Total Synthesis of (-)-Phomoarcherin C

Article abstract of DOI:10.1021/acs.joc.9b02206

A full account on the first total synthesis of a chroman meroterpenoid, (-)-phomoarcherin C, has been described. Key synthetic transformations include phenyl boronic acid-mediated 6?€-electrocyclization reaction, a stereospecific hydrogenation driven by thermodynamic conformational stability of the product, and regioselective formylation. The strategy employed is considerably short, is atom-economical, and can open the doors to provide access to various other natural products of the same kind.

Full text of DOI:10.1021/acs.joc.9b02206

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Article
Total Synthesis of (-)-Phomoarcherin C
Dattatraya Hanumant Dethe, and Boda VijayKumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02206 • Publication Date (Web): 10 Oct 2019
Downloaded from pubs.acs.org on October 13, 2019
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Total Synthesis of (-)-Phomoarcherin C
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Dattatraya H. Dethe*a and Boda VijayKumara
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*Department of Chemistry, Indian Institute of Technology, Kanpur, 208016, India.
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*Email:ddethe@iitk.ac.in
Me
HO
Me
HO
Me
HO
Me
CHO
Me
H
6
-electro-

Me
Me
HO
OH
cyclization
Me
O
O
Me
O
O
H
Me
PhB(OH)2 (1 equiv.)
PhCO2H (50 mol%)
Me
BnO
Me
H
O
BnO
H
BnO
H
H
(-)-Phomoarcherin C
ABSTRACT: A full account on the first total synthesis of chroman meroterpenoid, (-)-
phomoarcherin C has been described. Key synthetic transformations include phenyl boronic acid
mediated 6π-electrocyclization reaction,
a
stereospecific hydrogenation driven by
thermodynamic, conformational stability of the product and regioselective formylation. The
strategy employed is considerably short, atom economical and can open the doors to provide
access to various other natural products of the kind.
INTRODUCTION
Terpenoids constitute most diversified and the largest class of metabolites derived from
plants and fungi.1 Meroterpenoids, a subclass of terpenoids, are molecules with part of their
structure derived from terpenoid unit. Like many other natural sources, fungi have been rich
source of secondary metabolites including meroterpenoids.2 For instance, endophytic fungi
belonging to the genus Phomopsis, is an ample source of bioactive natural products.3 Recently,
three new sesquiterpenes, phomoarcherins A-C (1-3), were isolated from phomopsis archeri.4
Phomoarcherins are tetracyclic terpenes containing an orcinol or an aromatic lactone moiety. All
these phomoarcherins were tested and proven to show moderate to excellent anticancer
properties. Most notably, phomoarcherin B (2) showed prominent activity against human
cholongiocarcinoma cell lines, KKU-M139 (with IC50 value 0.1 μg/mL) and KKU-M156 (with
IC50 value 2.0 μg/mL), which is very much comparable with the control drug, ellipticine. In
addition, the compound showed prominent antimalarial activity with IC50 value 0.79 μg/mL.5
Phomoarcherins are tetracyclic skeletons containing a characteristic trans-A/B decalin system
fused with a dihydrobenzopyran framework with cis-B/C ring junction (Figure 1).
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OH
OH
O
O
HO
HO
HO
Me
O
OH
D
O
O
H
C
Me
Me
Me
Me
H
Me
H
O
O
O
O
O
O
A
B
H
H
Me
H
Me
Me
Me
Me
HO
O
O
H
H
H
Phomoarcherin A (1)
Phomoarcherin B (2)
OMe
Phomoarcherin C (3)
(+)-Puupehenone (4)
Puupehenol (5)
OH
OH
OH
CO2Me
OH
HO
Me
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Me
O
Me
Me
O
Me
H
Me
O
O
O
Me
Me
Me
Me
Me
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R
H
H
H
H
(+)-8-epi-Puupehediol (10) (+)-epi-Chromazonarol (11)
R = H; (+)-Hongoquercin A (8)
R = OAc; (+)-Hongoquercin B (9)
(+)-ent-Chromazonarol (6) (-)-Chromazonarol (7)
Figure 1: Meroterpenoid families of natural products
Presence of a benzopyran fused mono/sesqui terpenoid unit with a cis stereochemistry at
the B/C ring junction makes these natural products challenging and interesting targets for
synthetic community. There are several reports addressing the synthesis of such type of
molecular frameworks such as total syntheses of puupehenol (4) and puupehenone (5),6 (+)-ent-
chromazonarol (6),7 (-)-chromazonarol (7),8 and hongoquercin A (8).9 We also have recently
reported total synthesis of hongoquercins A (8) and B (9), (+)-8-epi-puupehediol (10) and (+)-
epi-chromazonarol (11).10 But almost all of these methods are to construct the trans-B/C fused
skeleton. To our knowledge, there are very few reports to synthesize such scaffolds. Although,
they are indirect methods requiring more number of steps to achieve cis-B/C stereochemistry.11
Therefore there has been an unmet need of developing novel strategy which provides a direct
access to these kinds of molecules in a much efficient manner.
