Bio-inspired enantioselective total syntheses of (-)-viminalins A, B, H, I, and N and structural reassignment of (-)-viminalin M

Article abstract of DOI:10.1039/c9ob01426h

Bio-inspired enantioselective total syntheses of (-)-viminalins A, B, H, I, and N, isolated from the Myrtaceae family, were accomplished in a convergent fashion in 5, 5, 1, 1, and 3 steps, respectively. A highly regio- and diastereoselective oxidative [3 + 2] cycloaddition reaction of acylphloroglucinols with α-phellandrene, diastereoselective modified Friedel-Crafts reaction of acylphloroglucinols with piperetol, and stereoselective epoxidation of extremely hindered β-face were described as key reactions.

Full text of DOI:10.1039/c9ob01426h

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DOI: 10.1039/C9OB01426H
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ARTICLE
Bio-Inspired Enantioselective Total Syntheses of (−)-Viminalins A,
B, H, I, N, and Structural Reassignment of (−)-Viminalin M
Received 00th January
20xx,
Dattatraya H. Dethe,* and Appasaheb K. Nirpal
Accepted 00th January
20xx
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A bio-inspired enantioselective total syntheses of (−)-viminalins A, B, H, I, and N, isolated from Myrtaceae
family, were accomplished in a convergent fashion in 5, 5, 1, 1, and 3 steps respectively. A highly regio- and
diastereoselective oxidative [3+2] cycloaddition reaction of acylphloroglucinols with α-phellandrene, diastereoselective
modified Friedel-Crafts reaction of acylphloroglucinols with piperetol, and stereo selective epoxidation of extremely
hindered β-face were described as key reactions.
INTRODUCTION:
Over the last two decades, acylphloroglucinol containing natural
products (a class of secondary metabolites which belongs to
Myrtaceae, Guttiferae and Euphorbiaceae family)1 have shown a
wide variety of pharmacological activities, for example, Cytotoxic,
antibacterial, antimicrobial, anti-inflammatory, antiproliferative and
antiviral activities.2 To date, a series of novel phloroglucinol-
terpenoid adducts with cytotoxic or antibacterial activities have
been isolated from the medicinal plants of the family Myrtaceae.3 In
2016 Lu et al. isolated Callviminos A-E, five rare phloroglucinol
derivatives containing hexahydrodibenzo [b,d] furan or 2-
Me
O
H
O
HO
Me
R
O
Me
O
O
1 step
3 step
H
()-Viminalin H; R = CH2CH(CH3)2
()-Viminalin I ; R = CH(CH3)2
O
HO
OH
O
5 steps
HO
Me
O
R
O
H
R
O
R = CH2CH(CH3)2
R = CH(CH3)2
()-Viminalin A; R = CH2CH(CH3)2
()-Viminalin B; R = CH(CH3)2
O
H
HO
OH
R
O
()-Viminalin M; (revised structure)
R = CH2CH(CH3)2
()-Viminalin N; R = CH(CH3)2
phenylcyclohexanol nucleus derived from
a phloroglucinol-
monoterpenoid adduct, from the leaves of Callistemon viminalis,5C
in addition to that Ling-Yi Kong and co-workers in 2017 isolated
viminalins A-O from the fruits of Callistemon viminalis.5a Callviminos
show prominent biological aspects such as antimicrobial activity
against the microbes Escherichia coli and Staphylococcus aureus,
and cytotoxicity against a panel of human cancer cell lines MCF-7
(breast cancer) and NCL-H460 (lung cancer), as well as SF-268
containing 2,3-dihydrofuran connected to terpenoids are rare.5b
The structures and relative stereochemistry of all the viminalins
including viminalins A (1), B (2), H (3), I (4), M (5 & 6), viminalins N
(7), E (8) and F (9) were elucidated by spectral analysis, HRESIMS
and X-ray crystallography.5Among the viminalin A-O, viminalin F (9)
showed moderate Cytotoxic activity against HepG-2 (IC50 = 9.2 mM),
MCF-7 (IC50 = 17.0 mM) and U2-OS (IC50 = 27.4 mM) cells,5a whereas
the other viminalins showed either low activity or were inactive
against all of the tested cell lines (IC50 > 50 mM).5 A new carbon
skeleton with [3+2] adducts of acylphloroglucinoals and α-
phellandrene in viminalins have attracted the attention of many
synthetic chemists and pharmacologists. Herein, we report the first
bio-inspired enantioselective total syntheses of (−)-viminalins A (1),
B (2), H (3), I (4), N (7) and structural reassignment of (−)-viminalin
M (6).
(human glioblastoma carcinoma). Callistemon viminalis is
a
flowering plant belonging to the family Myrtaceae and often used
for treatment of cold and arthralgia in Chinese folk medicine.
Among all the isolated viminalis, acylphloroglucinol derivatives
a. Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016,
India.
b. ddethe@iitk.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 | 1
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ARTICLE
Journal Name
Me
Me
Me
O
Me
O
View Article Online
O
Me
3+2
cycloaddition
O
H
O
H
H
H
DOI: 10.1039/C9OB01426H
[O]
+
O
O
O
H
HO
OH
HO
O
O
HO
HO
O
HO
Me
O
R
O
O
H
R
O
R
O
R
O
O
()-Viminalin A (1); R = CH2CH(CH3)2 ()-Viminalin H (3); R = CH2CH(CH3)2 11; R = CH2CH(CH3)2 10
()-Viminalin A (1); R = CH2CH(CH3)2
()-Viminalin B (2); R = CH(CH3)2
()-Viminalin M (5)
(Proposed)
O
12; R = CH(CH3)2
HO
(

)-Viminalin B (2); R = CH(CH )
(

)-Viminalin I (4); R = CH(CH )
3
2
3
2
R
O
Me
O
Me
O
Me
O
Me
O
Me
O
()-Viminalin E (8); R = CH2CH(CH3)2
()-Viminalin F (9); R = CH(CH3)2
H
H
FC
alkylation
H
+
OH
HO
O
O
OH
H
HO
HO
HO
OH
O
H
HO
R
O
R
O
R
O
R
O
O
()-Viminalin H (3); R = CH2CH(CH3)2
()-Viminalin I (4); R = CH(CH3)2
()-Viminalin M (5); R = CH2CH(CH3)2
()-Viminalin N (7); R = CH(CH3)
11; R = CH2CH(CH3)2
12; R = CH(CH3)2
13
()-Viminalin N (7)
Figure 1. Molecular Structures of Naturally Occurring (−)-Viminalins
A (1), B (2), H (3), I (4), M (5 and 6), N (7), E (8) and F (9)
Scheme 2. Retrosynthetic Analysis of (−)-Viminalins A (1), B (2), H
(3), I (4) and M (5)
Synthesis commenced with preparation of acyl phloroglucinol
derivatives 11 and 12. Selective methylation of commercially
available phloroglucinol 14 using Me2SO4 and K2CO3 gave its mono-
methyl derivative 15 in 70% yield.7a Friedel-Crafts acylation of 15
with appropriate acyl chloride [RCOCl; R = CH2CH(CH3)2 or CH(CH3)2]
provided acylphloroglucinols 11 and 12 as a single regioisomer in
84% and 85% yields respectively7b (Scheme 3).
