Total Synthesis of (±)-Taiwaniaquinol F and Related Taiwaniaquinoids

Article abstract of DOI:10.1021/acs.joc.5b01345

Total synthesis of (±)-taiwaniaquinol F (1a) has been accomplished via an efficient Lewis acid-catalyzed Nazarov-type cyclization of aryldiallylcarbinols (±)-2e derived from safranal 7. The methodology works under mild conditions using only 2 mol % of met

Full text of DOI:10.1021/acs.joc.5b01345

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Article
Total Synthesis of (±)-Taiwaniaquinol F and Related Taiwaniaquinoids
Badrinath N. Kakde, pooja kumari, and Alakesh Bisai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01345 • Publication Date (Web): 21 Sep 2015
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Total Synthesis of (±)-Taiwaniaquinol F and Related
Taiwaniaquinoids
†
Badrinath N. Kakde, Pooja Kumari, and Alakesh Bisai*
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Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Bhopal Bypass Road, Bhopal, Madhya Pradesh - 462 066, INDIA
TOC GRAPHIC
ABSTRACT
First total synthesis of (±)-taiwaniaquinol F (1a) has been accomplished via an
efficient Lewis acid catalyzed Nazarov type cyclization of aryldiallylcarbinols (±)-2a derived
from safranal 7. The methodology works under mild conditions using only 2 mol% metal
triflate as catalyst to afford a previously unknown carbotricyclic core sharing an olefin
functionality in excellent yields. The aforementioned methodology also offers enough
flexibility to complete the total syntheses of various taiwaniaquinoids, (±)-taiwaniaquinone H
(1d), (±)-dichroanone (1e), (±)-5-epi-taiwaniaquinone G (ent-1h), and (±)-taiwaniaquinol B
(
1b).
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INTRODUCTION
1
The taiwaniaquinoids (1a-k, Figure 1) are a family of unusual diterpenoids
possessing a [6,5,6]-abeo-abietane skeleton sharing an all-carbon quaternary stereocenter at
the pseudobenzylic position. Most of these diterpenoids have been isolated since 1995 from
Taiwania cryptomerioides Hayata (Taxodiaceae) of the central mountains of Taiwan
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independently by Cheng and Kuo, from Salvia dichroantha Stapf (Lamiaceae) a Turkish
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flowering sage by Kawazoe, and from Thuja standishii (Cupressaceae) a Japanese conifer by
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Tanaka. Reportedly, a few members of taiwaniaquinoids are found to exhibit potent
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b
cytotoxic activity against KB epidermoid carcinoma cancer cells and one of the members
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standishinal (1i) has shown aromatase inhibitory activity. Because of their diverse biological
profiles and uncommon structural features, the taiwaniaquinoids have gained extensive
attention from the synthetic community leading to numerous efficient approaches.
Figure 1: Selected taiwaniaquinoids (1a-k).
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The approaches to taiwaniaquinoids include, Pd(0)-catalyzed intramolecular reductive
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cyclization by Banerjee, domino intramolecular acylation carbonyl -tert-alkylation reaction
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by Fillion, intramolecular Heck cyclization by Node, Nazarov cyclization by Trauner,
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tandem acylation-Nazarov cyclization reaction by Chiu, acid promoted Friedel−Crafts
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acylation/alkylation approach independently by She
and Cheng,
intramolecular
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cyclization of aryldienes independently by Balme, Alvarez-Manzaneda and Majetich
1
6
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(
Scheme 1), ring contraction from abietane diterpenoids by Li, our Friedel-Crafts
1
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alkylations to set all-carbon quaternary center (Scheme 1), and thermal ring expansion/4π-
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electrocyclization by Hu, and other approaches. Asymmetric syntheses include,
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enantioselective decarboxylative allylation by Stoltz,
enantiospecific thermal 6π-
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electrocyclization by Alvarez-Manzaneda, enantioselective Heck reaction by Node, ring
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contraction of abietane diterpenoids by Gademann, semisynthesis involving cleavage of the
2
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C7−C8 double bond of abietane diterpenes by Alvarez-Manzaneda, iridium catalyzed
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borylation and palladium-catalyzed asymmetric -arylation by Hartwig, and recent Pd(0)-
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catalyzed enantioselective conjugate addition of arylboronic acid by Stoltz.
All these
above syntheses mainly concentrate on taiwaniaquinoids comprising a saturated gem-
dimethyl cyclohexane ring system (A ring of 1a-k). However, there is no report on
taiwaniaquinoids with various oxidation pattern of A-ring, such as (±)-taiwaniaquinol F (1a)
till date, mainly due to difficulty of functionalization of A-ring.
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Scheme 1: Our approach to taiwaniaquinoids.
We envisioned that, carbotricyclic core of type (±)-3 (Scheme 1) having an olefin
functionality at A-ring could be advanced intermediate to access various oxidized variants of
taiwaniaquinoids (1a). Herein, we report synthesis of carbotricycle (±)-3 by Lewis acid-
catalyzed Nazarov type cyclization and its application to a protecting-group-free first total
synthesis of (±)-taiwaniaquinol F (1a).
RESULTS AND DISCUSSION
For our study, arylvinyl carbinol (±)-2a-b was synthesized by 1,2-addition of the
aryllithium corresponding to arylbromides 6a or 6b to safranal 7 (Scheme 2). Having the key
intermediate aryldivinylcarbinol (±)-2a in hand, the stage was set for cyclization to 3a. At the
outset, we examined Nazarov type cyclization of (±)-2a using various Lewis acids in
different solvents to affect the synthesis of carbotricyclic structure (±)-3a (Table 1).
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Scheme 2: Synthesis of arylvinylcarbinol (±)-2a.
Initially, the Nazarov type cyclization of (±)-2a was carried out using 5 mol% of
Bi(OTf) using different solvents (entries 1-6, table 1) and it was found that dichloromethane
3
was preferred, and afforded (±)-3a in 99% isolated yield at 0 ºC in just 5 min (entry 5). This
is important to note that, inert atmosphere is not required for efficient reaction. The use of 5
Mol% of metal triflates such as Cu(OTf) , In(OTf) , Yb(OTf) , Zn(OTf) , Sc(OTf) ,
2
3
3
2
3
La(OTf)
and 98% isolated yields, respectively (entries 7-14). Interestingly, we found that 2 mol% of
Bi(OTf) and Sn(OTf) (entries 16-17) are equally efficient to furnish carbotricycle (±)-3a in
8% and 93% isolated yields, respectively. The high reactivity of (±)-2a is presumably due
the formation of the tertiary bis-allyic carbocation 4a during the course of the reaction.
Gratifyingly, 1 mol% of Bi(OTf) and Sn(OTf) also afforded cyclization products in 94%
3 3 2
, Nd(OTf) , or Sn(OTf) afforded (±)-3a in 87%, 71%, 62%, 64%, 74%, 55%, 67%,
3
2
9
3
2
and 62% isolated yields, respectively (entries 18-19). Significantly, the reaction is highly
regioselective involving only the aryl carbon para to the i-Pr group and affording only (±)-3a
presumably involvement of the aryl carbon ortho to i-Pr group is disfavored due to severe
steric crowding. Based on our optimization studies, we further choose 2 mol% of each
Bi(OTf) (condition A) and Sn(OTf) (condition B) for further substrate scope.
3
2
Table 1: Selected optimization of Nazarov type reaction of 2a.
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S. No.
1.
2.
Lewis acid (mol%)
5 mol% Bi(OTf)3
5 mol% Bi(OTf)3
5 mol% Bi(OTf)3
5 mol% Bi(OTf)3
5 mol% Bi(OTf)3
5 mol% Bi(OTf)3
5 mol% Cu(OTf)2
solvent
temp
25 ºC
25 ºC
25 ºC
25 ºC
0 ºC
0 ºC
25 ºC
0 ºC
25 ºC
25 ºC
0 ºC
25 ºC
0 ºC
0 ºC
25 ºC
0 ºC
time
3 h
2.5 h
% yield (3)
c
Et O
2
51%
80%
c
CHCl3
3
4
5
6
7
8
9
1
1
.
.
.
.
.
.
.
0.
1.
