2
2
2
(7.0 equiv), rt; then saturated aq.
o
Na S O (excess), rt; then DBU (20.0 equiv), rt, 10 min (73% for 2 steps). (e) TMSOTf (5.0 equiv), CH Cl , -25 C,
2
2
3
2
2
o
1
5 min. (f) LiAlH (6.0 equiv), Et O, 10 min at -78 C, then warmed to rt. (g) MnO (50 equiv), CH Cl , rt,
4 2 2 2 2
overnight (58%, 3 steps from 14). TMSOTf = trimethylsilyl trifluoromethanesulfonate.
Having successfully accomplished the synthesis of cyrneine A (1), we then moved forward to
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2
2
2
2
2
2
2
3
3
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3
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3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the total synthesis of cyrneine B (2) and glaucopine C (3). To the end, compound 14 was
converted into diacetate 62 through reduction and acylation (Scheme 7A). Subsequently, removal
of TBS in 62 followed by Dess-Martin oxidation of the hydroxyl group gave ketone 16. To
establish a method for regio- and stereoselective introduction of C -H by means of double bond
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
migration, we investigated the reaction conditions using the more readily available racemic 67 as
the model compound which could be derived from 65 within three steps (Scheme 7B). It was
found that the double bond migration of 67 could proceed smoothly in the presence of an array of
bases under heating to give the thermodynamically preferred 68 with exclusive cis-selectivity.
Typically, the isomerization proceeded cleanly to give 68 in 85% yield under the effect of DBU in
refluxed benzene. The relative stereochemistry of 68 was confirmed by NOESY correlation.
Si-face
TBSO Me
O Me
A)
Me
Me
Me
Me
H
OR
O
OR
O
OAc
OAc
a, b
c, d
e
1
4
vs
52%
73%
Me
Me
H
Me
(4 steps) Me
Me
Me
Re-face
Me
62
Me
16
RO
RO
Me
Me
AcO
AcO
TS-3 (R = Ac or Na)
TS-4 (R = Ac or Na)
(favored)
(disfavored)
O Me
O Me
O Me
O Me
Me
Me
Me
OH
Me
OH
OAc
OH
f
H
82%
H
H
Me
Me
Me
Me
Me
Me
Me
64
Me
CHO
OH
OH
6
3
Glaucopine C (3)
epi-64
(not observed)
B)
TBSO
Me
HO
O
O
Me
Me
Me
Me
Me
cis
O
O
g
h, i
76%
(2 steps) Me
j
OMe
OMe
OMe
OMe
9
1%
85%
H
Me
Me
Me
Me
66
Me
65
67
68
o
4 2
Scheme 7. The completion of the synthesis of glaucopine C. (a) LiAlH (6.0 equiv), Et O, 20 min at -78 C, then
warmed to rt. (b) Ac
2
O (15.0 equiv), DMAP (20 mol%), pyridine, 30 min, rt. (c) HF•Py (excess), THF, rt, 2 h. (d)
o
DMP (1.6 equiv), CH Cl , 30 min, rt (52% for 4 steps). (e) NaOMe, MeOH, 35 C, 4 h (73%). (f) MnO (15 equiv),
2
2
2
o
CH Cl , rt, 3 h (82%). (g) TMSOTf (6.0 equiv), CH Cl , 0 C, 1.5 h (91%). (h) Et SiH (10.0 equiv), TFA (15.0
2
2
2
2
3
o
equiv), CH Cl , 0 C to rt, 2 h (92%). (i) DMP (1.3 equiv), CH Cl , rt, 30 min (82%). (j) DBU (5.0 equiv), PhH,
2
2
2
2
o
8
0 C, 2 h (85%). DMAP = 4-(dimethylamino)pyridine; Py = pyridine; DMP = Dess-Martin periodinane.
Unfortunately, when the reaction conditions were applied to the substrate 16, the desired
1
,3-proton shifted product was not obtained. The tetraene 63 was most likely formed as a result of
elimination of HOAc. We reasoned that this should attribute to the good leaving property of OAc
group. To overcome this problem, the hydrolysis of ester group was carried out prior to proton
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shift. After a further optimization of the reaction conditions, we found that treatment of 16 with
NaOMe in MeOH resulted in a simultaneous deprotection of Ac group and proton shift, affording
the diol 64 in 73% yield as a single C -H diastereoisomer. The stereochemistry of the product
4
2
2
was confirmed by NOESY correlation. The high stereoselectivity may be resulted from the
sterically less hindered si-face of TS-3 as compared to the more hindered re-face of TS-4. In
addition, the thermodynamically favorite cis-selectivity cannot be ignored. Finally, selective
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
38
oxidation of the allylic primary alcohol in 64 to aldehyde gave glaucopine C (3).
Table 2 Optimization of the conditions for double bond migration and -CH oxidation cascade
a
reactions.
Yield of 69
Entry
1
Conditions
b
(%)
o
25
DBU (5 equiv), O (balloon), DMSO, 80 C
2
o
2
3
4
5
DBU (5 equiv), O
2
(balloon), DMSO, 50 C
41
37
44
37
o
DBU (5 equiv), O (balloon), DMSO, 40 C
2
o
TMG (5 equiv), O (balloon), DMSO, 50 C
TMG (5 equiv), O (balloon),
P(OMe) (2 equiv) DMSO, 50 C
2
2
o
3
o
6
LiHMDS (2 equiv), THF, N , -78 C, 15 min;
65
2
o
then P(OMe) (2 equiv), O (balloon), -78 C
3
2
a
b
Reaction conditions: 15 mg (0.056 mmol) of 67 in 0.6 mL solvent. Isolated yield. TMG =
1
,1,3,3-tetramethylguanidine.
Encouraged by the base-mediated smooth double bond migration reaction of 16, we planned
to introduce the -OH at C toward synthesizing cyrneine B (2) by implementing a base-mediated
4
double bond migration and -CH oxidation cascade reaction. The optimization of the reaction
conditions was carried out employing 67 as a model compound based on some methods reported
39
in literature. As shown in Table 2, while the desired C -hydroxylation could proceed to give
4
the tertiary alcohol 69 under an array of conditions (entries 1−5), the yield was low to moderate.
In many cases, a by-product which was tentatively assigned as the dihydroxylated 70 was formed
due presumably to the relatively harsh reaction conditions. In considering of this, 67 was treated
with a strong base such as LiHMDS at a lowered temperature followed by trapping the anion with
molecular oxygen. With this alteration, the yield of 69 could be substantially improved to 65%
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3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with exclusive cis-selectivity. The relative stereochemistry of 69 was confirmed by NOESY
correlation.