RESULTS AND DISCUSSION:
Noting that, several viminalins were found to be acylphloroglucinol
derivatives, Wu- et al. proposed a biosynthetic route featuring the
oxidative [3+2] cycloaddition and subsequent epoxidation to form
(−)-viminalins A (1), B (2), H (3) and I (4).5
O
O
O
H
Me
H
O
-H+
O
Radical
Me
OH
O
K2CO3, Me2SO4
Acetone, 30 °C, 24h
RCOCl, AlCl3, CH2Cl2
coupling
O
HO
OH
HO
HO
OH
0 °C to 30 °C , 24h
84-85%
OH
HO
OH
R
O
70%
R
O
R
HO
OH
HO
R
O
14
15
11; R = CH2CH(CH3)2
12; R = CH(CH3)2
Me
Me
O
O
H
H
O
Scheme 3. Preparation of Acylphloroglucinols 11 and 12
O
O
O
HO
HO
R
O
R
O
()-Viminalin A (1); R=CH2CH(CH3)2
()-Viminalin B (2); R=CH(CH3)2
()-Viminalin H (3); R=CH2CH(CH3)2
()-Viminalin I (4); R=CH(CH3)2
With gram quantities of acyl phloroglucinol derivatives 11 and 12 in
hand, the stage was set for the key oxidative [3+2] cycloaddition
reaction with commercially available α-phellandrene (10) for the
synthesis of the viminalin H (3) and I (4). An equimolar mixture of
acyl phloroglucinol derivative 11/12 and (−)-α-phellandrene (10)
were treated with catalytic amount of AgCO3 and celite in
acetonitrile under reflux condition,12a,12b,13 gratifyingly it afforded
the natural products (−)-viminalin H (3) and I (4) in 61% and 62%
yields respectively13 (Scheme 4). The next task was stereoselective
epoxidation of alkene present in (−)-viminalin H (3) and I (4) 1-
(5aR,8R,9aR). Our initial attempts for epoxidation of (−)-viminalin H
(3) using DBDMH or m-CPBA resulted in the decomposition of
starting material. Probably due to highly electron rich aromatic ring
in (−)-viminalin H (3) that makes it prone to oxidation under these
conditions9. Acylation of (−)-viminalin H (3) and I (4) using Ac2O and
Et3N generated the adduct 16 and 17 in 90% and 91% yield
respectively. Epoxidation of compound 17 using m-CPBA afforded
epoxide 18 in 42% yield. Hydrolysis of acetate 18 using LiOH
afforded compound 19 with 88% yield. Unfortunately, the reported
spectral data (−)-viminalin B (2) didn’t match with 19. It was
contemplated that epoxidation could have occurred from less
hindered α-face, thus generating diastereomer of (−)-viminalin B
(19).
Scheme 1. Biosynthetic Pathway for the (−)-Viminalins A (1), B (2),
(3) and (4)
H
I
Considering the biosynthetic route, viminalins deemed attractive,
and thus we undertook the retrosynthetic analysis of viminalins A
(1), B (2), H (3), I (4) and M (5) as illustrated in Scheme 2. It is likely
that (−)-viminalins A (1), B (2), H (3), and I (4) were formed
biosynthetically through the union of two molecules α-
phellandrene (10) and acylphloroglucinols 11 or 12, and viminalin M
(5) formed through the union of piperetol (13) and
acylphloroglucinols 11. Inspired by this biosynthetic hypothesis as
shown in Scheme 1, it was contemplated that (−)-viminalin A (1)
and B (2) could be accessed by stereoselective epoxidation of the
(−)-viminalin H (3) and I (4) respectively.5b (−)-Viminalin H (3) and I
(4) could be assembled through the diastereoselective oxidative
[3+2] cycloaddition of acylphloroglucinols5 11 or 12 and
commercially available (−)-α-phellandrene (10), whereas (−)-
viminalin M (5) could be accessed by modified Friedel-Crafts
coupling reaction16 of piperetol (13) and acylphloroglucinols 11
followed by cyclization and late-stage elimination.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
required components, acyl phloroglucinol derivative
View Art1ic1le Onalninde
Me
Me
O
O
H
DOI: 10.1039/C9OB01426H
piperetol (13), as shown in retrosynthetic analysis (Scheme 1). This
route had the advantage of optimum convergence, and it was
presumed that the stereo chemical outcome of the Friedel-Crafts
coupling reaction would be governed by the bulky isopropyl group
at the C-9 position. The piperetol (13) was obtained by reduction of
the keto group of (−)-piperitone using Luche reduction.16a After
having required fragments in hand; next we investigated the key
Ac2O, Et3N,
DMAP
Ag2CO3, Celite
+
HO
OH
O
CH3CN, reflux,
8 h
HO
CH2Cl2, 30 °C,
3 h, 90-91%
R
O
R
O
--Phellandrene (10)
11; R = CH2CH(CH3)2
12; R = CH(CH3)2
()-Viminalin H (3); R = CH2CH(CH3) ,
2
61%
()-Viminalin I (4); R = CH(CH3)2, 62%
Me
O
Me
O
Me
O
H
H
H
O
m-CPBA
LiOH
O
O
HO
O
O
AcO
AcO
CH2Cl2, 0 °C to
30 °C, 12 h, 42%
THF:H2O (2:1)
30 °C, 1 h, 88%
Friedel-Crafts reaction. Treatment of
a
mixture of acyl
O
R
O
R
O
phloroglucinol derivative 11 and piperetol (13) with the 5 mol%
BF3·Et2O led to rapid formation of highly regio- and
diastereoselective coupling product 23 in 88% yield with >20:1
diastereomeric ratio (only major diastereomer is shown in Scheme
6).16a Compound 23 on treatment with Pd(OAc)2 and MnO in
acetonitrile as a solvent afforded the tricyclic intermediate 24
containing exocyclic double bond in 49% yield.17 Conversion of
tricyclic intermediate 24 to (−)-epi-viminalin M (5) required the
isomerisation of a double bond to the endo-site. After trying various
conditions such as H2SO4 in CH2Cl2, and PdCl2 in CH2Cl2, the reaction
was unsuccessful19a,19b (Scheme 6). Finally, after some extensive
trials, we were successful achieving the enantioselective total
synthesis of (−)-viminalin M (5).