(CH Cl)
20 min
5 min
5 min
10 min
30 min
20 min
12 h
2 h
20 min
12 h
12 h
5 min
1 h
10 min
10 min
10 min
10 min
85%
82%
2
2
c
CH Cl
2
2
CH Cl
2
2
99%
86%
87%
CH CN
3
CH Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
c
5 mol% In(OTf)
3
CH
2
Cl
71%
c
5 mol% Yb(OTf)3
5 mol% Zn(OTf)2
5 mol% Sc(OTf)3
5 mol% La(OTf)3
5 mol% Nd(OTf)3
5 mol% Sn(OTf)2
2 mol% Cu(OTf)2
CH Cl
62%
2
c
CH Cl
2
64%
c
CH Cl
2
2
2
2
2
74%
c
12.
13.
14.
CH Cl
55%
c
CH Cl
67%
CH Cl
98%
79%
1
1
1
1
1
5.
6.
7.
8.
9.
CH Cl
d
2 mol% Bi(OTf)
2 mol% Sn(OTf)
3
CH
CH
2
2
Cl
Cl
98%
e
2
0 ºC
0 ºC
0 ºC
93%
1 mol% Bi(OTf)3
1 mol% Sn(OTf)2
CH Cl
94%
62%
2
2
CH Cl
a
b
all the reactions were performed using 0.3 mmol of (±)-2a. isolated yields after column
c
d
chromatography. decomposition of the rest of the mass balance. 2 mol% of Bi(OTf) (condition A).
3
e
2
2 mol% of Sn(OTf) (condition B).
Aryldivinyl carbinols (±)-2b-d were then subjected to our optimized conditions to
access carbotricyclic cores (±)-3b-d and the results are shown in Scheme 3. We found that
the arylvinyl carbinols (±)-2a-c containing electron-donating group/s were good starting
materials for this process, which afforded products 3b-c in good to excellent yields (Scheme
3
). Interestingly, we also observed that arylvinylcarbinols (±)-2d with no aromatic ring
substituent also afforded (±)-3d in high yields (Scheme 3).
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2
mol% of Bi(OTf)
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(condition A); 2 mol% of Sn(OTf) (condition B)
Scheme 3: Substrate scope of Nazarov type cyclization of (±)-2a-d.
Targeting carbotricyclic core (±)-3e having additional olefin functionality (Scheme 5),
we synthesized aryldivinyl carbinol (±)-2e (Scheme 4). 1,2,4-Trimethoxybenzene (8a) was
reacted with acetone in presence of n-BuLi and TMEDA at 0˚C to afford benzylalcohols 8b
in 62% yield, which was then reacted in presence of Sn(OTf) to fºurnish -methylstyrenes
2
8c 79% yield. The later was hydrogenated in presence of Pd-C at 1 atm. pressure to afford
cumene derivative 8d in 97% yield, which was then reacted with N-bromo succinimide
(
(
NBS) to afford bromoarene 8e in 94% yield. From this bromoarene 8e, aryldivinyl carbinols
±)-2e was synthesized in 91% yield (Scheme 4). We found that, when (±)-2e was reacted
under our optimized conditions A and B, it afforded product (±)-3e in 80-95% (Scheme 5).
Scheme 4: Synthesis of arylvinylcarbinol (±)-2e.
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Scheme 5: Total synthesis of (±)-taiwaniaquinol F (1a).
With carbotricyclic core (±)-3e in hand, we were positioned to complete the total
2
synthesis of (±)-taiwaniaquinol F (1a). Thus, allylic oxidation of (±)-3e with SeO in
dioxane:water afforded allylalcohol (±)-9 as single diastereomer in 83% yield (Scheme 5).
The excellent diastereoselectivity observed in this allylic oxidation was attributed to approach
2
9
2
of the oxidant SeO from less hindered convex face of substrate (±)-3e. In fact energy
minimization (MM2) calculation of diene 3e (Figure 2) also supports our observed
selectivity.
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Figure 2. Energy-minimized representation of 3e.
Neopentyl alcohol (±)-9 was oxidized to obtain ,-unsaturated ketone (±)-10 in 94%
yield under Swern oxidation conditions. Enone (±)-10 was then hydrogenated in the presence
of 10% Pd-C at 5 bar pressure of H
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in MeOH to afford tricyclic ketone (±)-11 in 98% yield.
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in presence of 3,5-dimethylpyrazole to effect benzylic
Later, (±)-11 was reacted with CrO
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oxidation to furnish diketone (±)-12 in 86% yield, the structure of which was confirmed
from X-ray crystallography (CCDC: 1405987). From intermediate (±)-12, total synthesis of
(
±)-taiwaniaquinol F 1a was completed in 3 steps in 65% overall yield by the treatment with
BBr followed by oxidation using ceric(IV) ammonium nitrate (CAN) and finally reduction
with Na . The X-ray structure of (±)-1a (CCDC: 1405985) unambiguously proved the
3
2 2 5
S O
structure of (±)-taiwaniaquinol F 1a.
Further, we turned our attention to pursue total syntheses of (±)-taiwaniaquinone H
(
1d) and (±)-dichronanone (1e) from a common precursor (±)-3e. For this purpose, we
synthesized carbotricyclic core (±)-13 from (±)-3e via selective hydrogenation of the more
exposed disubstituted olefin (A-ring) over trisubstituted styrene olefin (B-ring) in presence of
1
2
0% Pd-C under 1 atm. pressure of H in MeOH (Scheme 6). This reaction led to the
formation of required carbotricycle (±)-13 in 50% isolated consistently produced the over
reduced cis-fused (±)-14 in 48% yield. This is probably due to the preferential hydrogenation
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from less hindered convex face (Figure 2) leading to the formation of highly stereoselective
cis-fused (±)-14.
With (±)-13 in hand, we then performed ceric(IV) ammonium nitrate (CAN) mediated
oxidative transformation of (±)-13 to p-quinone, thus completing total synthesis of (±)-
taiwaniaquinone H (1d) in 63% yield. The later was then demethylated using 2(N) KOH in
MeOH to complete total synthesis of (±)-dichroanone (1e) (Scheme 6).
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Scheme 6: Total syntheses of (±)-taiwaniaquinone H (1d) and (±)-dichroanone (1e).
For further synthetic elaboration, carbotricyclic core (±)-3e was completely
2
hydrogenated in presence of 10% Pd-C under 1 atm. pressure of H in MeOH for 1 h to
furnish (±)-14 in 98% yield, which was then followed by an oxidative quinone formation in
presence of CAN to accomplish total synthesis of (±)-5-epi-taiwaniaquinone G (1c) in 63%
overall yield from (±)-3e (Scheme 7). To our delight, it was found that oxidative quinone
formation of carbotricyclic cores (±)-13 and (±)-14 having electron-rich systems work fine
only in the presence of CAN (Schemes 6 and 7).
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Scheme 7: Total synthesis of (±)-5-epi-taiwaniaquinone G (ent-1h).
Next, we were interested to complete total synthesis of (±)-taiwaniaquinol B (1b)
from dimethylether of (±)-16. We thought that tricyclic ketone (±)-16 can be synthesized
.
22b
from a BF OEt -mediated rearrangement of epoxide (±)-15 (Scheme 8), which in turn can
3
2
be accesses from olefin (±)-13 via a reaction with m-chloroperbenzoic acid (m-CPBA). In
forward direction, we oxidized olefin (±)-13 in the presence of m-CPBA to furnish epoxide
.
(
±)-15 in quantitative yield. However, as per literature shown in Scheme 9, BF
3
OEt
2
22b
treatment of (±)-15 didn't afford even trace amount of the expected tricyclic ketone (±)-16.
MeO
Me
m-CPBA
NaHCO3
MeO
Me
Me OMe
OMe
Me
OMe
Me
.
BF3 OEt2
OMe
Me
CH Cl , 0 C
CH2Cl2, 0 C
2
2
O
Me
Me
74%
over 2 steps
quant
Me
Me
OMe
O
OMe
H
OMe Me
17
Me
Me
Me
Me
-
13
-
15
-
Me S-I
3
MeO
Me
NaH, DMF
OMe
Me
98%
Me OMe
OMe
Me
Me
Me
H
OMe
Me
O
O
H
Me
OMe Me
18
-16
not formed
Me
-
Scheme 8: Unexpected formation of (±)-17.