With the suitable conditions for C
reaction, we entered the final stage toward the completion of the synthesis of cyrneine B (2)
Scheme 8). Thus, treatment of 16 under the optimized conditions for model reaction afforded the
C -hydroxylated product 71 in 58% yield whose stereochemistry was also verified by NOESY
4
-hydroxylation being established through the model
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
4
22
correlation. Here, the high stereoselectivity for the oxidative hydroxylation should be arisen
from the same reasons as the stereoselective prototropic shift (vide supra). Hydrolysis of the two
ester groups in 71 followed by selective oxidation of the primary allylic alcohol in 72
38
accomplished the total synthesis of cyrneine B (2) in 51% yield over two steps.
o
Scheme 8. The completion of the synthesis of cyrneine B. (a) LiHMDS (1.0 M in THF, 2.0 equiv), THF, -78 C, 15
o
min, then P(OMe)
3
(4.0 equiv), O
2
, 2 h (58%). (b) K
2
CO
3
(excess), MeOH, 35 C, 4 h. (c) MnO
2
(15 equiv),
CH Cl , rt, 3 h (51% for 2 steps).
2
2
Finally, to further demonstrate the flexible applicability and efficiency of our new synthetic
strategy developed herein, we carried out the total synthesis of (+)-allocyathin B . Two
enantioselective syntheses for this compound have been reported. The first total synthesis was
2
24
accomplished by Nakada and co-workers in 2004 within a longest linear step of 23 steps (total
8 steps) from the known cyclopentanone derivative 73 (Scheme 9). In 2005, Trost and
2
1
3
co-workers reported a more efficient synthesis through a longest linear sequence of 17 steps
total 19 steps) from the cyclopentanone derivative 74. In the whole synthetic route, only the
(
Ru-catalyzed cycloisomerization of 75 for constructing 76 was somewhat less effective due to the
moderate yield and Z/E selectivity, and high catalyst loading. Since it was found in a very recent
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3
h
2
research by Gao that (+)-allocyathin B displayed promising biological property for inhibition of
nitric oxide (NO) production with an IC50 value of 19.8 M, the development of a new route
toward more practical synthesis of this molecule as well as its potential analogues would be much
appealing for an in-depth SAR evaluation and the discovery of new anti-neuroinflammatory
compounds.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Me
SO2Mes
O
Me
OtBu
74
73
CHO
CO2tBu
tBuO2C
OH
CpRu(CH3CN)3PF6
20 mol %)
(
55%
(Z/E = 6.7:1)
76
75
Scheme 9. Starting materials used in Nakada’s and Trost’s synthesis, and one of the key reactions in Trost’s
synthetic route
Our synthesis commenced with enantiomerically pure 9 (Scheme 10). Activation of the
hydroxy group in
9
with carbonochloridothioate afforded the carbonothioate 77.
4
0
Barton-McCombie radical deoxygenation followed by isopropylation of the deoxygenated
cyclopentanone gave 78 in 50% yield over two steps (64% brsm). Conversion of 78 into enol
triflate 79 and cross-coupling of 79 with boronic acid 23 catalyzed by palladacycle 26 provided
the arylated cyclopentene 80. Selective oxidation of the less hindered olefin outside the cycle
followed by a one-pot cyclization/methylation via aldehyde 81 produced the 5-6-6-tricyclic
intermediate 82. PCC oxidation of 82 afforded ketone 83. Birch reductive methylation of 83 led to
6
a regio- and stereoselective construction of C chiral quaternary carbon center in 84. Subsequently,
Wolff-Kishner-Huang reduction of the carbonyl group in the central ring and acid-promoted
hydrolysis of vinyl methyl ether gave ketone 85. Then -acylation of 85 afforded uneventfully a
mixture of -ketone ester 86 and its enol tautomer. Finally, by implementing a carbenoid-meidated
one-pot ring-expansion reaction, a reduction of carbonyl and ester groups, and a selective
2
oxidation of primary alcohol furnished the total synthesis of (+)-allocyathin B with a 16-step
linear sequence from the known compound 9 (total 18 steps from the commercially available 17).
It should be mentioned that most of the reactions in the synthetic route (from 17 to 85) could be
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
uneventfully performed on gram scale. While we did not examine the scalability of the last four
steps from 85 to (+)-allocyathin B
0–100 mg scale. These results demonstrated that the synthetic route presented herein would be
useful for supplying (+)-allocyathin B and its analogues on a level of dozens of milligrams.
2
on large scale, they could be reliably peformed on about
4
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 10. The completion of the synthesis of (+)-allocyathin B
2
. (a) PhOC(S)Cl (1.5 equiv), pyridine (2.0 equiv),
o
DMAP (0.1 equiv), CH Cl , rt, 4 h (86%). (b) AIBN (1 mol%), Bu
2
2
3
SnH (2.0 equiv), toluene, 100 C, 1 h. (c) NaH
(
5.0 equiv), iPrI (10.0 equiv), THF, reflux, overnight; then aq. HCl (2 M), rt, 3 h (50% for 2 steps). (d) LiHMDS
o
(1.3 equiv, 1.0 M in THF), PhNTf (1.3 equiv), THF, -78 C to rt, 3 h (80%). (e) Boronic acid 23 (2.0 equiv), cat.
2
2
6 (5 mol%), K CO (2.0 equiv), DMF/EtOH (v/v = 1:1), rt (98%). (f) OsO (4 mol%), NaIO (5.0 equiv), pyridine
2 3 4 4
o
(
3.0 equiv), dioxane/H
2
2 3
O (v/v = 5:1), rt. (g) EtMgBr (1.0 eqiuv, 1.0 M in THF), -78 C to rt, 4 h, then K CO (2.0
o
equiv), MeI (5.0 equiv), and DMF were charged in situ, 45 C, 6 h (64% for 2 steps). (h) PCC (4.0 equiv), NaOAc
o
(
4.0 equiv), celite (ca. 100 wt%), rt, 3 h (80%). (i) Liq. NH , tBuOH (1.0 equiv), K (2.5 equiv), THF, -78 C, 20
3
o
min; then LiBr (2.2 equiv), MeI (5.0 equiv), and THF were charged in situ, -78 C, 1 h, then warmed to rt over a
period of 1 h (76%). (j) 52 (5.0 equiv), NaOAc (5.0 equiv), EtOH, rt, 2 h. (k) KOtAm (10.0 equiv), degassed
o
xylene, 140 C, 2.5 h. (l) 2 N HCl (5.0 equiv), THF, rt, 20 min (65% for 3 steps). (m) LiHMDS ((1.0 M in THF, 2.0
o
equiv), THF, -78 C, 30 min, then CNCO Me (2.0 equiv), 2 h (82%). (n) ZnEt (1.0 M in hexane, 6.0 equiv), CH I
2
2
2 2
o
(
6.0 equiv), CH Cl , 0 C to rt, 1 h; then I (6.0 equiv), rt, 10 min; then saturated aq. Na S O (excess), rt; then
2 2 2 2 2 3
o
DBU (10.0 equiv), rt, 1 h (72%). (o) LiAlH (5.0 equiv), Et O, -78 C, 30 min. (p) MnO (20 equiv), CH Cl , rt, 1
4
2
2
2
2
h (63%, for 2 steps). AIBN = 2,2’-azobisisobutyronitrile.