16; R = CH2CH(CH3)2
17; R = CH(CH3)2
18; R = CH(CH3)2
()-di-epi-Viminalin B (19)
Scheme 4. Total Synthesis of (−)-Viminalin H (3), I (4), and (−)-di-epi-
viminalin B (19)
For epoxidation from more hindered β-face we relied on a two step
protocol i.e. formation of halohydrin followed by treatment with
base. Formation of bromohydrin using 20 and subsequent
epoxidation under treatment with NaOH and toluene reflux
condition produced epoxide 21 and 22 respectively as a single
diastereomer in 82% yield for each over the two steps.
Mechanistically C6−C7 double bond in 16/17 would form
bromonium ion at less hindered α- face which, on diaxial opening
with water would result in the formation of bromohydrin. Later
under the basic condition following nucleophilic attack of the
alkoxide ion on bromine, resulted in the formation of the desired
(β-side) epoxidation product 21 and 22 along with bromination of
aromatic ring14 as shown in Scheme 5. Debromination of
compound15a,15b 21 and 22 using 10 mol% Pd(PPh3)4, NaOCHO,
TBAB and Et3N in DMF reflux condition resulted in to the formation
of natural products (−)-viminalin A (1) and B (2) with 70% and 72%
yields respectively (Scheme 5). The spectral and physical properties
of the both synthetic samples were identical to those reported for
the natural (−)-viminalins A (1) and B (2).5a
Me
Me
O
O
BF3 Et2O
+
OH
HO
CH2Cl2, 30 °C,
5 min 88%
OH
HO
OH
O
O
23
dr: >20:1
11
13
Pd(OAc)2, MnO CH3CN, 30 °C
3h, 49%
Me
Me
O
O
1) P-TSA, CH2Cl2,
30 °C
H
H
2) PdCl2, CH2Cl2,
30 °C
O
O
H
H
HO
HO
O
O
O
5
24
Me
Me
O
O
N
N
Br
Br
H
H
20
Br
HO
O
1. Acetone:Water (10:1)
4 h, 30 °C
Scheme 6. Attempt Towards the Total Synthesis of (−)-Viminalin M
(5)
O
O
AcO
2. NaOH, toluene, 80 °C
1 h, 82% for the 2 steps
R
O
R
O
16; R = CH2CH(CH3)2
17; R = CH(CH3)2
21; R = CH2CH(CH3)2
22; R = CH(CH3)2
Pd(PPh3)4, NaOCHO,
TBAB, Et3N, DMF,
reflux, 12h, 70-72%
Treatment of 23 with DMDO furnished the tricyclic intermediate 25
in 50% yield16a by initial formation of epoxide followed by
nucleophilic attack of phenolic hydroxy group. Surprisingly, attempt
toward the elimination of tert-alcohol 25 using classical reagents
such as potassium bisulphate, anhydrous zinc chloride, phosphorus
pentaoxide or Martin's sulfurane were met with limited sucess.20a
To our delight, treatment of compound 25 with p-TSA in toluene
under reflux condition generated the diastereomeric compound (6)
in 49% overall yield20b(Scheme 7). Surprisingly the spectroscopic
data and then optical rotation of compound (6) were identical with
the isolated natural product viminalin M (5).5a We propose that the
relative stereochemistry of viminalin M (5aS,9R,9aR) is incorrect5b
because synthetic approach presented here proves that the
stereochemistry of the viminalin M (5) is suppose to have the
(5aR,9R,9aS) isopropyl group trans to aromatic ring and that is also
Me
O
H
O
O
HO
R
O
()-Viminalin A (1); R = CH2CH(CH3)2
()-Viminalin B (2); R = CH(CH3)2
Scheme 5. Total Synthesis of (−)-Viminalin A (1) and B (2)
Next, we targeted the total synthesis of natural product (−)-epi-
M (5). It was decided to employ the highly
diastereoselective Friedel-Crafts reaction16a,17 that involved two
viminalin
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
supported by our earlier BF3·Et2O catalyzed diastereoselective In summary, enantioselective first total syntheses of (−)-viminalin A
View Article Online
Friedel-Crafts reaction for the synthesis of adunctin B and E.16a,17On (1), B (2), H (3), I (4), N (7) and revised structure of (−)- viminalin M
DOI: 10.1039/C9OB01426H
the basis of the above observation, we propose revised structure of (6) were achieved with short and atom economical way in 5, 5, 1, 1,
(−)-viminalin M (6). It is worth mentioning that the stereochemistry 3 and 3 steps, respectively with 30%, 32%, 61%, 62% 21% and 21%
of the proposed
overall yield using a highly regio- and diastereoselective oxidative
[3+2] cycloaddition reaction of acyl phloroglucinols with α-
phellandrene, highly diastereoselective Friedel-Crafts reaction of
acyl phloroglucinols with allylic alcohol, and stereo selective
epoxidation of extremely hindered β-face as a key reactions. The
structure of (−)-viminalin M (6) was revised and conformed by its
total synthesis. This concise and convergent route and applications
of these reactions paves the way for the synthesis of structurally
relevant natural products and designed analogues thereof, which
may facilitate studies of the biology of this fascinating class.
Me
Me
O
O
H
Oxone, NaHCO3
OH
Acetone, 12h,
50%
O
H
HO
HO
OH
23
O
O
25
P-TSA, toluene
reflux, 1h,
49% overall
7'
7'
6'
9'
Me
6'
8'
9'
Me
8'
O
9
9
O
1
8
8
H
H
1
9b
7
9b
7
2
5a
9a
2
5a
6
9a
O
6
O
H
H
HO
4'
4a
HO
4'
4a
O
3
3
4
5
4
5
1'
1'
2'
3'
O
2'
3'
EXPERIMENTAL SECTION:
5'
5'
()-Viminalin M (5)
()-Viminalin M (6)
General Experimental Methods: All reactions were carried out
under a nitrogen atmosphere with dry solvents under anhydrous
conditions, unless otherwise mentioned. All the chemicals were
purchased commercially and used without further purification.
Anhydrous THF and diethyl ether were distilled from sodium
benzophenone, and dichloromethane was distilled from calcium
hydride. Yields refer to chromatographically pure compounds,
unless otherwise stated. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm silica gel plates (60F-
254) using UV light as a visualizing agent and a p-anisaldehyde or
ninhydrine stain, and heat as developing agents. Silica gel (particle
size: 100−200 and 230−400 mesh) was used for flash column
chromatography. Neat coumpounds were used for recording IR
spectra. NMR spectra were recorded on either 400 (1H, 400 MHz;
13C, 100 MHz) or 500 (1H, 500 MHz; 13C, 125 MHz). Mass
spectrometric data were obtained using Q-TofPremier-HAB213 and
Q-Tof-Premier-ESI-MS instruments. Melting points measurements
(proposed)
(revised)
Scheme 7. Total Synthesis of Revised Structure of (−)-Viminalin M
(6)
(−)-viminalin M (5) was found to be exactly opposite at position C-
5a and C-9a. Further it is also supported by the synthesis of (−)-
viminalin N (7)5b using similar strategy and reaction conditions as
mentioned in scheme 8. Treatment of 12 and 13 with BF3·Et2O led
to rapid formation of highly regio- and diastereoselective Friedel-
Crafts alkylation product 26 in 88% yield with >20:1 diastereomeric
ratio. Reaction of 26 with DMDO directly generated tricyclic
intermediate 27. Finally p-TSA mediated dehydration to produced
(−)-viminalin N (7) in 50% yield. [Cao et al. introduced two
rearranged phloroglucinol-monoterpenoid adducts Callisretones A
and B isolated from callistemon rigidus5b and also revised the
previously assigned absolute configuration of viminalins H (3), L and
N (7). The relative stereochemistry of viminalin H (3), L and N (7)
were determined by X-ray crystallographic analysis].
were made using
a hot stage apparatus. 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.