In fact, from this reaction, we could only isolate unexpected ring expansion ketone
(±)-17 as the sole product in 74% yield. Reaction of ketone (±)-17 with trimethylsulfonium
iodide in the presence of sodium hydride afforded product (±)-18, which was unambiguously
confirmed from X-ray structure (CCDC: 1405989).
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2
2b
Scheme 9: Synthesis of tricyclic ketone 20 by Alvarez-Manzaneda.
A plausible mechanism of the formation of cycloheptane ring of (±)-17 shown in
.
Scheme 10. In presence of BF
3
OEt
2
, (±)-15 forms intermediate 21 which forms a benzylic
carbocation 22, from where a 1,2-migration of 3º alkyl group leads to the formation of ketone
±)-17 via a carbocation 23. The stability of carbocation 22 is attributed because of highly
(
electron-rich aromatic ring, which stabilizes 22 via intermediates 22a-b (Scheme 10).
Scheme 10: Unexpected formation of 7-membered (±)-17.
Thus, we adopted an alternate route, in which carbotricyclic core (±)-14 was reacted
3
with CrO in the presence of 3,5-dimethylpyrazole to effect benzylic oxidation to furnish
ketone (±)-16 in 91% yield. From this intermediate, total synthesis of (±)-taiwaniaquinol B
was accomplished in a three step sequence in 52% overall yield via demethylation using
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BBr
3
2 2 5
, oxidation in presence of CAN followed by reduction with Na S O (Scheme 11). It was
observed that oxidative quinone formation of carbotricyclic cores (±)-12 and (±)-16 with
electron-deficient systems with CAN was unsuccessful and, hence, a three-step sequence was
used (Scheme 11).
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11
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13
14
15
16
17
18
19
20
21
22
23
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45
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47
48
49
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52
53
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56
57
58
59
60
Scheme 11: Total synthesis of (±)-taiwaniaquinol B (1b).
CONCLUSIONS
In summary, we have demonstrated an operationally simple, inexpensive, yet efficient
process for the synthesis of a variety of taiwaniaquinoids via a Nazarov type cyclization of
aryldivinyl carbinols in the presence of a catalytic amount of a metal triflate as Lewis acid.
The methodology affords a variety of carbotricyclic structures in excellent yields. This
methodology has been applied to first total synthesis of (±)-taiwaniaquinol F (1a) by using
minimum protecting groups in 36.4% overall yield starting from safranal (7) over 8 steps. In
addition, we have also accomplished concise and straightforward total syntheses of (±)-
taiwaniaquinone H (1d), (±)-dichronanone (1e), (±)-5-epi-taiwaniaquinone G (ent-1h) and
(±)-taiwaniaquinol B (1b). Further exploration of this strategy towards the synthesis of trans-
fused taiwaniaquinoids is currently under active investigations in our laboratory.
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EXPERIMENTAL SECTION
EXPERIMENTAL SECTION
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Materials. Unless otherwise stated, reactions were performed in oven-dried glassware fitted
with rubber septa under a nitrogen atmosphere and were stirred with Teflon-coated magnetic
stirring bars. Liquid reagents and solvents were transferred via syringe using standard
Schlenk techniques. Tetrahydrofuran (THF), diethyl ether (Et
2
O) was distilled over
sodium/benzophenone ketyl. Dichloromethane (CH Cl ) and toluene were distilled over
2
2
calcium hydride. All other solvents such as acetonitrile, chloroform, methanol, 1,2-
dichloroethane and reagents were used as received. Thin layer chromatography was
performed using silicagel 60 F-254 precoated plates (0.25 mm) and visualized by UV
irradiation, anisaldehyde stain and other stains. Silicagel of particle size 100-200 mesh was
1
13
used for flash chromatography. H and C NMR spectra were recorded on 400 MHz, 500
1
3
MHz and 500 MHz spectrometers with C operating frequencies of 100, 125 MHz,
respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent (CDCl
3
1
13
1
6
and DMSO-d ) signal (δ = 7.26 for H NMR and δ = 77.0 for C NMR). Data for H NMR
spectra are reported as follows: chemical shift (multiplicity, coupling constants, number of
hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broad). IR spectra were recorded on a FT-IR system (Spectrum BX) and are
-1
reported in frequency of absorption (cm ). Only selected IR absorption bands are reported.
High-Resolution Mass Spectrometry (HRMS) data were recorded on MicrOTOF-Q-II mass
spectrometer using methanol as solvent.
General procedure for the synthesis of arylvinylcarbinol ±(2a-c and 2e): A flame-dried
round-bottom flask was charged with substituted bromoarene (13.56 mmol; 1.1 equiv) under
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nitrogen atmosphere in dry THF (30 mL). To this solution was added 7.5 mL of 2.0 M
solution of n-BuLi in cyclohexane (14.92 mmol; 1.2 equiv) dropwise via syringe over a
period of 5 min at 78 ºC. After 5 min. of stirring at this temperature, safranal 7 (1.8 mL,
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
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1.30 mmol; 1.0 equiv) (dissolved in 10 mL THF) was added dropwise via syringe over a
period of 5 min. The mixture was treated with saturated aq. solution of NH Cl over a period
4
of 5 min. Then, it was transferred to the separatory funnel and shaken vigorously. An aqueous
layer was extracted with EtOAc (50 mL X 2). The combined EtOAc extracts were dried over
anhydrous Na SO and concentrated in rotary evaporator under vacuum. The crude product
2
4
was finally purified by column chromatography with EtOAc/hexane (1:9) to afford pure
compound (±)-2.
(
3-Isopropyl-4-methoxyphenyl)(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)methanol ±(2a):
The product was obtained as colorless viscous oil (2.3 g, 68%), R = 0.5 (20% EtOAc in
f
1
hexane). H NMR (400 MHz, CDCl
3
) δ 7.30 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 8.4, 1.6 Hz,
1
H), 6.80 (d, J = 8.5 Hz, 1H), 5.78-5.77 (m, 2H), 5.69 (d, J = 4.6 Hz, 1H, CH-OH), 3.81 (s,
3H), 3.30 (septet, J = 6.9 Hz, 1H), 2.08-2.07 (m, 2H), 1.88-1.87 (m, 1H), 1.74 (s, 3H), 1.20
13
(
d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H), 1.04 (s, 3H), 0.99 (s, 3H); C NMR (100
MHz, , CDCl ) δ 155.6, 140.9, 136.6, 135.2, 130.1, 128.8, 125.5, 124.23, 124.2, 109.9, 71.5,
3
5
1
5.4, 40.7, 34.2, 27.0, 26.8, 26.5, 22.8, 22.7, 19.6; IR (film) υmax 3460, 3033, 2959, 1498,
-1
+
465, 1245, 1089, 1035, 734 cm . HRMS (ESI) m/z 323.1998 [(M + Na)] ; calculated for
+
[C20
H
28
O
2
+ Na] : 323.1982.
(
4-Methoxy-3-methylphenyl)(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)methanol
(2b):
The product was obtained as colorless viscous oil (2.0 g, 66%), R
f
= 0.6 (10% EtOAc in
1
hexane). H NMR (500 MHz, CDCl
3
) δ 7.23-7.21 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 5.81-
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2
2
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1
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1
.73 (m, 2H),5.66 (d, J = 2.6 Hz, 1H), 3.82 (s, 3H), 2.22 (s, 3H), 2.10-2.07 (m, 1H), 1.83-
1
3
.82 (m, 1H), 1.74 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H); C NMR (125 MHz, CDCl ) δ 156.6,
3
39.9, 135.1, 130.1, 128.8, 128.7, 126.2, 125.5, 124.5, 73.3, 55.3, 40.6, 34.2, 27.1, 26.5, 19.6,
0
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2
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4
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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
6.4; IR (film) υmax 3500, 3433, 2956, 2918, 1503, 1463, 1250, 1127, 1110, 1036, 814, 700
-1
+
+
24 2
cm ; HRMS (ESI) m/z 295.1673 [(M + Na)] ; calculated for [C18H O + Na] : 295.1669.