CONCLUSION
In conclusion, through an extensive investigation of different strategies and methodologies,
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we have successfully established an efficient route for a collective synthesis of various
cyathane-type diterpenoids from the very cheap 2-methyl 1,3-cyclopentanedione 17. Namely,
2
cyrneine A and (+)-allocyathin B could be accomplished more efficiently through a longest linear
sequence of 20 and 18 steps, respectively. The cyrneine B and glaucopine C were conquered for
the first time consisting of the longest linear sequence of 24 and 23 steps, respectively. Notably,
most of the transformations involved in the route could be reliably performed on multigram scales,
making the current route potentially useful for large scale synthesis of natural products and their
potential analogues. Additional highlights are that by employing the mild Suzuki coupling and the
chelation-controlled Friedel-Crafts cyclization as the key reactions, a concise synthesis of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
41
(−)-hamigeran B and (−)-4-bromohamigeran B could also be achieved in a 13-step procedure.
These results demonstrated that the new synthetic strategy as well as some of the key
transformations established herein could find extensive applications for efficient and flexible
synthesis of various types of terpenoid natural prodcuts. Further application of the synthetic
strategy and methodologies toward synthesizing more challenging targets is underway.
EXPERIMENTAL SECTION
General Informations: Unless otherwise stated, all oxygen or moisture sensitive reactions were
conducted in flame-dried glassware under an atmosphere of nitrogen or argon. All solvents were
purified and dried according to standard methods prior to use. Reagents purchased from
commercial sources were used without further purification. Analytical thin layer chromatography
(
TLC) was performed on 0.2 mm thick silica gel 60-F254 plates (Merck) and visualized by
exposure to ultraviolet light, or an ethanolic solution of phosphomolybdic acid. Chromatographic
purification of products was accomplished using forced-flow chromatography on 230-400 mesh
1
silica gel. The H-NMR spectra were recorded on Bruker AV at 300, 400, or 600 MHz and
1
3
C-NMR spectra were recorded at 75, 101, 126, or 151 MHz. Chemical shifts are given relative to
TMS or the appropriate solvent peak. High resolution mass spectra (HRMS) were obtained on an
IonSpec Ultima 7.0 T FT-ICR-MS (IonSpec, USA) using ESI as ionization method. HPLC
analysis was performed on Shimadzu LC solution (CTO-10AS, LC-20AD, RID-10A). X-ray
crystallographic analysis was performed on a Bruker D8 ADVANCE diffractometer with Cu-Kα
radiation (λ = 1.54178 Å).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
5
6
2
5
2
-Allyl-2-methylcyclopentane-1,3-dione
(18):
To
a
solution
of
2-Methyl
cyclopentane-1,3-dione 17 (10.0 g, 89.2 mmol) and TBAI (330 mg, 0.89 mmol) in H
2
O (100 mL)
was added 2 N NaOH (45 ml) dropwise at 0 °C. The mixture was allowed to warm to room
temperature and stirred for 10 min. To this mixture was added allyl bromide (15.0 mL, 178 mmol),
the resulting solution was stirred at 50 °C for 8 h. The reaction mixture was extracted with ethyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
acetate (3 × 50 mL). The combined organic layers were washed successively with H
2
O (2 × 50 mL)
and brine (50 mL), dried over Na SO , and concentrated under reduced pressure. The crude
2
4
reaction mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 20:1) to provide the 2-allyl-2-methyl-1,3-cyclopentanedione 18 (12.3 g, 91% yield ) as a
1
colorless oil (R
f
= 0.5, petroleum ether/ethyl acetate = 4:1). H NMR (300 MHz, CDCl
3
) δ (ppm)
5
.53–5.53 (m, 1H), 5.10–5.03 (m, 2H), 2.81–2.66 (m, 4H), 2.36 (d, J = 7.5 Hz, 2H), 1.12 (s, 3H).
27
(
2S,3S)-2-Allyl-3-hydroxy-2-methylcyclopentan-1-one (19): To a solution of D-glucose (65.0
g) in H O (430 mL) was added dry active baker’s yeast (43.7 g) and yeast extract (1.85 g) at room
2
temperature. 2-Allyl-2-methyl-1,3-cyclopentanedione 18 (3.7 g, 24.5 mmol) was added dropwise,
and the resulting mixture was vigorously stirred at room temperature for 48 h. The reaction
mixture was extracted with dichloromethane (3 × 150 mL). The combined organic layers were
washed with H
2 2 4
O (2 × 30 mL) and brine (30 mL), dried over Na SO , and concentrated under
reduced pressure. The crude product was purified by column chromatography on silica gel
(
petroleum ether/ethyl acetate = 10:1→9:1→8:1→ 7:1) to provide the enantiomerically pure
1
hydroxy ketone 19 (1.4 g, 40% yield for two steps) as a colorless oil. H NMR (300 MHz, CDCl
3
)
δ (ppm) 5.97–5.80 (m, 1H), 5.21–5.09 (m, 2H), 4.16–4.09 (m, 1H), 2.55 (m, 5H), 2.03–1.91 (m,
H), 1.79 (bs, 1H), 1.00 (s, 3H).
2S,3R)-2-Allyl-3-hydroxy-2-methylcyclopentan-1-one (20): To a stirred solution of 19 (2.63 g,
1
(
1
3
7.09 mmol), triphenylphophine (8.97 g, 34.2 mmol, 2.0 equiv), and p-nitrobenzoic acid (5.71 g,
4.2 mmol, 2.0 equiv) in THF (70 mL) was added DEAD (5.38 mL, 34.2 mmol, 2.0 equiv)
o
o
dropwise over a 10 min period at 0 C under argon. The solution was then stirred at 50 C
overnight. The solvent was removed under reduced pressure to leave an oil, which was purified by
column chromatography on silica gel (petroleum ether/EtOAc = 15/1→10/1) to give the
corresponding p-nitrobenzoate (2.72 g, 52% yield) as a white solid.