Me
Me
O
O
BF3 Et2O
+
Synthesis of 5-methoxybenzene-1,3-diol (15): A 500-mL flame-
dried round-bottom flask equipped with a stir bar was charged with
phloroglucinol (300 mmol) and K2CO3 (300 mmol). Acetone (200
mL) was added and the mixture was stirred at 30 °C. Me2SO4 (100
mmol) (caution: use dimethyl sulfate in well ventilated area due to
its known toxicity) was then added drop wise using an addition
funnel over 15 min. Once all Me2SO4 was added, the addition funnel
was rinsed, the flask was capped with a rubber septum, and the
reaction mixture was stirred overnight at 55 °C. After 12 h, acetone
was removed in vacuo and the residue was transferred to a
separatory funnel with EtOAc (250 mL) and extracted with 1M HCl
(2 x 150 mL) followed by brine (1 x 50 mL). The organic layer was
collected, dried over Na2SO4, and evaporated. The crude product
was purified by silica gel column chromatography (gradient 20 –
40% EtOAc in hexanes) to afford the desired product mono-O-
HO
OH
OH
CH2Cl2, rt, 5 min
91%
HO
OH
26
O
O
12
13
Oxone, NaHCO3
Acetone, 12h,
48%
Me
O
Me
H
O
H
P-TSA, toluene
OH
O
H
HO
reflux, 1h,
50% overall
O
H
HO
O
O
()-Viminalin N (7)
27
Scheme 8. Total Synthesis of (−)-Viminalin N (7)
CONCLUSION:
4 | J. Name., 2012, 00, 1-3
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methylphloroglucinol in 55 % yield (based on dimethylsulfate as NMR (125 MHz, CDCl3) δ 204.8, 166.1, 162.6, 161.6, 135.3, 129.3,
View Article Online
DOI: 10.1039/C9OB01426H
limiting reagent). Spectroscopic data was in agreement with the 107.8, 102.7, 92.1, 88.7, 55.5, 51.7, 44.2, 38.1, 31.5, 26.4, 26.2,
literature7a.
26.0, 22.9, 22.7, 19.9, 19.7; HRMS: m/z calcd for C22H31O4 [M+H]+:
1-(2,6-dihydroxy-4-methoxyphenyl)-3-methylbutan-1-one(11)and
359.2222; found: 359.2224.
1-(2,6-dihydroxy-4-methoxyphenyl)-2-methylpropan-1-one(12): A (5aR,8R,9aR)-4-isobutyryl-8-isopropyl-1-methoxy-5a-methyl-
500-mL flame-dried round-bottom flask equipped with a stir bar 5a,8,9,9a-tetrahydrodibenzo[b,d]furan-3-yl acetate (17): To
a
was charged with phloroglucinol-derivative (25 mmol) and AlCl3 (50 magnetically stirred solution of 4 (315 mg, 0.91 mmol) in CH2Cl2 (10
mmol). CH2Cl2 (45 ml) was added and the reaction vessel was mL) was added Et3N (0.4 mL, 3.21 mmol), DMAP (204 mg, 0.91
capped with a rubber septum attached to a balloon of argon and mmol) and acetic anhydride (0.3 mL, 2.28 mmol) dropwise and the
submerged in an ice bath. Once chilled, the acyl chloride (25 mmol) resulting mixture was then stirred at 30 °C. After completion of
was added drop wise over 5– 10 min. The syringe was rinsed with reaction, indicated by TLC, the reaction mixture was extracted with
CH2Cl2 (5 mL) and the reaction was left to slowly warm up to 30 °C ethyl acetate. The combined organic layer was washed with
overnight. After the allotted reaction time, CH2Cl2 was removed NaHCO3 and dried over Na2SO4. Evaporation of the solvent and
with a steady stream of nitrogen. Crushed ice was then added until crude residue was purified by silica gel column chromatography
the reaction was quenched (caution: addition of ice was using EtOAc-hexane (1:14) as an eluent furnished 17 (320 mg, 90%)
28
exothermic). The quenched reaction mixture was then transferred as a yellow oil; Rf = 0.20 EtOAc−hexane (1:12); [α]D = −60.0 (c =
to a separator funnel with EtOAc (200 mL) and was extracted with 0.13, CHCl3); IR (neat): νmax/cm-1 2966, 2932, 2871, 1769, 1679,
1
1M HCl (2 x 50 mL) followed by brine (1 x 50 mL). The organic layer 1614, 1464, 1367, 1208, 1194, 1090, 963, 894, 790; H NMR (400
was then dried over MgSO4 and evaporated. The product was either MHz, CDCl3) δ 6.11 (s, 1H), 5.84 (dd, J = 2.4, 10.4 Hz, 1H), 5.58 (dd, J
subjected to silica gel chromatography (10 – 20 % EtOAc in = 2.4, 10.4 Hz, 1H), 3.79 (s, 3H), 3.48 − 3.42 (m, 2H), 2.26 (s, 3H),
hexanes). Spectroscopic data was in agreement with the literature.
1.91 − 1.86 (m, 1H), 1.70 − 1.64 (m, 1H), 1.62 − 1.56 (m, 2H), 1.54 (s,
Synthesis of (−)-Viminalin I (4): To a mixture of 12 (1.0 g, 4.7mmol), 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.9
(−)-α-phellandrene 10 (3.8 g, 28.5 mmol), Ag2CO3 (5.2 g, 19.0 mmol) Hz, 3H) 0.88 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.1,
and celite (900 mg) in acetonitrile (30 mL) was refluxed for 8 h. The 170.1, 159.8, 158.8, 151.1, 135.2, 129.2, 115.1, 109.7, 99.5, 88.5,
mixture was cooled to 30 °C, filtered and solvents were removed in 55.6, 44.5, 40.1, 38.1, 31.5, 26.3, 25.7, 21.2, 19.9, 19.6, 18.6, 18.3 ;
vacuo. The crude residue was purified by silica gel column HRMS: m/z calcd for C23H30O5Na [M+Na]+: 409.1991; found:
chromatography using EtOAc-hexane(1:4) as an eluent to afford 4 409.1994.