Me
Me
HO
OH HO
OH
14b
O
O
Me
Me
Me
i) NaBH4, MeOH
0 °C, 10 min
Me
Me
HO
AcO
neat, 90 °C, 24 h
ref. 15
14a
no reaction
H
ii) POCl3, py, reflux
5 h, 50% (2 steps)
O
BnO
BnO
Wieland-Mischer
Ketone
12
13
Scheme 1: Unsuccessful attempts towards the synthesis of phomoarcherin core
RESULTS AND DISCUSSION
In continuation to our ongoing research interest in total synthesis of natural products
having tetrahydro benzopyran/chromane core,12 we became interested to develop an efficient
synthetic strategy that gives access to phomoarcherin family of natural products also. Typically,
chromanes are outcomes of hetero Diels-Alder reaction (HDA) between o-quinone methide and
an appropriate olefin.13 We have reasoned that an HDA between appropriate o-quinone methides
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and olefins would be a perfect synthetic tool to achieve the core skeleton of the aforementioned
natural products. O-quinone methides are transient and highly reactive due to their extreme
tendency to undergo rearomatization reacting either by Michael addition fashion with
nucleophiles or by a cycloaddition with 2π systems to yield benzopyrans.14
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Me
H
HO
Me
HO
Me
HO
Me
O
D
CHO
Me
6
H
-electro-

H
H
HO
OH
Me
cyclization
16
C
Me
Me
Me
O
O
O
O
O
O
A
B
H
Me
H
Me
BnO
Me
H
O
BnO
BnO
H
H
H
Phomoarcherin C (3)
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Scheme 2: Retrosynthetic analysis to execute 6π-electrocyclization
Me
H
16
H
H
O
O
Me
Me
Me
POCl3, DMF
Me
HO
OH
H
no reaction
H
PhB(OH)2, PhCO2H
toluene, 110 °C
BnO
0 °C, 30 min, 51%
BnO
13
17
Scheme 3: Unsuccessful attempt of 6π-electrocyclization to give tetracyclic core
Table 1: Optimization of 6π-electrocyclization reaction
Me
HO
Me
HO
Me
Me
O
Ph
Me
HO
Me
H
O
B
O
HO
OH
18
Me
Me
PhB(OH)2 (1 equiv.)
Me
Me
Me
Me
O
O
HO
H
O
+
Conditions
yield %
Me
Me
Me
BnO
H
H
BnO
BnO
BnO
BnO
H
H
17
19a
19b
(7:3)
Inseparable mixture of diastereomers
Conc.
mL/mm
ol
Time
(h)
Temp
Yield
(°C)
S. N.
Reagent
Additive
Solvent
1
2
3
4
5
Pyridine
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
--
--
--
5
5
5
5
24
24
24
15
15
115
110
110
80
trace
20
CH3CH2CO2H
(20 mol%)
Toluene
Toluene
Benzene
Toluene
CH3CO2H (20
mol%)
15
PhCO2H
(20 mol%)
30
PhCO2H
(20 mol%)
110
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PhCO2H
(20 mol%)
6
7
PhB(OH)2
PhB(OH)2
Xylene
5
5
15
15
140
110
33
40
PhCO2H
(50 mol%)
Toluene
7
160
(seal
tube)
8
9
PhCO2H
(50 mol%)
8
9
PhB(OH)2
PhB(OH)2
Toluene
Toluene
5
15
15
40
60
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PhCO2H
(50 mol%)
0.5
110
a = All the reaction were carried out taking 1 equivalent of PhB(OH)2
Over the years, many research groups have been engaged in developing new and efficient
strategies to generate o-quinone methides.15 One among such methods constitutes a Knoevenagel
condensation of phenolic derivative and an aldehyde in basic medium to generate various o-
quinone methides. In this respect, it was conceived that members of phomoarcherin family of
natural products could be targeted by using terpenoids in combination with appropriate o-
quinone methides by HDA strategy. Unfortunately, our initial attempts to operate HDA reactions
between olefin 13, prepared from a known ketone 12,16 and precursors of o-quinone methides
(14a or 14b) were unsuccessful to generate the desired benzopyran products resulting in the
decomposition of aryl partners (14a or 14b) with the olefin left unreacted in the reaction mixture
(Scheme 1). We attribute these results to the low reactivity of olefin 13 due to severe steric
hindrance exerted by methyl groups from either sides of the double bond.