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To a solution of p-nitrobenzoate (2.72 g, 8.97 mmol) in the mixed solvents of THF (30 mL)
2 3
and MeOH (15 mL) was added K CO (2.48 g, 17.9 mmol). The reaction mixture was stirred at 0
o
C for 30 min. The solvent was removed under reduced pressure and the residue was partitioned
Cl (60 mL). The organic layer was separated, and the aqueous
(2 × 50 mL). The combined organic layers were dried over
between water (60 mL) and CH
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
layer was extracted with CH Cl
2
2
Na
2
SO
4
, filtered, concentrated, and purified by column chromatography on silica gel (petroleum
1
ether/EtOAc = 5/1→5/2) to afford 20 (1.35 g, 97% yield) as a colorless oil. H NMR (300 MHz,
3
CDCl ) δ (ppm) 5.83–5.66 (m, 1H), 5.14–5.05 (m, 2H), 4.21 (t, J = 6.3 Hz, 1H), 2.52 (m, 1H),
13
1
2
2
.31–2.09 (m, 4H), 1.92–1.79 (m, 2H), 1.00 (s, 3H); C{ H} NMR (75 MHz, CDCl
3
) δ (ppm)
20.2, 133.6, 118.9, 75.5, 53.1, 39.9, 35.0, 27.6, 15.1.
(
2S,3R)-2-Allyl-3-((tert-butyldimethylsilyl)oxy)-2-methylcyclopentan-1-one (21): To a solution
of compound 20 (2.59 g, 16.78 mmol) in DMF (30 mL) was added imidazole (1.37 g, 20.1 mmol,
1.2 equiv) and TBSCl (3.04 g, 20.1 mmol, 1.2 equiv). The solution was stirred overnight at room
temperature. The reaction mixture was poured into aqueous sodium bicarbonate solution (50 mL)
and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with
2 4
brine (5 × 20 mL), dried over Na SO , filtered, concentrated, and purified by column
chromatography on silica gel (petroleum ether/EtOAc = 30/1) to afford 21 (3.96 g, 88% yield) as a
1
colorless oil. H NMR (300 MHz, CDCl
3
) δ (ppm) 5.73–5.59 (m, 1H), 5.10–4.99 (m, 2H),
4
0
2
.18–4.11 (m, 1H), 2.50–2.02 (m, 5H), 1.88–1.75 (m, 1H), 0.96 (s, 3H), 0.89 (s, 9H), 0.08 (s, 3H),
13
1
.06 (s, 3H); C( H) NMR (75 MHz, CDCl
3
) δ (ppm) 220.6, 133.7, 118.3, 75.2, 53.7, 39.6, 35.2,
8.5, 25.8, 18.1, 16.2, -4.2, -4.8.
(4R,5S)-5-Allyl-4-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclopent-1-en-1-yl
trifluoromethanesulfonate (22): To a stirred suspension of NaH (60% dispersion in mineral oil,
2
.88 g, 72.0 mmol, 5.0 equiv) in THF (35 mL) was added dropwise a solution of 21 (3.86 g, 14.4
o
mmol) in THF (20 mL) at 0 C. Then 2-iodopropane (14.4 mL, 144 mmol, 10.0 equiv) was added.
2
The reaction mixture was refluxed overnight. The resulting mixture was quenched at 0 °C by H O.
Then 2 N HCl (36 mL) was added, and the mixture was stirred at room temperature for 3 h. Then
brine was added to the solution to form a biphasic solution. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
washed with brine (30 mL), dried over Na
chromatography on silica gel (petroleum ether/CH
isopropylated product (2.81 g, 63% yield) as a colorless oil.
2
SO
4
, concentrated, and purified by column
2
Cl = 3/1) to afford the TBS protected
2
The isopropylated product (2.81 g, 9.06 mmol) was dissolved in dry THF (20 mL) and the
solution was cooled to -78 °C. LiHMDS (1.0 M in THF, 11.8 mL, 11.8 mmol, 1.3 equiv) was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
added and the solution was stirred at the same temperature for 1 h. Then a solution of PhNTf
2
(
4.21 g, 11.8 mmol, 1.3 equiv) in dry THF (20 mL) was added slowly. The reaction mixture was
allowed to warm to room temperature and stirred for 7 h. Brine (50 mL) was added to the reaction
mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3
×
50 mL). The combined organic layers were dried over Na
2
SO
4
, filtered, concentrated, and
Cl = 50/1) to give 22 (3.09
3
) δ (ppm) 5.76–5.60 (m, 1H),
purified by column chromatography on silica gel (petroleum ether/CH
2
2
1
g, 77% yield) as a colorless oil. H NMR (300 MHz, CDCl
5.11–5.02 (m, 2H), 4.12 (t, J = 6.9 Hz, 1H), 2.83 (m, J = 6.9 Hz, 1H), 2.46 (dd, J = 15.3, 7.2 Hz,
1H), 2.27–2.05 (m, 3H), 1.06 (s, 3H), 1.01 (d, J = 6.9 Hz, 3H), 1.01 (s, J = 6.9 Hz, 3H), 0.91 (s,
13
1
3
9H), 0.07 (s, 3H), 0.07 (s, 3H); C{ H} NMR (75 MHz, CDCl ) δ (ppm) 143.3, 135.5, 134.3,
118.8 (d, J = 317 Hz), 118.3, 73.1, 49.9, 40.9, 34.4, 25.9, 25.6, 20.6, 20.1, 18.1, 17.6, -4.1, -4.7.
3-((4R,5R)-5-Allyl-4-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclopent-1-en-1-yl)p
henol (24): To a solution of 22 (44.3 mg, 0.10 mmol) in a mixed solvent of DMF (1.0 mL) and
EtOH (1.0 mL) was added arylboronic acid 23 (27.4 mg, 0.20 mmol, 2.0 equiv), palladacycle 26
(
2 3
2.8 mg, 5 mmol%), and K CO (41.4 mg, 0.3 mmol, 3.0 equiv) at room temperature under
nitrogen. The resulting mixture was stirred at the same temperature for 2.5 h. The reaction mixture
was then poured into water and extracted with ethyl acetate (3 × 15 mL). The combined organic
2 4
layers were washed with brine, dried over Na SO , filtered, and concentrated under vacuum. The
residue was purified by silica gel column chromatography to afford the desired 24 (37.9 mg, 98%
1
yield, containing a small inseparably 25). H NMR (300 MHz, CDCl
3
) δ (ppm) 7.18 (d, J = 7.8 Hz,
1
1
2
0
H), 6.77–6.56 (m, 3H), 5.74–5.57 (m, 1H), 5.07 (bs, 1H), 4.98–4.87 (m, 2H), 4.14 (t, J = 6.9 Hz,
H), 2.50 (dd, J = 15.6, 7.2 Hz, 1H), 2.41 (m, J = 6.9 Hz, 1H), 2.18 (dd, J = 15.3, 6.9 Hz, 1H),
.09–1.94 (m, 2H), 1.03 (s, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H),
.09 (s, 3H), 0.08 (s, 3H).