(1.0 g, 62%) as a crystalline solid, Rf = 0.7; (EtOAc-hexane 1:4); mp (5aR,8R,9aR)-8-isopropyl-1-methoxy-5a-methyl-4-(3-
28
= 80−82 °C; [α]D = −42.6(c = 0.15, MeOH); IR (neat): νmax/cm-1 methylbutanoyl)-5a,8,9,9a-tetrahydrodibenzo[b,d]furan-3-yl
2961, 2930, 2871, 1628, 1603, 1464, 1382, 1258, 1241, 1099, 967, acetate (16): To a magnetically stirred solution of 3 (329 mg 0.91
1
880, 787, ; H NMR (400 MHz, CDCl3) δ 13.56 (s, 1H), 5.97 (s, 1H), mmol), in 10 mL CH2Cl2 was added Et3N (0.4 mL, 3.21 mmol), DMAP
5.86 (dd, J = 2.4, 9.8 Hz 1H), 5.60 (dd, J = 2.4, 9.8 Hz, 1H), 3.80 (s, (112 mg, 0.91 mmol) and acetic anhydride (0.2 mL, 2.29 mmol)
3H), 3.72 (m, 1H), 3.39 (t, J = 4.9 Hz, 1H), 2.28 (dt, 14.0, 5.0 Hz 1H), dropwise and the resulting mixture was then stirred at 30 °C. After
1.92 −1.86 (m, 1H), 1.61 (m, 1H), 1.60 (m, 1H), 1.55 (s, 3H), 1.14 (d, J completion of reaction, the reaction mixture was extracted with
= 7.0 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.88 (d, ethyl acetate. The combined organic layer was washed with
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.1, 166.4, 162.5, NaHCO3 and dried over Na2SO4, and crude residue was purified by
161.3, 135.3, 129.2, 107.9, 101.7, 92.3, 88.7, 55.6, 44.1, 38.5, 38.1, silica gel column chromatography using EtOAc-hexane (1:14) as an
31.5, 26.4, 26.2, 19.9, 19.7, 19.1, 18.8 ; HRMS: m/z calcd for eluent furnished 16 (334 mg, 91%) as a yellow oil; Rf = 0.20
28
C21H29O4 [M+H]+: 345.2066; found: 345.2061.
(EtOAc−hexane (1:12); [α]D = −10.0 (c = 0.70, CHCl3); IR (neat):
(−)-Viminalin H (3): To a magnetically stirred solution of 11 (500 mg νmax/cm-1 2957, 2870, 1769, 1677, 1614, 1464, 1407, 1367, 1297,
2.2 mmol), (−)-α-phellandrene 10 (1.8 g 13.3 mmol), Ag2CO3 (2.4 g, 1194, 1022, 872; 1H NMR (400 MHz, CDCl3) δ 6.10 (s, 1H), 5.84 (dd, J
8.9 mmol) and celite (400 mg) in acetonitrile (15 mL) was refluxed = 3.5, 10.2 Hz, 1H), 5.58 (dd, J = 2.3, 10.2 Hz, 1H), 3.79 (s, 3H), 3.44
for 8 h. The mixture was cooled to 30 °C, filtered and solvents were (t, J = 4.8 Hz, 1H), 2.78 − 2.68 (m, 2H), 2.34 - 2.29 (m, 1H), 2.28 (s,
removed in vacuo. The crude residue was purified by silica gel 3H), 2.12 (td, J = 6.7, 13.4 Hz, 1H), 1.92 (br. s., 1H), 1.60 − 1.58 (m,
column chromatography using EtOAc-hexane(1:4) 3 (490 mg, 61%) 2H), 1.55 (s, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.91(d, J = 7.0 Hz, 3H), 0.90
as an crystalline solid, Rf = 0.70; (EtOAc-hexane 1:4); mp = 90−92 °C; (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
28
[α]D = −44.1 (c = 0.18, MeOH); IR (neat): νmax/cm-1 2957, 2929, δ 199.0, 170.2, 160.3, 158.9, 150.9, 135.2, 129.2, 115.2, 110.2, 99.5,
2870, 1632, 1614, 1463, 1386, 1212, 1153, 1062, 988, 875, 787, ; 1H 88.6, 55.6, 53.1, 44.6, 38.1, 31.5, 26.4, 25.7, 25.3, 22.9, 22.7, 21.2,
NMR (500 MHz, CDCl3) δ 13.50 (s, 1H), 5.96 (s, 1H), 5.87 (dd, J = 1.9, 19.9, 19.6; HRMS: m/z calcd for C24H32O5Na [M+Na]+: 423.2147;