(
2,4,5-Trimethoxyphenyl)(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)methanol (2c): The
f
product was obtained as colorless viscous oil (2.76 g, 77%), R = 0.45 (20% EtOAc in
1
hexane). H NMR (400 MHz, CDCl
3
+DMSO-D
6
) δ 7.0 (s, 1H), 6.46 (s, 1H), 5.70-5.56 (m,
3H), 3.91 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.66 (s, 3H), 1.98 (d, J = 17.0 Hz, 1H), 1.86 (dd,
1
3
J = 17.0, 4.5 Hz, 1H), 1.76 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H); C NMR (100 MHz,
CDCl +DMSO-D ) δ 151.7, 148.8, 142.3, 138.4, 130.6, 128.3, 124.6, 123.3, 113.5, 97.6,
67.1, 56.7, 56.2, 56.1, 40.6, 34.4, 26.7, 25.7, 20.0; IR (film) υmax 3500, 2934, 2360, 1609,
3
6
-1
+
1
506, 1466, 1309, 1206, 1105, 1035, 861, 768 cm ; HRMS (ESI) m/z 317.1739 [(M - H)] ;
+
calculated for [C19
H
26
O
4
- H] : 317.1747.
(
3-Isopropyl-2,4,5-trimethoxyphenyl)(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)methanol
f
(2e): The product was obtained as colorless solid (3.7 g, 91%), R = 0.5 (10% EtOAc in
1
hexane). H NMR (400 MHz, CDCl
3
) δ 6.82 (s, 1H), 5.81-5.82 (m, 2H), 5.77-5.73 (m, 1H),
3
.84 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.36 (septet, J = 7.0 Hz, 1H), 3.32 (d, J = 1.6 Hz, 1H),
2.13-2.00 (m, 2H), 1.83 (s, 3H), 1.36 (d, J = 7.1 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.10 (s,
13
3
1
H), 0.93 (s, 3H); C NMR (100 MHz, CDCl ) δ 150.1, 149.1, 148.6, 137.3, 135.0, 130.3,
3
30.26, 129.8, 125.0, 110.5, 69.0, 62.0, 60.6, 55.9, 40.3, 34.3, 26.8, 26.0, 25.6, 21.9, 20.3; IR
-1
◦
(
film) υmax 3472, 2957, 1589, 1455, 1235, 1105, 1041, 855 cm ; MP 105-108 C.
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Procedure for synthesis of (±)-2d: A flame-dried round-bottom flask was charged with
safranal 7 (3.21 mmol; 1.0 equiv) under nitrogen atmosphere in dry THF (10 mL). The
°
reaction mixture was cooled to 0 C. To this solution was added 1.0 M solution of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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60
phenylmagnesium bromide in THF (3.86 mmol; 1.2 equiv) drop wise via a syringe over a
period of 5 min and stirring was continued for additional 1 h. The mixture was treated with
saturated aq. solution of NH Cl for 5 min. It was transferred to the separatory funnel and
4
shaken vigorously. An aqueous layer was extracted with EtOAc. The combined EtOAc
extracts were dried over anhyd. Na SO and concentrated using rotator evaporator under
2
4
vacuum. The crude product was finally purified by column chromatography with
EtOAc/hexane to afford pure compound (±)-2d.
Phenyl(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)methanol±(2d): The product was obtained
1
as colorless viscous oil (734 mg, 94%), R
CDCl
m, 2H), 2.13 (m, 1H), 2.04 (d, J = 4.8 Hz, 1H), 1.75 (s, 3H), 1.14 (s, 3H), 1.03 (s, 3H); C
NMR (125 MHz, CDCl ) δ: 143.8, 139.9, 129.9, 128.1, 126.5, 125.9, 125.8, 71.45, 40.8,
4.3, 27.1, 26.7, 19.5; IR (film) υmax 3438, 2955, 2914, 1445, 1359, 1168, 1004, 984, 837,
f
= 0.5 (5% EtOAc in hexane). H NMR (500 MHz,
3
) δ: 7.52-7.50 (m, 2H), 7.38-7.35 (m, 2H), 5.29-7.25 (m, 1H), 5.84 (s, 1H), 5.83-5.80
13
(
3
3
7
-1
+
+
21, 703 cm ; HRMS (ESI) m/z 251.1384[(M + Na)] ; calculated for [C16H20O + Na] :
251.1406.
General procedure for metal triflate-catalyzed cyclization of arylvinylcarbinols: In an
oven-dried round-bottom flask, aryldivinyl carbinols (0.3 mmol; 1.0 equiv.) was dissolved in
dichloromethane (3 mL) and cooled to 0 ºC. To this solution solid Bi(OTf)
3
(2 mol%)
[Condition A] or Sn(OTf) (2 mol%) [Condition B] was added. The reaction mixture was
2
stirred at 0 ºC for indicated time (5-10 min). Upon complete consumption of starting material
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(
3
TLC) the reaction mixture was quenched with saturated NaHCO solution. The whole
reaction mixture was transferred to a separatory funnel and extracted with 5 mL of EtOAc.
The organic layer was dried over anhydrous Na SO and concentrated in a rotary evaporator
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
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7
8
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1
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4
5
6
7
8
9
0
under vacuum. The crude products were purified by flash chromatography (10:1
hexanes/EtOAc) to afford cyclization products.
7
-Isopropyl-6-methoxy-1,1,4a-trimethyl-2,4a-dihydro-1H-fluorene (3a): The product
1
was obtained as colorless viscous oil (83 mg, 98%), R = 0.5 (2% EtOAc in hexane). H
f
3
NMR (400 MHz, CDCl ) δ 7.11 (s, 1H), 6.86 (s, 1H), 6.36 (s, 1H), 6.0 (d, J = 9.4 Hz, 1H),
5.58-5.54 (m, 1H), 3.85 (s, 3H), 3.34-3.28 (m, 1H), 2.18 (dd, J = 17.2, 5.0 Hz, 1H), 1.96 (bd,
J = 17.2 Hz, 1H), 1.44 (s, 3H), 1.35 (s, 6H), 1.23 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 7.0 Hz,
1
3
3
H); C NMR (100 MHz, CDCl ) δ 161.1, 154.8, 150.1, 135.3, 134.7, 131.8, 125.1, 120.8,
3
118.1, 104.9, 56.0, 53.3, 45.4, 34.9, 29.3, 27.1, 27.0, 26.7, 23.2, 22.9; IR (film) υmax 2960,
-1
+
2
931, 1464, 1419, 1256, 1044, 888 cm ; HRMS (ESI) m/z 283.2076 [(M + H)] ; calculated
+
for [C20
H
26O + H] : 283.2056.
6
-Methoxy-1,1,4a,7-tetramethyl-2,4a-dihydro-1H-fluorene (3b): The product was
1
f
obtained as colorless viscous oil (73 mg, 96%), R = 0.5 (2.5% EtOAc in hexane). H NMR
(400 MHz, CDCl
3
) δ 7.03 (s, 1H), 6.85 (s, 1H), 6.32 (s, 1H), 6.02-6.00 (m, 1H), 5.59-5.54
(
m, 1H), 3.86 (s, 3H), 2.21 (s, 3H), 2.17-2.15 (m, 1H), 1.98-1.94 (m, 1H), 1.44 (s, 3H), 1.35
1
3
(s, 6H); C NMR (100 MHz, CDCl ) δ 161.2 155.7, 151.6, 134.5, 131.7, 125.1, 124.7,
3
1
1
22.7, 120.5, 104.5, 55.8, 53.3, 45.4, 35.0, 29.2, 27.0, 26.97, 16.4; IR (film) υmax 3024, 2915,
-1
+
482, 1463, 1292, 1195, 1042, 880, 701 cm ; HRMS (ESI) m/z 255.1730 [(M + H)] ;
+
calculated for [C18
H
22O + H] : 255.1743.