(((1R,2R)-2-Allyl-4-isopropyl-3-(3-methoxyphenyl)-2-methylcyclopent-3-en-1-yl)oxy)(tert-but
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9
yl)dimethylsilane
(27)
and
tert-butyl(((1R,2R)-4-isopropyl-3-(3-methoxyphenyl)-2-methyl-2-((E)-prop-1-en-1-yl)cyclope
nt-3-en-1-yl)oxy)dimethylsilane (28): To a solution of a mixture 24 and 25 (85 mg, 0.22 mmol,
the ratio of 24:25 was varied depending on the variation of reaction conditions) in DMF (1.0 mL)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 3
was added K CO (61 mg, 0.44 mmol, 2.0 equiv) and MeI (27 μL, 0.44 mmol, 2.0 equiv). The
mixture was stirred overnight at room temperature. The reaction mixture was poured into water
and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with
brine (5 × 10 mL), dried over Na
2 4
SO , filtered, and evaporated to dryness. The residue was
purified by column chromatography on silica gel (petroleum ether/CH
2
Cl
2
= 40/1→30/1→25/1) to
1
afford 27 and 28 as colorless oil, respectively, in quantitative overall yield. Compound 27: H
NMR (300 MHz, CDCl
3
) δ (ppm) 7.22 (t, J = 7.8 Hz, 1H), 6.83–6.76 (m, 1H), 6.71–6.61 (m, 2H),
5
.73–5.56 (m, 1H), 4.96–4.85 (m, 2H), 4.14 (t, J = 6.9 Hz, 1H), 3.80 (s, 3H), 2.49 (dd, J = 15.3,
7.5 Hz, 1H), 2.40 (m, J = 6.9 Hz, 1H), 2.17 (dd, J = 15.3, 6.9 Hz, 1H), 2.09–1.92 (m, 2H), 1.03 (s,
3H), 0.95 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H);
1
3
1
3
C( H) NMR (151 MHz, CDCl ) δ (ppm) 159.2, 142.1, 140.7, 139.7, 136.3, 128.8, 122.2, 116.5,
115.6, 111.6, 76.4, 55.3, 53.6, 42.8, 37.1, 27.6, 26.0, 21.7, 21.3, 19.3, 18.2, -3.9, -4.7; compound
1
28: H NMR (300 MHz, CDCl
3
) δ (ppm) 7.18 (t, J = 7.8 Hz, 1H), 6.79–6.73 (m, 1H), 6.69–6.59
(
m, 2H), 5.39–5.23 (m, 2H), 4.02 (t, J = 6.0 Hz, 1H), 3.78 (s, 3H), 2.58–2.45 (m, 2H), 2.19 (dd, J
=
15.6, 5.7 Hz, 1H), 1.62 (d, J = 5.1 Hz, 3H), 1.03 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.93 (d, J =
1
3
1
6
1
2
3
.9 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); C{ H} NMR (151 MHz, CDCl ) δ (ppm)
59.0, 142.1, 140.2, 140.0, 137.9, 128.5, 123.2, 122.1, 115.3, 111.6, 79.4, 56.6, 55.2, 37.0, 27.6,
6.0, 21.6, 21.4, 18.3, 18.2, 17.1, -4.4, -4.5.
For the detailed synthetic procedures, characterization data, and copies of spectra for the
compounds 9–11 and 29–32 in Scheme 2, see the Supplementary Information (SI) of ref 22.
Acid-mediated cyclization of 32: To a solution of 32 (159 mg, 0.41 mmol) in freshly distilled
ethyl ether (40.0 mL) was added BF
3
•OEt
2
(0.26 mL, 2.06 mmol, 5.0 equiv) at 0 °C over a period
o
of 15 min. The mixture was stirred for 1 h at 0 C. The reaction mixture was quenched with
saturated aqueous NaHCO
3
and extracted with ethyl ether (2 × 25 mL). The combined organic
, filtered, concentrated, and purified by column chromatography on
layers were dried over Na SO
2
4
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2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
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4
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5
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5
5
5
5
5
6
silica gel (petroleum ether/EtOAc = 100/1→80/1→50/1) to afford 34 (36 mg, 24% yield) and 35
1
(
89 mg, 59% yield). Compound 34: H NMR (300 MHz, CDCl
3
) δ (ppm) 7.09–6.97 (m, 2H),
6
.68–6.61 (m, 2H), 6.02 (d, J = 9.6 Hz, 1H), 4.76 (bs, 1H), 4.14 (dd, J = 9.0, 7.8 Hz, 1H), 3.19 (m,
J = 6.9 Hz, 1H), 2.49 (dd, J = 15.0, 7.5 Hz, 1H), 2.21 (dd, J = 15.0, 9.0 Hz, 1H), 1.17 (d, J = 6.9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.94 (s, 9H), 0.86 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H); C{ H}
NMR (151 MHz, CDCl
3
) δ (ppm) 151.2, 143.2, 137.4, 133.7, 132.6, 127.2, 120.9, 120.1, 117.1,
1
1
14.1, 79.1, 50.3, 35.5, 27.0, 26.0, 21.9, 21.2, 18.3, 16.5, -4.2, -4.6. Compound 35: H NMR (300
3
MHz, CDCl ) δ (ppm) 6.98 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.1, 2.7 Hz,
1
1
1
3
H), 6.25 (d, J = 9.6 Hz, 1H), 5.88 (d, J = 9.6 Hz, 1H), 5.04 (bs, 1H), 4.12 (dd, J = 9.0, 7.5 Hz,
H), 3.19 (m, J = 6.9 Hz, 1H), 2.48 (dd, J = 15.0, 7.5 Hz, 1H), 2.21 (dd, J = 15.0, 9.3 Hz, 1H),
.17 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.94 (s, 9H), 0.86 (s, 3H), 0.12 (s, 3H), 0.11 (s,
13
1
3
H); C{ H} NMR (151 MHz, CDCl ) δ (ppm) 154.3, 143.3, 135.4, 133.8, 132.6, 128.1, 127.5,
123.9, 114.1, 113.7, 79.1, 50.4, 35.5, 26.9, 26.0, 21.9, 21.1, 18.2, 16.7, -4.2, -4.6.
Acid-mediated cyclization of 33: To a solution of 33 (24 mg, 0.06 mmol) in freshly distilled
ethyl ether (6.0 mL) was added BF
15 min. The mixture was stirred for 1 h at 0 °C and then at room temperature for an additional 6 h.