10.2 Hz, 1H), 5.60 (dd, J = 10.2, 2.3 Hz, 1H), 3.80 (s, 3H), 3.39 (t, J = found: 423.2147.
4.8 Hz, 1H), 2.84 (dd, J = 14.0, 6.6 Hz, 1H), 2.77 (dd, J = 14.0, 6.6 Hz, (1aS,2R,3aR,8aS,8bS)-7-isobutyryl-2-isopropyl-4-methoxy-8a-
1H), 2.27 (dt, J = 13.8, 5.0 Hz, 1H), 2.16 − 2.11 (m, 1H), 1.91−1.87 methyl-1a,2,3,3a,8a,8b-hexahydrobenzo[b]oxireno[2,3-
(m, 1H), 1.60 (m, 2H), 1.56 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.96 (d, J g]benzofuran-6-yl acetate (18): To a magnetically stirred solution of
= 6.9, Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C the compound 17 (220 mg, 0.56 mmol) in anhydrous 10ml CH2Cl2,
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was added m-CPBA (210 mg, 0.85 mmol) and the reaction mixture mixture was heated at 80 °C for 1 h until all the starting material
View Article Online
DOI: 10.1039/C9OB01426H
was stirred for 5 h. A saturated solution of Na2SO3 was added and was consumed (TLC). The reaction mixture was cooled and diluted
stirred for 15 min at 30 °C, extracted with CH2Cl2 and organic layer with water (10 mL) and extracted with Et2O (3 × 15 mL). The
was then washed with brine and dried over Na2SO4. Evaporation of combined organic layer were washed with brine (15 mL) and dried
the solvent and crude residue was purified by silica gel column with Na2SO4. Evaporation of the solvent and crude residue was
chromatography using EtOAc-hexane (1:11) as an eluent gave the purified by silica gel column chromatography using EtOAc-hexane
epoxide 18 (97 mg, 42%) as colourless oil; Rf = 0.4 (EtOAc-hexane (1:99) as an eluent furnished the product 22 (250 mg, 82% over 2
28
1:4); [α]D28 = +20.3 (c = 0.21, CHCl3); IR (neat): νmax/cm-1 3519 (br. s), steps) as a yellow foam, Rf = 0.55 (EtOAc−hexane 1:9); [α]D
=
2967, 2933, 2872, 1769, 1680, 1593, 1467, 1446, 1369, 1338, 1285, −30.0 (c = 0.13, CHCl3); IR (neat): νmax/cm-1 2966, 2873, 1624, 1594,
1197, 1137, 1012, 963, 818, 798; 1H NMR (400 MHz, CDCl3) δ 6.14 1475, 1412, 1386, 1369, 1248, 1135, 1105, 1064, 997, 846, 758; 1H
(s, 1H), 3.78 (s, 3H), 3.43 (td, J = 7.0, 11.0 Hz, 1H), 3.29 (t, J = 3.1 Hz, NMR (500 MHz, CDCl3) δ 14.08 (s, 1H), 3.94 (s, 3H), 3.83 - 3.78 (m,
1H), 3.14 (d, J = 4.3 Hz, 1H), 2.98 (d, J = 3.7 Hz, 1H), 2.27 (s, 3H), 2.21 1H), 3.48 (t, J = 3.3 Hz, 1H), 3.30 (d, J = 4.2 Hz, 1H), 3.00 (dd, J = 5.7,
(dd, J = 4.0, 10.0 Hz, 1H), 1.74 (dt, J = 4.9, 6.7 Hz, 1H), 1.63 (s, 3H), 12.4 Hz, 1H), 1.95 (ddd, J = 3.1, 5.5, 14.0 Hz, 1H), 1.88 − 1.84 (m,
1.48 (d, J = 4.9 Hz, 2H), 1.10 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 1H), 1.67 − 1.62 (m, 2H), 1.52 (s, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.17
3H), 0.97 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H); 13C NMR (100 (d, J = 6.9 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H); 13
C
MHz, CDCl3) δ 202.9, 170.0, 159.3, 158.7, 151.5, 113.3, 109.4, 99.9, NMR (125 MHz, CDCl3) δ 209.6, 161.8, 159.9, 159.6, 114.4, 103.8,
86.2, 55.7, 55.6, 55.0, 45.1, 40.3, 36.7, 30.9, 24.3, 21.1, 20.2, 20.0, 95.9, 87.7, 60.8, 55.9, 54.7, 40.4, 39.1, 29.8, 28.3, 26.1, 24.7, 21.8,
18.7, 18.4, 18.4; HRMS: m/z calcd for C23H31O6 [M+H]+: 403.2121; 21.3, 19.2, 18.5; HRMS: m/z calcd for C21H28BrO5 [M+H]+: 439.1120;
found: 403.2123.
found: 439.1128.
(−)-di-epi-Viminalin B (19): To a magnetically stirred solution of 1-((1aR,2R,3aR,8aS,8bR)-5-bromo-6-hydroxy-2-isopropyl-4-
acetate 18 (77 mg, 0.19 mmol) in THF (3 mL) was added a solution methoxy-8a-methyl-1a,2,3,3a,8a,8b-
of LiOH (9 mg, 0.38 mmol) in water (1.5 mL) and resulting reaction hexahydrobenzo[b]oxireno[2,3-g]benzofuran-7-yl)-3-methylbutan-
mixture stirred magnetically for 3 h at 30 °C. The reaction mixture 1-one (21): To a magnetically stirred solution of 16 (334 mg, 0.83
was extracted with ethyl acetate, washed with brine and dried over mmol) in acetone/H2O (10:1, 6 mL) was added 20 (477 mg, 1.67
Na2SO4. Evaporation of solvent and crude residue was purified by mmol) in small portions over 5 min. The entire setup was covered
silica gel column chromatography using EtOAc-hexane (1:19) as an with aluminium foil, placed in the dark and stirred for 4 h until all
eluent furnished the epi-Viminalin B 19 (60 mg, 88%) as a white the starting material was consumed indicated by TLC. The reaction
foam; Rf = 0.60 (EtOAc−hexane 1:4); [α]D28 = −20.8 (c = 0.21, MeOH); mixture was concentrated in vacuo, extracted with ethyl acetate (3
IR (neat): νmax/cm-1 2967, 2932, 2871, 1737, 1629, 1603, 1504, 1464, × 5 mL). The combined extracts were washed with brine (5 mL) and
1445, 1381,1369, 1262, 1205, 1179, 1094, 966, 897,776; 1H NMR dried over Na2SO4. Evaporation of the solvent and crude residue
(400 MHz, CDCl3) δ 13.58 (s, 1H), 5.99 (s, 1H), 3.79 (s, 3H), 3.74 − was purified by Column chromatography over silica gel using EtOAc-
3.67 (m, 1H), 3.26 (t, J = 3.5 Hz, 1H), 3.14 (d, J = 4.0 Hz, 1H), 3.00 (d, hexane (1:7) as an eluent furnished bromohydrin; Rf = 0.50
J = 4.0 Hz, 1H), 2.18 − 2.11 (m, 1H), 1.80 − 1.70 (m, 1H), 1.64 (s, 3H), (EtOAc−hexane 1:99). To a magnetically stirred solution of the
1.50 − 1.43 (m, 2H), 1.16 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H), bromohydrin (320 mg) in toluene (10 mL) was added powdered
0.95 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, KOH (620 mg) and the mixture was heated at 80 °C, for 1 h until all
CDCl3) δ 208.9, 166.8, 162.4, 160.7, 106.0, 101.2, 92.8, 86.3, 55.7, the starting material was consumed (TLC). The reaction mixture was
55.6, 55.0, 44.7, 38.6, 36.6, 30.9, 24.4, 20.2, 20.1, 19.2, 18.9, 18.8; cooled and diluted with water (10 mL) and extracted with Et2O (3 ×
HRMS: m/z calcd for C21H29O5 [M+H]+: 361.2015; found: 361.2016.