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5
,6,8-trimethoxy-1,1,4a-trimethyl-2,4a-dihydro-1H-fluorene (3c): The product was
1
obtained as colorless viscous oil (63 mg, 70%), R
400 MHz, CDCl
H), 3.87 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 2.17-2.11 (dd, J = 17.1, 5.1 Hz, 1H), 2.0-1.92 (d,
f
= 0.55 (10% EtOAc in hexane). H NMR
(
3
) δ 6.41 (s, 1H), 6.40 (s, 1H), 6.28 (dd, J = 9.7, 2.2 Hz, 1H), 5.58-5.54 (m,
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
1
3
J = 17.1 Hz, 1H), 1.50 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
3
7
3
60.3, 151.2, 148.3, 145.3, 139.7, 131.1, 125.1, 123.8, 116.3, 97.0, 61.0, 56.5, 56.2, 45.1,
5.0, 29.3, 27.0, 24.6; IR (film) υmax 2958, 2835, 1614, 1468, 1314, 1269, 1125, 1045, 987,
-
1
+
+
35 cm ; HRMS (ESI) m/z 301.1798 [(M + H)] ; calculated for [C19
H
24
O
3
+ H] :
01.1798.
1
,1,4a-trimethyl-2,4a-dihydro-1H-fluorene ±(3d): The product was obtained as colorless
1
viscous oil (55 mg, 88%), R = 0.5 (in hexane). H NMR (500 MHz, CDCl ) δ: 7.31 (d, J =
f
3
7.2 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.28 (td, J = 7.4, 1.1 Hz, 1H), 7.13 (td, J = 7.4, 1.2 Hz,
1
1
H), 6.43 (s, 1H), 6.06-6.04 (m, 1H), 5.59-5.56 (m, 1H), 2.23-2.18 (m, 1H), 2.00-1.96 (m,
1
3
3
H), 1.45 (s, 3H), 1.37 (s, 3H), 1.37 (s, 3H); C NMR (125 MHz, CDCl ) δ: 163.3, 152.6,
142.2, 131.5, 126.5, 125.0, 124.3, 121.1, 121.06, 120.6, 53.2, 45.2, 35.0, 29.3, 26.9, 26.7; IR
-1
(
film) υmax 3017, 2960, 2916, 1465, 1363, 1256, 1048, 987, 872, 848, 792, 746, 712 cm ;
+
+
HRMS (ESI) m/z 211.1482 [(M + H)] ; calculated for [C H + H] : 211.1481.
16 18
7
-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,4a-dihydro-1H-fluorene (3e): The
f
product was obtained as colorless solid (992 mg, 95%, (in 3.05 mmol)), R = 0.6 (5% EtOAc
1
in hexane). H NMR (400 MHz, CDCl
3
) δ 6.4 (s, 1H), 6.28 (dd, J = 9.7, 2.1 Hz, 1H), 5.59-
5
4
.54 (m, 1H), 3.90 (s, 3H), 3.81 (s,3H), 3.80 (s, 3H), 3.47-3.39 (m, 1H), 2.17 (dd, J = 17.0,
1
3
.7 Hz, 1H), 1.99-1.95 (m, 1H), 1.52 (s, 3H), 1.34-1.33 (m, 9H), 1.31 (d, J = 2.2 Hz, 3H) ; C
NMR (100 MHz, CDCl
3
) δ 162.0, 149.5, 147.5, 145.5, 142.4, 132.2, 131.3, 130.2, 124.9,
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
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6
1
17.2, 62.0, 60.5, 60.2, 54.5, 45.2, 35.1, 29.3, 27.0, 24.8, 22.22, 22.21; IR (film) υmax 2960,
-1
+
1
455, 1415, 1120, 1051 cm ; HRMS (ESI) m/z 343.2296 [(M + H)] ; calculated for
+
°
22 30 3
[C H O + H] : 343.2268; MP 71-74 C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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8
9
0
Synthesis of (2,4a)-7-isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,4a-dihydro-1H-
fluoren-2-ol (9): In a sealed tube, compound 3e (910 mg, 2.66 mmol; 1.0 equiv) was taken
in mixture of dioxane (12 mL) and water (3 mL) (4:1 ratio). To this solution was added SeO2
(
354 mg, 3.19 mmol; 1.2 equiv) at room temperature. Then, the reaction mixture was hedted
to reflux at 105 °C and stirring was continued for 22 h. After full consumption of starting
material (judged by TLC) the reaction mixture was extracted with ethyl acetate and purified
by column chromatography (9:1 hexanes/EtOAc) to furnish 790 mg (83% yield) of (±)-9 as
1
white solid. R 0.5 (20% EtOAc in hexanes); H NMR (500 MHz, CDCl ) δ 6.56 (s, 1H),
f
3
6.44 (d, J = 9.6 Hz, 1H), 5.81 (dd, J = 9.6, 5.1 Hz, 1H), 3.91 (s, 3H), 3.83 (s,3H), 3.82 (s,
3
1
H), 3.73 (dd, J = 10.9, 5.1 Hz, 1H), 3.44 (septet, J = 7.1 Hz, 1H), 1.51 (s, 3H), 1.36 (s, 3H),
.338 (d, J = 7.0 Hz, 3H), 1.332 (s, 3H), 1.331 (d, J = 7.1 Hz, 3H), 0.86 (d, J = 11.1 Hz, 1H);
1
3
C NMR (125 MHz, CDCl
3
) δ 157.1, 149.9, 147.4, 145.5, 141.5, 134.8, 133.6, 129.6, 127.1,
1
3
3
21.1, 76.6, 62.1, 60.5, 60.2, 54.7, 40.9, 25.7, 25.4, 23.6, 23.5, 22.18, 22.16; IR (film) υmax
-
1
472, 3019, 2918, 1445, 1414, 1333, 1272, 1121, 1050, 989, 701 cm ; HRMS (ESI) m/z
+
+
°
30 4
59.2232 [(M + H)] ; calculated for [C22H O + H] : 359.2217; MP 69-71 C.
Synthesis
of
7-isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-1H-fluoren-2(4aH)-one
Cl (20

(10): To a stirred solution of dry DMSO (0.53 mL, 7.97 mmol; 4.5 equiv.) in CH
2
2
mL) at -78 °C was added oxalyl chloride (0.3 mL, 3.55 mmol; 2.0 equiv.) carefully. Then the
mixture was stirred for 20 min. at -78 °C followed by drop wise addition of compound (±)-9
2 2
(635 mg, 1.77 mmol, 1.0 equiv) in CH Cl (5 mL). The reaction mixture was stirred for 1 h at
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-
3
78 °C followed by addition of Et N (1.23 mL, 8.88 mmol; 5.0 equiv.) at same temperature.
Later, the reaction was slowly brought to room temperature. Upon completion of starting
material (monitored by TLC) the reaction mixture was diluted with water (20 mL) and
extracted with CH Cl (20 X 2 mL). The organic layer was dried over anhydrous Na SO and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
2
2
4
concentrated in vacuo. The crude material was purified in flash chromatography (15:1
hexanes/EtOAc) to give 593 mg (94% yield) of (±)-10 as white solid. R  0.6 (10% EtOAc
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.52 (d, J = 9.7 Hz, 1H), 6.57 (s, 1H), 5.97 (d, J
=
9.8 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 3.45 (septet, J = 7.0 Hz, 1H), 1.69 (s, 3H), 1.50 (s,
13
3
H), 1.48 (s, 3H), 1.33 (d, J = 7.1 Hz, 3H), 1.33 (d, J = 7.1 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 202.7, 155.9, 150.6, 150.1, 147.8, 145.7, 139.0, 134.5, 129.8, 127.3, 121.0, 62.2,
3
6
1
0.5, 60.2, 54.3, 47.8, 26.5, 25.7, 24.8, 23.7, 20.1; IR (film) υmax 2982, 2923, 1681, 1462,
-1
+
450, 1415, 1338, 1272, 1122, 1048, 1019, 826 cm ; HRMS (ESI) m/z 357.2067 [M+H] ;
+
calculated for [C22
H
28
O
4
+ H] : 357.2060; MP 104-106 °C.