This prompted us to adopt a different strategy. In this context, we believed that an
electrophilic activation property of aryl boronic acids17 may promote a 6π-electrocyclization18
between intermediate 16 and 17 through the formation of an intermediate with required 6π-
electronic system (Scheme 2). Advantages with alkyl boronic acid catalysis are i) they are
considerably less toxic, ii) they are mild Lewis acids with wide range of chemical properties and
iii) most of them are air stable with extended shelf lives. Aryl boronic acids are known to be
important in many crucial chemical transformations.19 Barrero et al. has reported an efficient
synthesis of puupehedione and related compounds employing 6π-electrocyclization.20 Therefore
we have envisioned that aryl boronic acids can activate the carbonyl compounds enabling them
to get attacked by a nucleophile such as ocinol derivative 16 in our case. Accordingly, compound
17 was prepared from olefin 13 through Vilsmeier-Haack formylation. Then a reaction was set
up between enal 17 and orcinol derivative 16 using phenyl boronic acid (1 equiv.), benzoic acid
(20 mol%) as co-catalyst in toluene at 110 °C (Scheme 3). There was no any reaction occurred
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even after prolonged heating for up to 24 h resulting in unreacted starting compounds left over in
the reaction mixture. This is might be due to the deactivation of compound 16 by electron
withdrawing formyl group.
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HO
Me
Me
H
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D
HO
H
H
H
HO
Me
Me
H
C
O
Me
H
Me
O
O
Me
HO
Me
10
A
Me
Me
B
BnO
Me
H
Me
HO
HO
Me
Me
H
D
H
H
HIgh energy T.S with
twist boat conformation
in C-Ring
Not observed
11
-face attack of H

C
2
Me
Pd-C / H2
EtOH, rt, 15 h
9
O
1
10
8
A
Me
B
3
5
7
12
Me
BnO
HO
D
Me
Me
H
HO
19a
HO
Me
C
H
Me
Me
O
O
Me
O
Me
HO
8
A
10
Me
B
Me
BnO
Me
H
H
Me
HO
Me
H
H
H
H
H
H
20a, 60%
HO
thermodynamically stable
conformer with
trans-anti-cis system
-face attack of H

2
HO
Me
Me
Me
Me
D
HO
HO
11
Me
Me
Me
Me
C
Me
Me
H
9
Me
O
Pd-C / H2
O
10
8
1
10
BnO
8
7
HO
O
O
A
Me
B
Me
3
5
EtOH, rt, 15 h
12
Me
H
BnO
HO
H
H
H
H
H
H
H
H
20b, 25%
19b
H2 addition was governed
by C8-Me and C10-Me
Scheme 4: Schematic explanation for the stereoselective hydrogenation
HO
Me
HO
Me
HO
Me
HO
Me
MeO
Me
Me
Pd-C / H2
EtOH, rt, 15 h, 85%
K2CO3, MeI
Me
Me
Me
H
Me
H
H
+
+
O
O
O
O
O
Acetone, 70 °C
5 h, 92%
Me
Me
Me
Me
Me
BnO
BnO
HO
HO
HO
H
H
H
H
H
(7:3)
separated by column chromatography
19a
19b
20a
20b
21
Ac2O, py, DMAP
DCM, rt, 15 h, 93%
HO
Me
O
HO
Me
MeO
Me
Me
MeO
Me
Me
O
O
NaSEt, DMF
140 °C, 3 h
POCl3, DMF
IBX, EtOAc
Me
H
Me
H
H
H
O
H
O
H
O
H
O
reflux, 2 h, 65%
HO
0 °C, 30 min
110 °C, 6h, 75%
Me
Me
Me
Me
O
AcO
AcO
H
H
H
H
(-)-Phomoarcherin C (3)
24
23
22
Scheme 5: Completion of total synthesis of phomoarcherin C (3)
Eventually, orcinol 18 was employed in the same reaction with enal 17 in presence of
phenyl boronic acid (1 equiv.) and benzoic acid (20 mol%). This time, to our delight, a 7:3
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diastereomeric mixture of annulation products 19a and 19b was formed in 30% combined yield
(Table 1). Phenyl boronic acid might be activating the enal 17 to form a boronate intermediate
which upon disproportionation forms an intermediate with perfect 6π-electronic system that
readily underwent electrocyclization to give the cyclic products (19a and 19b). The two isomers
differ in stereochemistry at C-8 methyl group and were inseparable by silica gel column
chromatography. In order to improve the yield, we sought to screen several bronsted acid and
solvent systems, keeping the phenyl boronic acid constant (Table 1) and found that the reaction
at high concentration was affording highest conversion rate with best yield i.e. 60%. We
proceeded for next step with the mixture of diastereomers.