The reaction mixture was quenched with saturated aqueous NaHCO and extracted with ethyl
ether (2 × 15 mL). The combined organic layers were dried over Na SO , filtered, concentrated,
O = 50/1→30/1) to give
) δ (ppm) 7.04 (d, J = 8.4
3 2
•OEt (76 μL, 0.60 mmol, 10.0 equiv) at 0 °C over a period of
3
2
4
and purified by column chromatography on silica gel (petroleum ether/Et
2
1
3
6 (17.5 mg, 76% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.26 (d, J = 9.3 Hz, 1H), 5.88 (d,
J = 9.3 Hz, 1H), 4.13 (dd, J = 9.0, 7.5 Hz, 1H), 3.83 (s, 3H), 3.21 (m, J = 6.9 Hz, 1H), 2.48 (dd, J
=
15.0, 7.5 Hz, 1H), 2.21 (dd, J = 15.0, 9.0 Hz, 1H), 1.19 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz,
1
3
1
3
H), 0.94 (s, 9H), 0.85 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H); C{ H} NMR (151 MHz, CDCl
ppm) 158.4, 143.0, 135.5, 134.1, 132.3, 127.9, 127.4, 123.9, 113.5, 111.5, 79.1, 55.4, 50.5, 35.5,
7.0, 26.0, 21.9, 21.2, 18.3, 16.7, -4.2, -4.6.
3R,3aR,5S)-3-((tert-Butyldimethylsilyl)oxy)-1-isopropyl-3a-methyl-3,3a,4,5-tetrahydro-2H-c
3
) δ
(
2
(
yclopenta[a]naphthalene-5,6-diol (46): To a solution of 32 (0.804 g, 2.07 mmol) in THF (20 mL)
was added EtMgBr (1.0 M in THF, 2.3 mL, 2.3 mmol, 1.1 equiv) slowly over a period of 20 min
o
at -78 C under argon atmosphere. The mixture was then warmed up slowly to 40 °C, and stirred
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at the same temperature overnight. The reaction mixture was poured into water and extracted with
ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (20 mL), dried
2 4
over Na SO , filtered, and concentrated under vacuum. The residue was purified by silica gel
column chromatography (petroleum ether/Et
2
O = 25/1→15/1→10/1) to afford 46 (0.386 g, 48%
) δ (ppm) 8.44 (s, 1H), 7.16 (t, J = 8.0 Hz, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield) as a colorless oil. H NMR (400 MHz, CDCl
3
7
3
.07 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.25–5.16 (m, 1H), 3.97 (t, J = 8.4 Hz, 1H),
.28 (m, J = 6.8 Hz, 1H), 2.56 (dd, J = 15.2, 8.0 Hz, 1H), 2.45 (dd, J = 11.6, 6.4 Hz, 1H), 2.37 (dd,
J = 15.6, 9.2 Hz, 1H), 2.10 (d, J = 8.8 Hz, 1H), 1.57 (t, J = 11.2 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H),
13
1
1
.04 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.91 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); C{ H} NMR (101
MHz, CDCl ) δ (ppm) 157.3, 140.2, 133.4, 133.0, 129.1, 122.2, 119.9, 115.3, 79.8, 69.3, 50.5,
6.8, 37.7, 27.4, 26.0, 21.7, 20.7, 18.2, 16.0, -4.2, -4.6.
4aR,5aS,6aR,7R)-7-((tert-Butyldimethylsilyl)oxy)-9-isopropyl-6a-methyl-6,6a,7,8-tetrahydro
3
4
(
cyclopenta[3,4]naphtho[1,8a-b]oxiren-4(5aH)-one (47): To a solution of 46 (43 mg, 0.11 mmol)
o
in MeCN (1.5 mL) at 0 C was added a solution of NaIO
4
(47 mg, 0.22 mmol, 2.0 equiv) in H
2
O
(
0.5 mL) over a period of 15 min. The reaction mixture was stirred at room temperature for an
additional 2 h and was extracted with ethyl acetate (3 × 15 mL). The combined organic layers
were washed with brine (20 mL), dried over Na SO , filtered, concentrated, and purified by
column chromatography on silica gel (petroleum ether/CH Cl /Et O = 100/10/1→50/5/1→20/2/1)
to give 47 (20 mg, 47% yield) as a yellow solid. H NMR (300 MHz, CDCl ) δ (ppm) 7.22 (dd, J
2
4
2
2
2
1
3
= 9.9, 6.3 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 6.19–6.13 (m, 1H), 4.07 (t, J = 8.2 Hz, 1H), 3.86 (d, J
= 3.6 Hz, 1H), 2.86 (m, J = 6.9 Hz, 1H), 2.48 (dd, J = 15.6, 7.5 Hz, 1H), 2.20 (d, J = 15.6 Hz, 1H),
2.12 (dd, J = 15.9, 8.7 Hz, 1H), 2.03 (dd, J = 15.6, 3.6 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.98 (d, J
13
1
=
3
6.9 Hz, 3H), 0.91–0.87 (m, 12H), 0.07 (s, 3H), 0.06 (s, 3H); C{ H} NMR (151 MHz, CDCl ) δ
(
ppm) 195.4, 145.6, 144.0, 142.5, 134.2, 124.7, 123.2, 82.0, 70.6, 59.1, 52.3, 38.6, 37.2, 26.9, 25.9,
+
2
3
1.5, 21.5, 21.2, 18.2, -4.2, -4.6; HRMS (ESI) m/z calcd for C23
87.2346.
H
35
O
3
Si [M+H] : 387.2350, found
For the detailed synthetic procedures, characterization data, and copies of spectra for the
compounds 12, 13, 51, and 54 in Scheme 5, see the Supplementary Information (SI) of ref 22.
(3R,3aR,5aR)-3-((tert-Butyldimethylsilyl)oxy)-1-isopropyl-3a,5a-dimethyl-2,3,3a,4,5,5a-hexah
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2
2
2
2
2
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5
5
6
ydro-6H-cyclopenta[a]naphthalen-6-one (55): To a stirred solution of NBS (102 mg, 0.57 mmol,
1
.1 equiv) in THF (3.0 mL) was added H
2
O (19 μL, 1.04 mmol, 2.0 equiv) and a solution of 54
o
(
210 mg, 0.52 mmol) in THF (4.0 mL) at 0 C. The reaction mixture was stirred at room
temperature for 10 min. Then a solution of DBU (158 mg, 1.04 mmol, 2.0 equiv) in THF (1.0 mL)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
was added and the mixture was stirred at 45 C for 3.5 h. Then brine (15 mL) was added and the
resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were
2 4
washed with brine (20 mL), dried over Na SO , filtered, concentrated, and purified by column
chromatography on silica gel (petroleum ether/Et
2
O = 20/1) to afford 55 (135 mg, 67% yield) as a
1
yellow solid. H NMR (300 MHz, CDCl
3
) δ (ppm) 7.06 (dd, J = 9.6, 6.0 Hz, 1H), 6.04–5.98 (m,
2
1
0
H), 4.04–3.95 (m, 1H), 2.89 (m, J = 6.9 Hz, 1H), 2.48 (dd, J = 15.3, 7.8 Hz, 1H), 2.23 (dd, J =
5.3, 9.0 Hz, 1H), 2.07–1.98 (m, 1H), 1.79–1.59 (m, 3H), 2.13 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H),
13
1
.95 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.83 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H); C{ H} NMR (151
MHz, CDCl
3
) δ (ppm) 206.6, 154.0, 142.4, 142.1, 136.7, 123.5, 117.2, 82.2, 51.8, 50.7, 37.5, 34.7,
39 2
31.8, 26.8, 26.0, 24.0, 21.6, 21.3, 18.2, 16.9, -4.3, -4.6; HRMS (ESI) m/z calcd for C24H O Si
+
[M+H] : 387.2714, found 387.2705.