Synthesis of (4a)-7-isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-4,4a,9,9a-tetrahydro-
H-fluoren-2(3H)-one (11): In an oven-dried pear shaped round bottom flask compound
±)-10 (500 mg, 1.40 mmol) was dissolved in HPLC grade methanol (70 mL). This solution
1
(
was passed through H-Cube Hydrogenator having 10% Pd/C cartridge at 34 °C and 5 bar
pressure having 0.3 mL/min flow of solution. Then the reaction mixture was concentrated
under reduced pressure. The crude product was purified by flash chromatography (10:1
f
hexanes/EtOAc) to afford 495 mg (98% yield) of (±)-11 as a white solid. R = 0.5 (10%
1
EtOAc in hexane); H NMR (500 MHz, CDCl
3
) δ 3.84 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H),
3
2
1
.39 (septet, J = 7.1 Hz, 1H), 3.10 (dd, J = 16.5, 9.1 Hz, 1H), 2.53 (dd, J = 16.5, 7.7 Hz, 1H),
.49-2.43 (m, 1H), 2.27 (dd, J = 9.0, 7.7 Hz, 1H), 2.24-2.21 (m, 2H), 2.17-2.11 (m, 1H),
.60 (s, 3H), 1.316 (d, J = 7.1 Hz, 3H), 1.314 (d, J = 7.1 Hz, 3H), 1.29 (s, 3H), 1.06 (s, 3H);
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2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
C NMR (125 MHz, CDCl
3
) δ 217.3, 151.5, 149.7, 146.2, 141.6, 133.6, 128.9, 60.4, 60.2,
6
2
3
0.0, 55.8, 47.3, 47.28, 36.4, 33.5, 33.4, 28.9, 26.7, 25.7, 23.7, 22.1; IR (film) υmax 2969,
-
1
909, 1712, 1463, 1449, 1412, 1337, 1268, 1118, 1047, 976, 741 cm ; HRMS (ESI) m/z
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
+
+
61.2348 [M+H] ; calculated for [C H O + H] : 361.2373; MP 79-81 °C.
2
2
32
4
Synthesis
of
(4a)-7-isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-4,4a-dihydro-1H-
fluorene-2,9(3H,9aH)-dione (12): To a stirred solution of 3,5-dimethylpyrazole (4.16 g,
3.31 mmol; 17.93 equiv) in CH Cl (10 mL) was added CrO (4.3 g, 43.31 mmol; 17.93
4
2
2
3
equiv) at -15 ºC. Then the reaction mixture was stirred for 15 min. at same temperature
before a solution of tricyclic compound (±)-11 (870 mg, 2.41 mmol; 1.0 equiv) in CH Cl (5
2
2
mL) was added drop wise. This dark mixture was stirred for 1 h at -10 ºC and it was directly
purified by flash chromatography (10:1 hexanes/EtOAc) to furnish 777 mg (86% yield) of
1
(±)-12 as a white solid. R
f
= 0.55 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl
3
) δ
3
2
.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.46 (septet, J = 7.1 Hz, 1H), 2.52-2.43 (m, 3H),
.33-2.26 (m, 1H), 2.26 (s, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H), 1.00 (s,
1
3
3H); C NMR (100 MHz, CDCl
3
) δ 215.3, 201.8, 159.1, 152.8, 152.4, 146.0, 135.7, 124.1,
6
2
3.2, 62.2, 60.2, 60.0, 46.7, 41.1, 34.8, 30.3, 28.3, 25.3, 25.2, 22.3, 21.7; IR (film) υmax 2962,
-1
925, 1704, 1579, 1469, 1449, 1415, 1316, 1272, 1129, 1045, 958, 701 cm ; HRMS (ESI)
+
+
30 5
m/z 375.2192 [M+H] ; calculated for [C22H O + H] : 375.2166; MP 112-114 °C.
Synthesis of ()-taiwaniaquinol F (1a): To a stirred solution of compound (±)-12 (166 mg,
.444 mmol; 1.0 equiv) in dry CH Cl (6 mL) was added BBr (147 µL, 1.55 mmol; 3.5
0
2
2
3
equiv) at -78 ºC. Then the reaction mixture was stirred for 1.5 h. After complete consumption
of starting material (judged by running tlc), the reaction mixture was quenched with water
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and extracted with ethyl acetate (10 X 2 mL). The organic layer was dried over anhydrous
Na SO and concentrated in vacuo.
2
4
2
The crude product was taken in 20 mL of MeCN:H O (3:1) at 0 ºC. To this reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mixture, a solution of ammonium ceric nitrate (CAN) (1217 mg, 2.22 mmol; 5.0 equiv) in
water (7 mL) was added and it was stirred for 20 minutes at 0 ºC. After complete
consumption of starting material, the reaction mixture was quenched with saturated aqueous
2 2 5
solution of Na S O and kept on stirring for 20 min. Upon completion of the reaction (judged
by running tlc), it was diluted by water (10 mL) and extracted with EtOAc (25 mL) by using
a separatory funnel. The organic filtrate was dried over anhydrous Na SO and concentrated
2
4
in a rotary evaporator under vacuum. The crude was purified by flash chromatography (4:1
hexanes/EtOAc) to afford 99 mg (overall 65% yield in two steps) of ()-taiwaniaquinol F
1
(
1a) as crystalline solid. R
f
= 0.45 (20% EtOAc/hexanes); H NMR (700 MHz, CDCl
3
) δ
9.41 (s, 1H), 5.48 (s, 1H), 3.81 (s, 3H), 3.28 (septet, J = 7.1 Hz, 1H), 2.50-2.39 (m, 4H), 2.38
(s, 1H), 1.51 (s, 3H), 1.41 (s, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.37 (d, J = 7.1 Hz, 3H), 1.13 (s,
1
3
3
3
H); C NMR (125 MHz, CDCl ) δ 214.9, 208.3, 152.9, 151.0, 141.4, 138.5, 127.0, 118.0,
63.2, 62.1, 46.8, 42.0, 34.6, 29.4, 26.7, 26.0, 25.8, 22.2, 20.53, 20.52; IR (film) υmax 3418
-1
(
(
[
br), 2997, 2967, 2915, 1708, 1660, 1425, 1328, 1112, 1021, 932, 891, 739, 701 cm ; HRMS
+
+
ESI) m/z 347.1832 [M+H] ; calculated for [C H O + H] : 347.1853; MP 119-121 °C.
20 26
5
Lit. Chang, C.I.; Chang, J. –Y; Kuo, C.C.; Pan, W.Y.; Kuo, Y.–H. Planta. Med. 2005,
1, 72.]
7
Synthesis of (±)-7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahydro-1H-
fluorene ±(13): A flame-dried round-bottom flask was charged with compound (±)-3e (85
mg, 0.30 mmol; 1.0 equiv) under nitrogen atmosphere in MeOH (5 mL) The solution was
purged under nitrogen atmosphere for 20 min. To this solution was added Pd on activated
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2
2
2
2
2
2
2
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6
charcoal (1.6 mg) and purged with hydrogen balloon for the period of 10 min. The reaction
mixture was filtered through celite and concentrated using rotary evaporator under vaccum.
The crude was finally purified by flash chromatography (10:1 hexanes/EtOAc) to furnich 52
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
mg in 50% yield of ()-13 as colorless solid. R = 0.6 (5% EtOAc/hexanes). H NMR (400
f
MHz, CDCl
3
) δ: 6.33 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.47-3.40 (m,1H), 2.44-
2
1
.40 (m, 1H), 2.0-1.87 (m, 1H), 1.62-1.58 (m, 2H), 1.43 (s, 3H), 1.33 (d, J = 1.7 Hz, 3H),
1
3
.31 (d, J = 1.3 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.15-1.06 (m, 2H); C NMR (100 MHz,
) δ: 162.9, 149.3, 147.2, 145.7, 145.0, 132.7, 130.3, 116.8, 61.9, 60.5, 60.2, 52.3, 36.8,
5.5, 31.4, 29.7, 25.7, 25.5, 22.3, 22.2, 21.6, 19.5; IR (film) υmax 2935, 1455, 1414, 1119,
CDCl
3
3
-1
+
+
1053 cm ; HRMS (ESI) m/z 367.2236 [(M + Na)] ; calculated for [C H O + Na] :
2
2
32
3
3
67.2244; MP 79-83 °C.