1-((1aR,2R,3aR,8aS,8bR)-5-bromo-6-hydroxy-2-isopropyl-4-
methoxy-8a-methyl-1a,2,3,3a,8a,8b-
15 mL). The combined organic layer were washed with brine (15
mL) and dried with Na2SO4. Evaporation of the solvent and crude
residue was purified by silica gel column chromatography using
EtOAc-hexane (1:99) as an eluent furnished the product 21 (310 mg,
hexahydrobenzo[b]oxireno[2,3-g]benzofuran-7-yl)-2-
methylpropan-1-one (22): To a magnetically stirred solution of 17 82% over 2 steps) as a white foam, Rf = 0.55 (EtOAc−hexane 1:9);
28
(267 mg, 0.69 mmol) in acetone/H2O (10:1, 6 mL) was added 1,3- [α]D = −42.0 (c = 0.17, CHCl3); IR (neat): νmax/cm-1 2960, 2872,
dibromo-5,5-dimethylhydantoin 20 (395 mg, 1.38 mmol) in small 1624, 1594, 1476, 1432, 1368, 1335, 1299, 1264, 1166, 1066, 978,
1
portions over 5 min. The entire setup was covered with aluminium 847, 742; H NMR (400 MHz, CDCl3) δ 14.04 (s, 1H), 3.93 (s, 3H),
foil, placed in the dark and stirred for 4 h until all the starting 3.47 (t, J = 4.0 Hz, 1H), 3.29 (d, J = 4.0 Hz, 1H), 2.99 (dd, J = 6.5, 14.0
material was consumed indicated by TLC. The reaction mixture was Hz, 1H), 2.90 (dd, J = 6.5, 14.0 Hz, 2H), 2.22 −2.16 (m, 1H), 1.95−1.89
concentrated in vacuo, extracted with ethyl acetate (3 × 5 mL). The (m, 1H), 1.85 (td, J = 3.4, 6.6 Hz, 1H), 1.70 − 1.62 (m, 2H), 1.51 (s,
combined extracts were washed with brine (5 mL) and dried over 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0
Na2SO4. Evaporation of the solvent and crude residue was purified Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.3,
by silica gel column chromatography using EtOAc-hexane (1:7) as an 161.4, 160.4, 159.6, 114.4, 104.7, 95.7, 87.8, 60.8, 55.8, 54.7, 52.1,
eluent furnished bromohydrin; Rf = 0.50 (EtOAc−hexane 1:5). To a 40.5, 39.1, 28.3, 26.2, 25.8, 24.7, 22.9, 22.7, 21.9, 21.4; HRMS: m/z
magnetically stirred solution of the bromohydrin (255 mg,) in calcd for C22H30BrO5 [M+H]+ : 453.1277; found: 453.1268.
toluene (10 mL) was added powdered KOH (500 mg) and the
6 | J. Name., 2012, 00, 1-3
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(−)-Viminalin B (2): Compound 22 (127 mg, 0.28 mmol) was taken eluent furnished the product 23 (1.3 g, 92%) as a pale yellow oil; Rf
View Article Online
28
DOI: 10.1039/C9OB01426H
in dry DMF (5 mL) and degassed for 15 min. To the degassed = 0.60 (EtOAc−hexane 1:4); [α]D = −13.7 (c = 0.58, CHCl3); IR
solution HCO2Na (24 mg, 0.36 mmol) and TBAB (187 mg, 0.57 (neat): νmax/cm-1 3360 (br.), 2956, 2931, 2870, 1622, 1584, 1492,
mmol) were added and stirred for 2 min. Then Et3N (0.09 mL, 0.63 1464, 1386, 1248, 1160, 1090, 977, 843, 628; 1H NMR(400 MHz,
mmol) and Pd(PPh3)4 (33 mg 0.02 mmol) were added and the CDCl3) δ 13.81 (s, 1H), 7.01 (s, 1H), 6.02 (s, 1H), 5.46 (br. s., 1H),
mixture was heated at 80 °C for 24 h. The mixture was cooled and 3.87 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 2.92 (dd, J = 1.4, 6.6 Hz, 2H),
solvent was evaporated. The residue obtained was washed with 2.23 (td, J = 6.6, 13.3 Hz, 1H), 2.20 − 2.14 (m, 1H), 2.13 - 2.08 (m,
diethyl ether (10 ml x 5) and combined ether extract was 1H), 1.80 (s, 3H), 1.77 (m, 1H), 1.59 −1.53 (m, 1H), 1.47 − 1.36 (m,
concentrated. Purification by silica gel column chromatography 2H), 0.96 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.9
using EtOAc-hexane (1:99) as an eluent furnished compound 2 (75 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.2,
mg, 72%) as a crystalline solid. Rf = 0.6 (EtOAc−hexane 1:9); mp = 165.1, 163.6, 158.6, 141.5, 124.5, 108.9, 106.3, 92.0, 55.6, 53.1,
28
133−135 °C; [α]D = −26.4 (c = 0.18, MeOH); IR (neat): νmax/cm-1 43.5, 34.7, 30.7, 28.0, 25.0, 23.8, 22.9 (2C), 22.2, 21.8, 16.2; HRMS:
2966, 2929, 2873, 1740, 1631, 1602, 1504, 1462, 1443, 1382, 1318, m/z calcd for C22H33O4 [M+H]+: 361.2379; found: 361.2373.
1258, 1150, 1065, 997, 844, 796; 1H NMR (400 MHz, CDCl3) δ 13.60 1-((1'R,2'R)-2,4-dihydroxy-2'-isopropyl-6-methoxy-5'-methyl-
(s, 1H), 5.97 (s, 1H), 3.81 (s, 3H), 3.80 (m, 1H), 3.45 (t, J = 4.0 Hz, 1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-yl)-2-methylpropan-1-one
1H), 3.28 (d, J = 4.0 Hz, 1H), 2.86 (dd, J = 5.8, 12.5 Hz, 1H), 1.95 (26): To a magnetically stirred solution of compound 12 (500 mg,
(ddd, J = 3.0, 5.5, 14.0 Hz, 1H), 1.84−1.75 (m, 1H), 1.64 (m, 1H), 1.58 2.38 mmol) and 13 (476 mg, 3.09 mmol) in anhydrous CH2Cl2 (10
(m, 1H), 1.47 (s, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H), mL) was added BF3·Et2O (0.010 mg, 0.07 mmol) at 30 °C. The
1.09 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, resulting reaction mixture was then stirred at 30 °C for 15 min. After
CDCl3) δ 209.1, 166.6, 162.0, 159.9, 108.7, 101.4, 92.5, 87.3, 55.9, completion of reaction, the reaction was quenched by saturated
55.7, 54.9, 39.5, 39.2, 38.6, 28.3, 26.1, 23.9, 21.9, 21.4, 19.5, 18.5; Na2CO3 solution (5 mL) and then extracted with CH2Cl2 (3 × 10 mL).
HRMS: m/z calcd for C21H29O5 [M+H]+: 361.2015; found: 361.2018.