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Compounds 19a and 19b were then subjected to a Pd-C hydrogenation protocol to reduce
the double bond and also to deprotect the benzyl group in one-pot. Only two diastereomeric diols
20a and 20b were obtained instead of four. Formation of 20b is essentially because of the
preferential α-face addition of hydrogen onto the double bond of 19a which would be governed
by the steric hindrance posed by both C8-β-Me and C10-β-Me present on either sides of the
double bond.21 On the other hand, diastereomer 20a might be forming through a preferential α-
face addition of hydrogen onto the double bond of 19a. In this case, addition of hydrogen could
not be completely governed by the C10-β-Me. Because, among the two adjacent angular methyl
groups, C8-Me is in α-face and the C10-Me is in β-face. At this juncture, the formation of 20a
can be rationalised by the kinetic control of the reaction. If the hydrogen adds onto the double
bond of the substrate 19a, through β-face, it would generate a high energetic transition state with
twist boat conformation in the ring-D. Therefore addition of the hydrogen onto the double bond
of 19a was taking place preferentially through the α-face to produce the tetracyclic skeleton with
a thermodynamically stable trans-anti-cis A/B/C system (Scheme 4). This observation confirms
the stereochemistry and relative configuration of the major isomer 20a as 3S, 5R, 8S, 9R and
10S. At this stage, fortunately, the two diastereomers 20a and 20b were separated by careful
silica gel column chromatography. In order to perform formylation on the aromatic ring,
anticipating that both the free aliphatic and aromatic OH groups would possibly interfere, they
were protected successively as acetyloxy and methoxy groups to get compound 22. A Vilsmeier-
Haack formylation on the compound 22 afforded aldehyde 23 in 75% yield. BBr3 mediated
methoxy deprotection was always a disappointment resulting in either decomposition or
benzopyran ring opening reaction of 23. Alternatively a reaction using excess of sodium ethyl
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thiolate, to our delight, resulted in the deprotection of not only the methoxy group but also the
acetyl group to afford dihydroxy compound 24 which was directly preceded for next step without
further purification. IBX oxidation of 24 afforded the natural product, (-)-phomoarcherin C (3) in
65% yield (Scheme 5). Spectroscopic data and optical rotation of synthesized 3 was identical
with those of isolated natural product (Tables S1-S3; see supporting information).
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In conclusion, a structurally intriguing benzopyran natural, Phomoarcherin C has been
synthesized for the first time in considerably concise route. A 6π-electrocyclization strategy
catalysed by boronic acid-bronsted acid co-catalyst system was employed for the synthesis of the
natural product in 9 steps from the known ketone 12 in 29.83 % overall yield. With the synthesis
of this natural product, we have, in addition to confirming the structure of the molecule, also
established its absolute configuration.
EXPERIMENTAL SECTION
General Information: All reactions were carried out under nitrogen atmosphere with dry
solvents under anhydrous conditions unless otherwise mentioned. All the chemicals and reagents
used were purchased commercially, and used without further purification. Anhydrous diethyl
ether was prepared by distilling from sodium - benzophenone. Dichloromethane was distilled
from calcium hydride. DMF was distilled from dry KOH. Yields refer to chromatographically
pure material, unless otherwise stated. Reactions were monitored by Agilent Infinite Series LC-
MS and thin layer chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-
254) using UV-light as a visualizing agent and p-anisaldehyde stain as coloring agent, and heat
as developing agent. Merck silica gel (particle size 100-200 and 230-400 mesh) was used for
flash column chromatography. NMR spectra were recorded on JEOL ECX 500 (1H: 500 MHz,
13C: 125 MHz) in CDCl3 having TMS 0.03% as internal standard. EI-MS/ESI-MS was recorded
on a Waters Micromass Quattro Micro triplequadrupole mass spectrometer.
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublet, ddd = doublet of a doublet of a doublet, dt = doublet
of a triplet, td = triplet of a doublet, m = multiplet, br = broad.
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Preparation of (3S,8aR)-3-(benzyloxy)-4,4,7,8a-tetramethyl-1,2,3,4,4a,5,6,8a-octahydro
naphthalene (13):
6
7
8
9
Ketone 12 (314 mg, 1 mmol) was dissolved in MeOH (5 mL) and cooled to 0 °C. NaBH4 (113
mg, 3 mmol) was added in portion wise to the above mixture at the same temperature. Once the
addition of NaBH4 is over, the reaction mixture was stirred for 10 min at the same temperature
and reaction progress was monitored by TLC. Methanol was evaporated under reduced pressure
followed by the addition of ice cold water (10 mL) and DCM (10 mL). Organic layer was
separated through separating funnel. Aqueous layer was extracted twice (2 x 10 mL) with DCM.
Combined organic layers were washed with brine, dried over NaSO4, evaporated to obtain the
crude alcohol which was preceded for the next step without further purification.