(
3R,3aR,5aR)-3-((tert-Butyldimethylsilyl)oxy)-8-(dibromomethyl)-1-isopropyl-3a,5a-dimethyl
2,3,3a,4,5,5a-hexahydro-6H-cyclopenta[a]naphthalen-6-one (58): To a stirred solution of 55
-
(30 mg, 0.078 mmol) and CHBr
3
2
(34 μL, 0.38 mmol, 5.0 equiv) in Et O (1.0 mL) was added
o
LiHMDS (1.0 M in THF, 87 μL, 0.087 mmol, 1.5 equiv) at -78 C under argon atmosphere. The
reaction mixture was stirred at the same temperature for 2 h and then quenched with H
reaction mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were
dried over Na SO , filtered, concentrated, and purified by column chromatography on silica gel
(petroleum ether/CH Cl = 50/1) to afford 57 (34 mg, 68% yield).
2
O. The
2
4
2
2
To a solution of 57 (34 mg, 0.053 mmol) in THF (1.0 mL) was added DBU (16 mg, 0.106
mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at the same temperature
for 15 min and quenched with H
2
O. The reaction mixture was extracted with ethyl acetate (3 × 10
SO , filtered, concentrated, and purified by
O = 20/1) to afford 58 (25 mg, 84%
mL). The combined organic layers were dried over Na
2
4
column chromatography on silica gel (petroleum ether/Et
2
1
yield). H NMR (300 MHz, CDCl
3
) δ (ppm) 6.27 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.94 (d, J = 1.8
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Hz, 1H), 4.05–3.97 (m, 1H), 2.97 (m, J = 6.9 Hz, 1H), 2.51 (dd, J = 15.3, 7.8 Hz, 1H), 2.27 (dd, J
=
15.3, 9.3 Hz, 1H), 2.07–1.99 (m, 1H), 1.82–1.61 (m, 3H), 1.13 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H),
1
3
1
0
.99 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 3H), 0.08 (s, 3H), 0.08 (s, 3H); C{ H} NMR (151
MHz, CDCl ) δ (ppm) 205.9, 154.2, 152.3, 143.9, 136.4, 116.4, 116.2, 82.2, 51.5, 50.2, 40.8, 37.6,
4.7, 31.4, 27.1, 26.0, 24.1, 21.7, 21.3, 18.2, 16.9, -4.3, -4.6; HRMS (ESI) m/z calcd for
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
+
C
25 2 2
H39Br O Si [M+H] : 557.1081; found 557.1078.
For the detailed synthetic procedures, characterization data, and copies of spectra for the
compounds 14, 60, 61, and cyrneine A in Scheme 6, see the Supplementary Information (SI) of ref
2
2.
For the detailed synthetic procedures, characterization data, and copies of spectra for the
compounds 16, 62, 64, and glaucopine C in Scheme 7A, see the Supplementary Information (SI)
of ref 22.
1
-Isopropyl-6-methoxy-3a-methyl-2,3a,4,5-tetrahydro-3H-cyclopenta[a]naphthalen-3-one
(
67): To a solution of 65 (108 mg, 0.27 mmol, prepared according to the procedure for the
2 2
synthesis of chiral compound 12) in dry CH Cl (4.0 mL) was added TMSOTf (0.29 mL, 1.62
o
mmol, 6.0 equiv) at 0 C. The clear solution was stirred at the same temperature for 1.5 h and
quenched by saturated aqueous NaHCO
was extracted with CH Cl . The combined organic layers were dried over Na
concentrated, and purified by column chromatography on silica gel (petroleum ether/EtOAc =
3
. The organic layer was separated and the aqueous layer
2
2
2
SO , filtered,
4
5
/1→3/1) to give compound 66 (70 mg, 91% yield).
To a solution of 66 (120 mg, 0.42 mmol) and Et
3
SiH (0.67 mL, 4.20 mmol, 10 equiv) in dry
o
CH
2
Cl
2
(5.0 mL) was added TFA (0.49 mL, 6.30 mmol, 15 equiv) at 0 C. The clear solution was
stirred at room temperature for 2 h and quenched by saturated aqueous NaHCO
layer was separated, and the aqueous layer was extracted with CH Cl . The combined organic
layers were dried over Na SO , filtered, concentrated, and purified by column chromatography on
3
. The organic
2
2
2
4
silica gel (petroleum ether/EtOAc = 15/1→10/1) to give the decarbonylated product (105 mg,
92% yield).
2 2
To a solution of the decarbonylated product (105 mg, 0.39 mmol) in CH Cl (5.0 mL) was
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2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
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5
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5
5
5
5
5
5
5
6
added DMP (213 mg, 0.50 mmol, 1.3 equiv) at room temperature. The reaction mixture was
stirred for 30 min. The reaction mixture was quenched by saturated aqueous Na
The organic phase was separated, and the aqueous layer was extracted with CH
The combined organic layers were dried over Na SO
column chromatography on silica gel (petroleum ether/Et
2
SO
3
2
and NaHCO
3
.
2
Cl
(2 × 10 mL).
2
4
, filtered, concentrated, and purified by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
O = 20/1) to give 67 (85 mg, 82% yield).