Synthesis of ()-taiwaniaquinone H (1d): A oven dried round-bottom flask was charged
with compound (±)-(13) (270 mg, 0.783 mmol; 1 equiv) in MeCN:H O (3:1) (30 mL). To this
2
solution was added a solution of ceric ammonium nitrate (CAN) (1288 mg, 2.35 mmol; 3.0
equiv) in water (12 mL) at 0 ºC. The reaction mixture was stirred at that temperature for 10
min. and then diluted with water (20 mL) and extracted with EtOAc (20 mL X 2). The
2 4
combined organic phase washed with brine and dried over Na SO and concentrated using
rotator evaporator under vaccum. The crude product was finally purified by flash
chromatography (20:1 hexanes/EtOAc) to afford 167 mg (63% yield) of (±)-taiwaniaquinone
1
H (1d) as a red syrup. R
f
= 0.4 (5% EtOAc in hexane); H NMR (500 MHz, CDCl
3
) δ 6.34 (s,
1
1
3
H), 4.0 (s, 3H), 3.24 (septet, J = 7.1 Hz, 1H), 2.40-2.35 (m, 1H), 1.89 (qt, J = 13.8, 3.5 Hz,
H), 1.68-1.64 (m, 1H), 1.61-1.60 (m, 1H), 1.42 (s, 3H), 1.24 (s, 3H), 1.22 (d, J = 7.0 Hz,
1
3
3
H), 1.21 (d, J = 7.1 Hz, 3H), 1.21 (s, 3H), 1.09-1.03 (m, 2H); C NMR (125 MHz, CDCl )
δ 186.3, 178.8, 175.5, 157.3, 150.6, 145.8, 136.0, 116.7, 61.4, 55.6, 43.4, 37.2, 36.7, 31.0,
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2
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4.8, 24.5, 20.7, 20.67, 20.1, 19.1; IR (film) υmax 2922, 1646, 1560, 1536, 1354, 1290, 1265,
-1
+
152, 1025, 930 cm ; HRMS (ESI) m/z 315.1941 [(M + H)] ; calculated for [C H O +
20 26
3
+
H] : 315.1955. [Lit.: Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc. 2006,
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
28, 11022.
Synthesis of ()-dichroanone (1e): An oven dried round-bottom flask was charged with
()-taiwaniaquinone H (60 mg, 0.19 mmol; 1.0 equiv) in MeOH (5 mL). To this solution was
added a solution of 2M KOH solution in MeOH (3 mL) at room temprature. The reaction
mixture was stirred at room temperature for 24 h. Then, 2N HCL (1.5 mL) was added slowly
and the mixture was diluted with dichloromethane (15 mL). The combined organic phase
washed with brine and dried over Na SO and concentrated using rotator evaporator under
2
4
vaccum. The crude product was purified by flash chromatography (20:1 hexanes/EtOAc) to
f
give 35 mg (66% yield) of ()-dichroanone (1e) as a red syrup. R = 0.4 (2.5% EtOAc in
1
hexane); H NMR (500 MHz, CDCl
3
) δ 7.30 (brs, 1H), 6.45 (s, 1H), 3.21 (septet, J = 7.0 Hz,
1H), 2.39-2.35 (m, 1H), 1.93 (qt, J = 14.1, 3.4 Hz, 1H), 1.73-1.69 (m, 1H), 1.65-1.60 (m,
1
3
1
H), 1.45 (s, 3H), 1.28 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H), 1.234 (s,
1
3
3
H), 1.14-1.06 (m, 2H); C NMR (125 MHz, CDCl ) δ 186.3, 178.8, 175.5, 157.3, 150.6,
45.8, 136.0, 116.7, 61.4, 55.6, 43.4, 37.2, 36.7, 31.0, 24.8, 24.5, 20.7, 20.67, 20.1, 19.1; IR
-1
(
film) υmax 3354, 2912, 1643, 1633, 1527, 1372, 1360, 1319, 1170, 965, 919, 871cm ;
+
+
24 3
HRMS (ESI) m/z 301.1776[(M + H)] ; calculated for [C19H O + H] : 301.1798. [Lit.:
Kawazoe, K.; Yamamato, M.; Takaishi, Y.; Honda, G.; Fujita, T.; Sezik, E.; Yesilada, E.
Phytochemistry 1999, 50, 493]
Synthesis
of
(4a,9a)-7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-
hexahydro-1H-fluorene ( 14): A flame-dried round-bottom flask was charged with
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compound (±)-3e (630 mg, 1.83 mmol; 1.0 equiv) under nitrogen atmosphere in MeOH (5
mL) and purged with nitrogen gas. To this reaction mixture was added Pd on activated
charcoal (19 mg, 0.18 mmol; 0.1 equiv) and placed with a hydrogen balloon for the period of
0
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8
9
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9
0
1
2
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4
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8
9
0
1
h. The reaction mixture was filtered through celite and concentrated using rotary evaporator
under vaccum. The crude products were purified by flash chromatography (9:1
hexanes/EtOAc) to afford 618 mg of compound ±-(14) in 98% yield as colorless viscous oil,
1
R = 0.55 (5% EtOAc and hexane); H NMR (400 MHz, CDCl ) δ 3.78 (s, 3H), 3.77 (s, 3H),
f
3
3.70 (s, 3H), 3.40-3.31 (m, 1H), 2.85-2.79 (m, 1H), 2.63-2.56 (m, 1H), 1.82-1.73 (m, 2H),
1
1
1
1
.59 (s, 3H), 1.43-1.40 (m, 1H), 1.39-1.35 (m, 2H), 1.32 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H),
1
3
.10 (s, 3H), 0.91 (s, 3H); C NMR (100 MHz, CDCl ) δ 151.0, 150.3, 146.3, 144.3, 132.3,
3
28.9, 60.5, 60.3, 60.2, 56.6, 47.1, 35.2, 35.0, 32.2, 31.2, 31.1, 29.9, 25.6, 25.5, 22.24, 22.23,
-1
8.7; IR (film) υmax 2919, 1452, 1413, 1338, 1255, 1154, 1042 cm ; HRMS (ESI) m/z
+
+
34 3
369.2425[(M + Na)] ; calculated for [C22H O + Na] : 369.2400.
Symthesis of ()-5-epi-taiwaniaquinone G (ent-1h): A oven dried round-bottom flask was
charged with compound 14 (187 mg, 0.30 mmol; 1.0 equiv) in MeCN:H O (3:1) (25 mL). To
2
this solution was added a solution of ceric ammonium nitrate (CAN) (1480 mg, 2.69 mmol;
◦
5
.0 equiv) in water (8 mL) at 0 C. Reaction mixture was stirred at that temperature for 1 h
and then diluted with water (20 mL) and extracted with EtOAc (20 mL X 2). The combined
organic phase washed with brine and dried over Na SO and concentrated using rotary
2
4
evaporator under vaccum. The crude products were purified by flash chromatography (20:1
hexanes/EtOAc) to furnish 116 mg (68% yield) of (±)-5-epi-taiwaniaquinone G as a red color
1
viscous oil. R
f
= 0.5 (5% EtOAc and hexane); H NMR (500 MHz, CDCl
3
) δ 3.91 (s, 3H),
3.18 (septet, J = 7.1 Hz, 1H), 2.65 (dd, J = 18.0, 8.1 Hz, 1H), 2.34 (dd, J = 18.0, 11.5 Hz,
1H), 1.90 (dt, J = 13.5, 3.4 Hz, 1H), 1.73 (dd, J = 11.5, 8.1 Hz, 1H), 1.61-1.52 (m, 1H), 1.50
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(
s, 3H), 1.41 (dt, J = 13.9, 3.9 Hz, 1H), 1.29-1.26 (m, 2H), 1.22-1.20 (m, 1H), 1.19 (d, J =
1
3
7
.2 Hz, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.10 (s, 3H), 0.91 (s, 3H); C NMR (125 MHz,
) δ 187.3, 182.6, 156.5, 152.4, 146.2, 136.7, 61.1, 54.9, 47.9, 34.9, 34.2, 31.7, 31.1,
1.0, 29.4, 24.5, 24.2, 20.6, 20.5, 17.9; IR (film) υmax 2984, 2964, 2919, 2845, 1658, 1651,
CDCl
3
10
11
12
13
14
15
16
17
18
19
20
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48
49
50
51
52
53
54
55
56
57
58
59
60
3
-
1
+
1596, 1449, 1262, 1162 cm ; HRMS (ESI) m/z 339.1935 [(M + nNa)] ; calculated for
+
[
C H O + nNa] : 339.1931. [Lit. ref.: Tapia, R.; Guardia, J. J.; Alvarez, E.; Haidӧur, A.;
2
0
28
3
Ramos, J. M.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. J. Org. Chem.