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The above crude alcohol was dissolved in pyridine (5 mL) and cooled to 0 °C, prior to the gentle
addition of POCl3 (0.28 mL, 3 mmol). Reaction mixture was slowly allowed to attain room
temperature then refluxed for 5 h. Once the reaction is completed as monitored by TLC, crushed
ice was added to quench unreacted POCl3 followed by extracting the reaction mixture with DCM
(2 x 10 mL). The combined organic layers were washed initially with 1N HCl to remove
pyridine, then with brine. Organic layer was dried over NaSO4, evaporated to get crude olefin 13
which was purified by silica gel column chromatography using hexane/EtOAc (99:1) to get pure
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olefin 13 as colorless oil. Yield = 149 mg (50% over two steps). Rf = 0.5 in 100% hexane; H
NMR (400 MHz, CDCl3) δ 7.38 – 7.25 (m, 5H), 5.06 (d, J = 1.4 Hz, 1H), 4.68 (d, J = 11.9 Hz,
1H), 4.44 (d, J = 11.9 Hz, 1H), 2.96 (dd, J = 11.6, 4.4 Hz, 1H), 2.00 – 1.82 (m, 3H), 1.73 – 1.65
(m, 1H), 1.59 (s, 3H), 1.52 – 1.42 (m, 2H), 1.20 (td, J = 13.4, 3.9 Hz, 2H), 1.05 (d, J = 2.0 Hz,
1H), 1.01 (s, 3H), 0.94 (s, 3H), 0.86 (s, 3H); 13C NMR {1H} (100 MHz, CDCl3) δ 139.6, 135.2,
130.4, 128.3, 128.3, 127.6, 127.6, 127.3, 87.0, 71.6, 58.3, 50.7, 38.8, 37.9, 35.1, 32.0, 23.6, 23.3,
21.7, 18.9, 16.4; HRMS (ESI) m/z calcd. for C21H31O [M+H]+ 299.2375, found 299.2368.
Preparation of 6-(benzyloxy)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-
1-carbaldehyde (17):
To an ice cold DMF (1.9 mL, 50 mmol), was added slowly, POCl3 (0.07 mL, 1.5 mmol) and the
mixture was stirred vigorously under inert atmosphere at 0 °C for 30 minutes until a thick
colorless syrup has formed. To this syrup, was added a solution of compound 13 (150 mg, 0.5
mmol) in 0.5 mL of dry DMF under inert atmosphere. The reaction mixture was stirred for 30
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minutes at room temperature and reaction progress was monitored by TLC, after which, it was
poured into crushed ice and then extracted with EtOAc twice (2x10 mL).
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The combined organic layers were dried over NaSO4, evaporated to get crude 17 which was
purified by silica gel column chromatography using hexane/EtOAc (9:1) to get pure aldehyde 17
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as colorless oil. Yield = 82 mg (51%). Rf = 0.5 in 10% EtOAc in hexane; H NMR (400 MHz,
CDCl3) δ 10.04 (s, 1H), 7.35 – 7.32 (m, 5H), 4.69 (d, J = 11.9 Hz, 1H), 4.42 (d, J = 11.9 Hz,
1H), 2.95 (dd, J = 11.8, 4.4 Hz, 1H), 2.68 (dt, J = 13.4, 3.5 Hz, 1H), 2.33 – 2.25 (m, 2H), 2.04 (s,
3H), 1.90 (ddd, J = 10.6, 7.6, 3.6 Hz, 2H), 1.73 (ddd, J = 7.6, 4.0, 2.3 Hz, 2H), 1.64 – 1.56 (m,
2H), 1.19 (s, 3H), 1.02 (s, 3H), 0.88 (s, 3H); HRMS (ESI) m/z calcd. for C21H31O [M+H]+
227.2324, found 227.2332.
Preparation of
(3S,4aR,6aS,12aR,12bS)-4,4,6a,9,12b-pentamethyl-2,3,4,4a,5,6,6a,12,
12a,12b-decahydro-1H-benzo[a]xanthene-3,11-diol (20a) and (3S,4aR,6aR,12aR,12bS)-
4,4,6a,9,12b-pentamethyl-2,3,4,4a,5,6,6a,12,12a,12b-decahydro-1H-benzo[a]xanthene-3,11-
diol (20b):
A mixture of aldehyde 17 (326 mg, 1 mmol), orcinol 18 (196 mg, 1.5 mmol), PhB(OH)2 (122
mg, 1 mmol) and PhCO2H (61 mg, 0.5 mmol) were taken in 0.5 mL of dry toluene and refluxed
for 15 h under nitrogen atmosphere. Once the aldehyde was consumed as monitored by TLC,
reaction mixture was diluted with 2 mL of DCM, absorbed on silica gel and directly purified by
column chromatography using hexane/EtOAc (99:1 to 95:5) to get 7:3 mixture of diastereomers
19a and 19b as colorless oil. Yield = 206 mg (60% combined yield for 19a and 19b). Yield =
149 mg (50% over two steps). Rf = 0.5 in 5% EtOAc-hexane. Since the diastereomers were
inseparable by column chromatography, next reaction was done on the mixture of diastereomers.