1
3
H NMR (300 MHz, CDCl ) δ (ppm) 7.21 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.78 (d, J
=
7.8 Hz, 1H), 3.84 (s, 3H), 3.34 (m, J = 6.9 Hz, 1H), 3.21 (d, J = 23.4 Hz, 1H), 3.01 (d, J = 23.4
Hz, 1H), 2.96–2.83 (m, 1H), 2.82–2.66 (m, 1H), 2.03–1.92 (m, 1H), 1.77–1.64 (m, 1H), 1.25 (d, J
13
1
=
3
6.9 Hz, 3H), 1.04 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ (ppm)
2
2
20.9, 157.4, 137.0, 136.2, 133.1, 126.3, 124.9, 120.1, 108.5, 55.4, 51.7, 40.7, 30.1, 27.0, 21.6,
+
1.2, 20.8, 18.7; HRMS (ESI) m/z calcd for C18
H22NaO
2
[M+Na] : 293.1512; found 293.1524.
1
-Isopropyl-6-methoxy-3a-methyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[a]naphthalen-3-one
(
68): To a solution of 67 (10 mg, 0.04 mmol) in PhH (1.0 mL) was added a solution of DBU (28
o
mg, 0.19 mmol, 5.0 equiv) in PhH (0.2 mL). The reaction mixture was stirred at 80 C for 2 h.
Then H
2
O was added and the reaction mixture was extracted with ethyl acetate (3 × 10 mL). The
SO , filtered, concentrated, and purified by column
O = 10/1→5/1) to afford 68 (8.5 mg, 85% yield).
combined organic layers were dried over Na
2
4
chromatography on silica gel (petroleum ether/Et
2
1
H NMR (600 MHz, CDCl
7.8 Hz, 1H), 5.99–5.97 (m, 1H), 3.79 (s, 3H), 3.75 (d, J = 1.8 Hz, 1H), 2.93 (dt, J = 16.2, 3.6 Hz,
H), 2.39 (m, J = 6.6 Hz, 1H), 2.25 (dt, J = 13.2, 3.6 Hz, 1H), 1.81 (td, J =15.0, 3.6 Hz, 1H), 1.25
3
) δ (ppm) 7.18 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.76 (d, J
=
1
13
1
(
td, J = 13.2, 3.6 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.21 (s, 3H), 0.89 (d, J = 6.6 Hz, 3H); C{ H}
NMR (151 MHz, CDCl
3
) δ (ppm) 214.5, 187.7, 156.5, 136.3, 128.7, 126.6, 126.2, 122.0, 108.8,
+
5
2
6.3, 55.6, 49.6, 35.5, 29.1, 25.2, 22.0, 21.2, 19.5; HRMS (ESI) m/z calcd for C18
71.1693; found 271.1680.
b-Hydroxy-1-isopropyl-6-methoxy-3a-methyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[a]napht
H
23
O
2
[M+H] :
9
halen-3-one (69): To a solution of 67 (15 mg, 0.06 mmol) in dry THF (0.6 mL) was added
o
LiHMDS (1 M in THF, 0.112 mL, 0.11 mmol, 2.0 equiv) at –78 C under argon atmosphere. The
3
resulting solution was stirred for 15 min. P(OMe) (26 μL, 0.22 mmol, 4.0 equiv) was added and
the argon balloon was replaced with O balloon. After being stirred for an additional 2 h, the
2
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2
3
4
5
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7
8
9
reaction mixture was quenched by water. The reaction mixture was extracted with ethyl acetate (3
×
2 4
10 mL). The combined organic layers were dried over Na SO , filtered, concentrated, and
purified by column chromatography on silica gel (petroleum ether/EtOAc = 10/1→5/1) to give 69
1
(
10.5 mg, 65% yield). H NMR (300 MHz, DMSO-d
6
) δ (ppm) 7.49 (d, J = 7.8 Hz, 1H), 7.25 (d, J
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.02 (s, 1H), 5.72 (s, 1H), 3.73 (s, 3H), 2.83 (dt, J = 16.2,
3
1
.6 Hz, 1H), 2.68 (m, J = 6.9 Hz, 1H), 2.00 (dt, J = 12.6, 3.6 Hz, 1H), 1.61 (td, J = 15.0, 3.6 Hz,
13
1
3
H), 1.22–1.09 (m, 4H), 1.05 (s, 3H), 0.45 (d, J = 6.9 Hz, 3H); C{ H} NMR (151 MHz, CDCl )
δ (ppm) 212.2, 187.8, 156.0, 138.7, 127.6, 126.8, 126.6, 118.9, 109.6, 82.0, 55.7, 53.9, 33.9, 27.0,
+
2
3
3.7, 23.5, 20.9, 19.5; HRMS (ESI) m/z calcd for C18
09.1458.
H22NaO
3
[M+Na] : 309.1461; found
For the detailed synthetic procedures, characterization data, and copies of spectra for the
compounds 71, 72, and cyrneine B in Scheme 8, see the Supplementary Information (SI) of ref 22.
O-((1S,2S)-2-Methyl-2-(3-methylbut-2-en-1-yl)-3-oxocyclopentyl) O-phenyl carbonothioate
(
77): To a solution of compound 9 (5.40 g, 29.6 mmol) and DMAP (0.36 g, 2.96 mmol, 0.1 equiv)
in DCM (70 mL) was added pyridine (4.8 mL, 59.3 mmol, 2.0 equiv) and PhOC(S)Cl (7.68 g,
4.5 mmol, 1.5 equiv). The reaction mixture was stirred for 4 h at room temperature. The solution
was quenched by H O (50 mL) and extracted with CH Cl (3 × 20 mL). The combined organic
layers were washed with brine (2 × 30 mL), dried over Na SO , filtered, and evaporated to dryness.
The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 30/1)
4
2
2
2
2
4
to afford the compound 77 (8.13 g, 86% yield) as a yellow oil.
= + 693.2 (c = 1.0 in
1
CHCl
3
); H NMR (300 MHz, CDCl
3
) δ (ppm) 7.44 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H),
7
2
.10 (d, J = 7.5 Hz, 2H), 5.60 (t, J = 3.6 Hz, 1H), 5.09 (t, J = 7.5 Hz, 1H), 2.52–2.42 (m, 2H),
1
3
1
3
.40–2.26 (m, 4H), 1.75 (s, 3H), 1.67 (s, 3H), 1.11 (s, 3H); C{ H} NMR (101 MHz, CDCl ) δ
(
ppm) 218.9, 194.2, 153.3, 135.3, 129.7, 126.8, 121.9, 118.5, 89.2, 53.3, 34.1, 29.6, 26.3, 25.1,
+
2
0.0, 18.1; HRMS (ESI) m/z calcd for C18
H
22NaO
3
S [M+Na] : 341.1182; found 341.1186.
(
2R)-5-Isopropyl-2-methyl-2-(3-methylbut-2-en-1-yl)cyclopentan-1-one (78): To a solution of
compound 77 (7.6 g, 23.8 mmol) and AIBN (0.04 g, 0.24 mmol, 1 mol%) in toluene (60 mL) was
added Bu SnH (12.7 mL, 47.6 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at 100
3
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