2012, 77, 573.]
Synthesis of (4a,9a)-7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahydro-
1
H-fluoren-9(9aH)-one ()-16: To a stirred solution of 3,5-dimethylpyrazole (1.5 g, 15.55
mmol; 17.93 equiv) in CH Cl (5 mL) was added CrO (1555 mg, 15.55 mmol; 17.93 equiv)
at -15 ºC. Then the reaction mixture was stirred for 15 min. at same temperature before
solution of tricyclic compound ±(14) (300 mg, 0.867 mmol; 1.0 equiv) in CH Cl (3 mL) was
2
2
3
2
2
added. This dark mixture was stirred at -10 ºC till the tlc showed complete consumption of
starting material (1 h). Then, it was directly purified by flash chromatography (15:1
f
hexanes/EtOAc) to afford 284 mg (91% yield) of (±)-16 as a colorless solid. R = 0.6 (10%
1
EtOAc in hexane); H NMR (500 MHz, CDCl
3
) δ 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H),
3
.47 (septet, J = 7.0 Hz, 1H), 2.28-2.23 (m, 1H), 2.01 (s, 1H), 1.86-1.81 (m, 1H), 1.70-1.63
(
m, 1H), 1.59-1.50 (m, 1H), 1.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H), 1.23 (s, 3H), 0.77 (s, 3H);
1
3
3
C NMR (125 MHz, CDCl ) δ 204.8, 158.6, 152.9, 152.7, 146.2, 134.8, 124.8, 65.6, 62.1,
6
1
0.3, 59.9, 41.9, 124.8, 65.6, 62.1, 60.3, 59.9, 41.9, 37.5, 34.2, 32.7, 31.5, 25.3, 24.6, 21.9,
-1
8.1; IR (film) υmax 2934, 1743, 1454, 1413, 1340, 1294, 1259, 1187, 1116 cm ; HRMS
+
+
◦
32 4
(ESI) m/z 383.2204 [(M + Na)] ; calculated for [C22H O + Na] : 383.2193; MP 87-89 C.
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Synthesis of ()-taiwaniaquinol B (1b): To a stirred solution of compound (±)-16 (270 mg,
2 2 3
0.75 mmol; 1.0 equiv) in dry CH Cl (3 mL) was added BBr (180 µL, 1.87 mmol; 2.5 equiv)
at 78 ºC. Then the reaction mixture was stirred for 1.5 h at 78 ºC. After complete
consumption of starting material (judged by running tlc), the reaction mixture was quenched
with water and extracted with ethyl acetate (10 X 2 mL). The organic layer was dried over
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anhydrous Na SO and concentrated in vacuo.
The crude product was taken in 20 mL of MeCN:H O (3:1) at 0 ºC. To this reaction
2
mixture, a solution of ammonium ceric nitrate (CAN) (2.1 g, 3.75 mmol; 5.0 equiv) in water
(
8 mL) was added and it was stirred for 20 minutes at 0 ºC. After complete consumption of
starting material, the reaction mixture was quenched with saturated aqueous solution of
Na S O and kept on stirring for additional 20 min. Upon completion of the reaction
2
2
5
(
monitored by running tlc), it was diluted by water (5 mL) and extracted with EtOAc (10 X 2
mL) by using a separatory funnel. The organic layer was dried over anhydrous Na SO and
2
4
concentrated in a rotary evaporator under vacuum. The crude was purified by flash
chromatography (10:1 hexanes/EtOAc) to afford 130 mg (overall 52% yield in two steps) of
1
(
±)-taiwaniaquinol B as crystalline solid. R
f
= 0.6 (10% EtOAc in hexane); H NMR (500
MHz, CDCl ) δ 9.54 (s, 1H), 5.31 (brs, 1H), 3.80 (s, 3H), 3.27 (septet, J = 7.1 Hz, 1H), 2.12
3
(s, 1H), 2.08-1.96 (m, 2H), 1.75-1.67 (m, 1H), 1.63-1.55 (m, 1H), 1.44 (s, 3H), 1.42-1.40 (m,
13
2
H), 1.38 (d, J = 7.1 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.25 (s, 3H), 0.88 (s, 3H); C NMR
(
125 MHz, CDCl ) δ 211.1, 152.3, 151.1, 142.7, 138.4, 126.1, 118.3, 65.1, 62.1, 42.7, 36.5,
3
34.3, 33.0, 30.3, 28.8, 25.9, 24.3, 20.6, 17.5; IR (film) υmax 2945, 2927, 2850, 1720, 1450,
-1
+
1
426, 1286, 1256, 1187, 1125 cm ; HRMS (ESI) m/z 333.2040 [(M + H)] ; calculated for
+
[C
22
H
28
O
4
+ H] : 333.2060; MP 143-145 °C. [Lit.: MP 142-144 °C, see ref.: Lin, W. -H.;
Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40, 871.]
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-isopropyl-1,2,4-trimethoxy-5,6,6-trimethyl-6,7,8,9-tetrahydro-5H-5,9-
methanobenzo[7]-annulen-10-one ±(17): A oven dried round-bottom flask was charged
2 2
with compound 13 (104 mg, 0.302 mmol; 1.0 equiv) in CH Cl (15 mL) was added m-CPBA
10
11
12
13
14
15
16
17
18
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60
◦
(
115 mg, 0.453 mmol; 1.5 equiv) at 0 C. Then, solid NaHCO (76 mg, 0.908 mmol; 3.0
3
equiv) was added to reaction mixture at same tempature and reaction mixture was allowed to
stir for 1 h. The reaction mixture was treated with aq. saturated solution of Na SO (2 mL)
and stirred for an additional 10 min. It was poured into a mixture of CH Cl (15 mL) and ice
2
3
2
2
water (3 mL) and the mixture was shaken and separated. The organic phase was washed with
saturated aq. NaHCO solution and dried over Na SO and concentrated using rotary
3
2
4
evaporator under vacuum.
.
Crude product (95 mg) was taken in CH
2
Cl
mmol; 2.1 equiv) was added at 0 C. After 30 min of stirring, water (1 mL) was added to this
mixture and stirring continued for additional 15 min. Then saturated aq. solution of NaHCO
8 mL) was added to the reaction mixture and it was extracted with CH Cl (8 mL). The
organic layer was dried over Na SO and concentrated using rotary evaporator under vacuum.
The crude compound was finally purified by column chromatography (9:1 hexanes/EtOAc)
2 3 2
(8 mL) and BF Et O (0.205 mL, 0.65
°
3
(
2
2
2
4
f
to afford compound 17 in 74% overall yield as colorless viscous oil, R = 0.4 (5% EtOAc in
1
hexane); H NMR (400 MHz, CDCl
3
) δ: 3.82 (s, 3H), 3.80 (s, 3H), 3.61 (s, 3H), 3.42-3.37
(m, 1H), 3.25 (s, 1H), 1.97 (dt, J = 13.4, 4.4 Hz, 1H), 1.59-1.48 (m, 1H), 1.46 (s, 3H), 1.40-
1
3
1
2
.36 (m, 1H), 1.33 (d, J = 7.2 Hz, 3H), 1.30 (d, J = 7.1 Hz, 3H), 1.26-1.23 (m, 1H), 1.17 (s,
1
3
3
H), 1.15-1.05 (m, 2H), 0.97 (s, 3H); C NMR (100 MHz, CDCl ) δ: 217.6, 152.1, 151.3,
40.2, 136.4, 134.1, 127.6, 60.5, 60.1, 59.8, 54.5, 42.1, 41.6, 35.7, 30.8, 26.9, 25.8, 22.3,
-1
1.9, 20.4, 20.3; IR (film) υmax 2934, 1743, 1454, 1413, 1340, 1294, 1259, 1187, 1116 cm .
[Lit. ref.: Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.; Haidӧur, A.;
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