A mixture of 19a and 19b was dissolved in EtOH at room temperature and added with 300 mg of
Pd/C (10 %) (2 w/v with respect to the starting compound) and stirred under hydrogen pressure
(applied with balloon) for 15 h. Once the reaction was completed as monitored by TLC,
palladium charcoal was filtered off and the solvents were evaporated to get crude product.
Purification was done by silica gel column chromatography using hexane/EtOAc (97:3 to 90:10)
to get 71 mg of 20a, Yield = 60%, and 30 mg of 20b, Yield = 25%. ). Rf = 0.3 in 20% EtOAc-
hexane.
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[휶]ퟐ푫ퟖ
Spectroscopic data of major compound 20a: ;
= -4.22 (c 1.02, CHCl3); IR (neat):
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ʋmax/cm-1 3345, 2925, 2853, 1626, 1590, 1461, 1350, 1166, 1133, 1064, 1018, 997, 823; H
NMR (400 MHz, CDCl3) δ 6.21 (s, 1H), 6.14 (s, 1H), 3.24 (dd, J = 11.5, 4.6 Hz, 1H), 2.74 –
2.55 (m, 3H), 2.20 (s, 3H), 2.15 (d, J = 10.9 Hz, 1H), 1.91 (dt, J = 13.0, 3.5 Hz, 1H), 1.71 – 1.58
(m, 5H), 1.55 – 1.52 (m, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.16 (s, 3H), 1.07 (dd, J = 13.1, 3.8 Hz,
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1H), 1.02 (s, 3H), 0.93 – 0.86 (m, 2H), 0.78 (s, 3H), 0.71 (s, 3H); C NMR {1H} (100 MHz,
CDCl3) δ 155.9, 153.4, 137.1, 110.5, 107.6, 107.0, 79.4, 75.3, 54.7, 49.1, 41.0, 39.1, 38.5, 38.4,
28.9, 27.5, 27.3, 21.5, 18.3, 17.5, 16.0, 14.5; HRMS (ESI) m/z calcd. for C22H33O3 [M+H]+
345.2430, found 345.2422.
Preparation of (3S,4aR,6aS,12aR,12bS)-11-methoxy-4,4,6a,9,12b-pentamethyl- 2,3,4,4a,5,
6, 6a,12,12a,12b-decahydro-1H-benzo[a]xanthen-3-ol (21) :
Major diastereomer 20a (70 mg, 0.2 mmol) was dissolved in acetone, added with K2CO3 (84 mg,
0.6 mmol) followed by MeI (0.04 mL, 0.6 mmol) at room temperature. The reaction mixture was
slowly heated to reflux for 5h under nitrogen atmosphere. Once the reaction is completed as
monitored by TLC, reaction mixture was filtered to get clear solution which was then evaporated
under reduced pressure to get crude compound. Purification of the crude compound was done by
silica gel column chromatography using hexane/EtOAc (97:3 to 95:5) to get 21 as a colorless oil.
[휶]ퟐ푫ퟖ
Yield = 66 mg (92%). Rf = 0.5 in 20% EtOAc-hexane. ;
= -4.65 (c 1.02, CHCl3); IR
(neat): ʋmax/CM-1 3359, 2928, 1618, 1587, 1496, 1463, 1352, 1327, 1303, 1277, 1225, 1165,
1133, 1112, 1022, 1002, 948, 934, 909, 888, 843, 811, 670, 580; 1H NMR (400 MHz, CDCl3) δ
6.23 (d, J = 15.0 Hz, 2H), 3.79 (s, 3H), 3.23 (dd, J = 11.5, 4.8 Hz, 1H), 2.71 (d, J = 18.4 Hz, 1H),
2.55 (dd, J = 18.4, 8.2 Hz, 1H), 2.26 (s, 3H), 2.18 – 2.10 (m, 1H), 1.92 (dt, J = 13.1, 3.5 Hz, 1H),
1.72 – 1.44 (m, 7H), 1.31 (d, J = 8.1 Hz, 1H), 1.15 (s, 3H), 1.02 (s, 3H), 0.93 – 0.84 (m, 1H),
0.78 (s, 3H), 0.70 (s, 3H); C NMR {1H} (100 MHz, CDCl3) δ 157.3, 155.4, 136.7, 110.6,
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108.5, 103.0, 79.4, 75.2, 55.6, 54.7, 49.2, 41.0, 39.1, 38.5, 38.4, 28.8, 27.5, 27.2, 22.0, 18.3, 17.7,
16.0, 14.5. HRMS (ESI) m/z calcd. for C23H35O3 [M+H]+ 359.2586, found 359.2589.
Preparation
of
(3S,4aR,6aS,12aR,12bS)-11-methoxy-4,4,6a,9,12b-pentamethyl-
2,3,4,4a,5,6,6a,12,12a,12b-decahydro-1H-benzo[a]xanthen-3-yl acetate (22):
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Compound 21 (66 mg, 0.18 mmol) was dissolved in dry DCM (2 mL) and added with pyridine
(0.09 mL, 1.1 mmol), acetic anhydride (0.1 mL, 1.1 mmol) and catalytic amount of N,N-
dimethyl amino pyridine at room temperature. The reaction mixture was then stirred for 15 h
under nitrogen atmosphere. Once the reaction was completed, as monitored by TLC, it was
cooled to 0 °C and 1N HCl (5 mL) was added to the mixture. Two layers were separated. The
aqueous layer was extracted twice with DCM (2 x 5 mL). Combined organic fractions were
washed with brine, dried over NaSO4 and evaporated under reduced pressure to get crude
compound. Purification of the crude compound was done by silica gel column chromatography
using hexane/EtOAc (99:1 to 95:5) to get 22 as a colorless oil. Yield = 72 mg (93%). Rf = 0.5 in
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10% EtOAc-hexane;
ퟐퟖ = -4.0 (c 1.02, CHCl3); IR (neat): ʋmax/CM-1 3; 1H NMR (400 MHz,
[휶]푫
CDCl3) δ 6.24 (s, 1H), 6.20 (s, 1H), 4.49 (dd, J = 11.5, 4.8 Hz, 1H), 3.79 (s, 3H), 2.69 (d, J =
18.4 Hz, 1H), 2.56 (dd, J = 18.4, 8.1 Hz, 1H), 2.26 (s, 3H), 2.18 – 2.10 (m, 1H), 2.04 (s, 3H),
1.92 (dt, J = 13.2, 3.4 Hz, 1H), 1.73 – 1.62 (m, 2H), 1.51 – 1.55 (m, 2H), 1.32 (d, J = 8.0 Hz,
1H), 1.15 (s, 3H), 1.10 (dd, J = 13.4, 3.9 Hz, 1H), 1.02 – 0.93 (m, 2H), 0.89 (s, 3H), 0.85 (s, 3H),
13
0.72 (s, 3H); C NMR {1H} (100 MHz, CDCl3) δ 171.4, 157.3, 155.4, 136.7, 110.6, 108.5,
103.0, 81.3, 75.2, 55.6, 54.8, 49.1, 40.9, 38.3, 38.2, 38.0, 28.8, 27.2, 23.8, 22.0, 21.7, 18.2, 17.8,
17.1, 14.5; HRMS (ESI) m/z calcd. for C25H37O4 [M+H]+ 401.2692, found 401.2688.
Preparation of (3S,4aR,6aS,12aR,12bS)-8-formyl-11-methoxy-4,4,6a,9, 12b-pentamethyl-
2,3,4,4a,5,6,6a,12,12a,12b-decahydro-1H-benzo[a]xanthen-3-yl acetate (23):
Dry DMF (0.02 mL, 0.27 mmol) was taken in a round bottom flask under nitrogen atmosphere
and cooled to 0 °C. Distilled POCl3 (0.025 mL, 0.27 mmol) was added slowly to the dry DMF
with vigorous stirring at 0 °C and kept stirring for 30 min at the same temperature to get thick
colorless syrup. Then compound 22 (72 mg, 0.18 mmol) in dry DMF (2 mL) was added to the
above syrup at 0 °C. Reaction mixture was gradually warmed to room temperature and then
heated at 110 °C for 6 h. Once the starting compound was consumed completely as shown in
TLC, crushed ice was added to cease the reaction and the mixture was extracted thrice with
EtOAc (3x5 mL). Combined organic fractions were washed with brine, dried over NaSO4 and
evaporated under reduced pressure to get crude aldehyde. Purification of the crude compound
was done by silica gel column chromatography using hexane/EtOAc (95:5 to 90:10) to get 23 as
[휶]ퟐ푫ퟖ
a colorless oil. Yield = 55 mg (72%). Rf = 0.3 in 10% EtOAc-hexane;
= -5.6 (c 1.02,
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CHCl3); IR (neat): ʋmax/CM-1 2925, 2852, 1732, 1674, 1603,1570,1463, 1394, 1371, 1342, 1312,
1
1280, 1245, 1217, 1167, 1085, 1028, 1005, 936, 886, 803, 555; H NMR (400 MHz, CDCl3) δ
10.52 (s, 1H), 6.24 (s, 1H), 4.52 (dd, J = 11.6, 4.7 Hz, 1H), 3.88 (s, 3H), 2.72 (d, J = 18.4 Hz,
1H), 2.63 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H), 2.26 – 2.21 (m, 1H), 2.07 (s, 3H), 1.95 – 1.91 (m,
1H), 1.73 – 1.69 (m, 2 H), 1.61 – 1.57 (m, 3H), 1.39 (d, J = 8.0 Hz, 1H), 1.22 (s, 3H), 1.16 (d, J
= 3.6 Hz, 1H), 1.02 (d, J = 10.6 Hz, 1H), 0.93 (s, 3H), 0.88 (s, 3H), 0.75 (s, 3H); 13C NMR {1H}
(100 MHz, CDCl3) δ 191.6, 171.4, 161.1, 160.3, 141.5, 117.5, 109.1, 105.6, 81.1, 76.5, 55.8,
54.6, 48.4, 40.6, 38.3, 38.1, 38.0, 28.8, 27.3, 23.8, 22.7, 21.7, 18.1, 17.7, 17.2, 14.5; HRMS
(ESI) m/z calcd. for C26H37O5 [M+H]+ 429.2641, found 429.2647.
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Preparation of phomoarcherin C (3):
To a mixture of NaH (26 mg, 0.65 mmol) in dry DMF at 0 °C under nitrogen atmosphere, was
added EtSH (0.055 mL, 0.77 mmol) and stirred for 30 min at the same temperature. A solution of
compound 23 (55 mg, 0.13 mmol) in dry DMF was slowly added to the above sodium ethane
thiolate mixture at 0 °C and allowed to warm gradually to room temperature. Then the reaction
mixture was heated 140 °C for 3 h. Once the reaction was completed as indicated by TLC, it was
cooled down to 0 °C and was quenched by adding crushed ice. Reaction mixture was extracted
thrice with EtOAc (3x5 mL) and the combined organic fractions were washed with brine (2x5
mL), dried over NaSO4 and evaporated to get crude compound 24 which was preceded for the
next step without purification.
The above crude compound 24 was dissolved in EtOAc (2 mL) and added with IBX (108 mg,
0.38 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was refluxed
for 2 h. Once the reaction was completed as shown in TLC, it was cooled to room temperature
and the solids were filtered off. The clear solution obtained so was evaporated under reduced
pressure and purified by silica gel column chromatography using hexane/EtOAc (95:5 to 90:10)
to get Phomoarcherin C (3) as a colorless oil. Yield = 31 mg (65% over two steps). Rf = 0.6 in
20% EtOAc-hexane;
ퟐퟖ = -2.6 (c 1.02, CHCl3); IR (neat): ʋmax/CM-1 2924, 2853, 1695, 1647,
[휶]푫
1584, 1510, 1449, 1424, 1385, 1324, 1238, 1083, 1014, 813, 520; 1H NMR (400 MHz, CDCl3) δ
10.47 (s, 1H), 6.23 (s, 1H), 2.76 (s, 2H), 2.56 (m, 1H), 2.52 (s, 3H), 2.47 – 2.39 (m, 1H), 2.30 –
2.23 (m, 1H), 2.17 – 2.09 (m, 1H), 1.85 – 1.76 (m, 1H), 1.67 (dd, J = 13.4, 3.4 Hz, 1H), 1.54 –
13
1.48 (m, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.05 (s, 3H), 0.84 (s, 3H); C NMR {1H} (100 MHz,
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CDCl3) δ 217.3, 191.0, 160.8, 158.3, 141.6, 116.8, 110.4, 106.9, 76.1, 54.1, 47.3, 47.1, 39.7,
38.4, 37.6, 34.1, 26.8, 26.7, 21.9, 21.6, 19.0, 17.4, 14.0; HRMS (ESI) m/z calcd. for C23H31O4
[M+H]+ 371.2222, found 371.2229.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1H and 13C spectra for all products and table of results from kinetics NMR
experiments
AUTHOR INFORMATION
Corresponding Author
* Email: ddethe@iitk.ac.in
Notes
The authors declare no competing financial interest.
Present Addresses
aDepartment of Chemistry, Indian Institute of Technology, Kanpur, 208016, India.
.Conflicts of interest
There are no conflicts to declare.
ACKNOWLEDGMENT
BVK thanks Nagabhushana and Manmohan Shukla for helping in the synthesis and obtaining
pure 13C spectrum of the starting compound. Department of Chemistry, Indian Institute of
Technology, Kanpur is greatly acknowledged for providing infra structure and facilities
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