(−)-Viminalin A (1): Compound 21 (50 mg, 0.11 mmol) was taken in column chromatography using EtOAc−hexane (1:49) as eluent
Evaporation of the solvent and residue was purified by silica gel
dry DMF (3 mL), HCO2Na (9 mg, 0.13 mmol) and TBAB (71 mg, 0.22 furnished the product 26 (750 mg, 91%) as a pale yellow oil; Rf
=
28
mmol) were added Et3N (0.03 mL, 0.24 mmol) and Pd(PPh3)4 (12 mg 0.60 (EtOAc−hexane 1:4); [α]D = −21.8 (c = 0.18, CHCl3); IR (neat):
0.01 mmol) and the mixture was heated at 80 °C for 24 h. The νmax/cm-1 3359 (br. s), 2959, 2933, 2871, 1621, 1584, 1514, 1464,
1
mixture was cooled and solvent was evaporated. The residue 1382, 1247, 1157,1034, 966, 877, 627; H NMR(400 MHz, CDCl3) δ
obtained was washed with diethyl ether (10 ml x 5) and combined 13.74 (s, 1H), 7.02 (s, 1H), 6.03 (s, 1H), 5.47 (br. s, 1H), 3.92 − 3.82
ether extract was concentrated. Purification by silica gel column (m, 2H), 3.77 (s, 3 H), 2.20 − 2.05 (m, 2H), 1.79 (s, 3H), 1.48 − 1.42
chromatography using EtOAc-hexane (1:99) as an eluent furnished (m, 1H), 1.36 (dd, J = 5.5, 11.6 Hz, 1H), 1.26 − 1.20 (m, 2H), 1.15 (d, J
compound 1 (29 mg, 70%) as a white crystalline solid. Rf = 0.6 = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.80 (d,
(EtOAc-hexane 1:9); mp = 130-132 °C; [α]D = −33.8 (c = 0.13, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 211.0, 165.4, 163.5,
28
MeOH); IR (neat): νmax/cm-1 2958, 2927, 2871, 1738, 1627, 1599, 158.3, 141.6, 124.4, 109.0, 105.2, 92.1, 55.6, 43.5, 39.4, 34.8, 30.7,
1504, 1462, 1417, 1388, 1369, 1275, 1153, 1097, 998, 887, 796; 1H 28.0, 23.9, 22.2, 21.8, 19.5, 19.2, 16.2; HRMS: m/z calcd for
NMR (400 MHz, CDCl3) δ 13.55 (s, 1H), 5.96 (s, 1H), 3.79 (s, 3H), C21H31O4 [M+H]+: 347.2222; found: 347.2224.
3.45 (t, J = 4.0 Hz, 1H), 3.28 (d, J = 4.0 Hz, 1H), 2.93 (dd, J = 6.5, 14.0 1-((5aR,9R,9aS)-3-hydroxy-9-isopropyl-1-methoxy-6-methylene-
Hz, 1H), 2.86 (dd, J = 5.5, 12.5 Hz, 1H), 2.83 (dd, J = 6.5, 14.0 Hz, 1H), 5a,6,7,8,9,9a hexahydrodibenzo[b,d]furan-4-yl)-3-methylbutan-1-
2.18 (m, 1H), 1.95 (ddd, J = 2.7, 5.5, 13.7 Hz, 1H), 1.83 − 1.77 (m, one(24): To a magnetically stirred solution of compound 23 (50 mg,
1H), 1.63 - 1.56 (m, 2H), 1.47 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H), 1.05 (d, 0.13 mmol) in acetonitrile (5 mL) was added Pd(OAc)2 (3 mg, 0.013
J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H); 13C mmol) and MnO (36 mg, 0.41 mmol) at 30 °C. The resulting reaction
NMR (100 MHz, CDCl3) δ 204.8, 166.3, 162.1, 160.3, 108.7, 102.4, mixture was then stirred at 30 °C for 30 min. After completion of
92.4, 87.4, 55.9, 55.7, 55.0, 51.7, 39.6, 39.2, 28.3, 26.2, 26.1, 23.9, reaction indicated by TLC, reaction mixture was passed through
23.0, 22.8, 21.9, 21.4; HRMS: m/z calcd for C22H31O5 [M+H]+: celite, evaporation of the solvent and residue was purified by silica
375.2171; found: 375.2178.
1-((1'R,2'R)-2,4-dihydroxy-2'-isopropyl-6-methoxy-5'-methyl-
1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-yl)-3-methylbutan-1-one
(23): To a magnetically stirred solution of compound 11 (900 mg, νmax/cm-1 3077, 2956, 2935, 2869, 1736, 1627, 1601, 1501, 1442,
4.031 mmol) and 13 (804 mg, 5.22 mmol) in anhydrous CH2Cl2 (10 1413, 1386, 1295, 1164, 1078, 995, 874, 774; H NMR (500 MHz,
gel column chromatography using EtOAc−hexane (1:49) as an
eluent furnished compound 24 (30 mg, 61%) as a colourless oil, Rf =
0.70 (EtOAc−hexane 1:4); [α]D = −14.0 (c = 0.10, CHCl3); IR (neat):
28
1
mL) was added BF3·Et2O (0.017 mg, 0.12 mmol) at 30 °C. The CDCl3) δ 13.48 (s, 1H), 6.01 (s, 1H), 5.14 (d, J = 12.8 Hz, 2H), 4.84 (d,
resulting reaction mixture was then stirred at 30 °C for 15 min. After J = 6.1 Hz, 1H), 3.80 (s, 3H), 3.10 (dd, J = 6.4, 8.9 Hz, 1H), 2.85 (dd, J
completion of reaction indicated by TLC, the reaction was quenched = 6.7, 14.0 Hz, 1H), 2.79 (t, J = 6.7 Hz, 1H), 2.46 − 2.41 (m, 1H), 2.34
by saturated Na2CO3 solution (5 mL) and then extracted with CH2Cl2 − 2.28 (m, 1H), 2.15 − 2.07 (m, 1H), 1.81 (dt, J = 4.9, 6.7 Hz, 1H),
(3 × 10 mL). Evaporation of the solvent and residue was purified by 1.69 − 1.64 (m, 1H), 1.24 (m, 2H), 0.95 (d, J = 7.0 Hz, 3H), 0.94 (d, J =
silica gel column chromatography using EtOAc−hexane (1:49) as an 7.0 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H); 13C NMR
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Journal Name
(125 MHz, CDCl3) δ 204.9, 165.9, 162.3, 161.6, 143.6, 116.5, 112.1, 39.6, 38.8, 35.4, 28.2, 27.2, 21.8, 18.9, 17.3, 15.5; HRVMieSw:Amrtic/lze Ocanllicnde
+
DOI: 10.1039/C9OB01426H
102.7, 92.5, 89.7, 55.5, 51.7, 46.0, 43.1, 29.8, 27.5, 26.3, 22.8, 22.7, for C21H31O5 [M+H] : 363.2171; found: 363.2176.
22.5, 21.8, 16.7; HRMS: m/z calcd for C22H31O4 [M+H]+: 359.2222; (−)-Viminalin M (6): To a magnetically stirred solution of compound
found: 359.2225.
25 (28 mg, 0.078 mmol) in toluene (3 mL) was added p-
1-((5aR,6R,9R,9aS)-3,6-dihydroxy-9-isopropyl-1-methoxy-6-
toluenesulfonic acid monohydrate (29 mg, 0.15 mmol). Then
methyl-5a,6,7,8,9,9a
hexahydrodibenzo[b,d]furan-4-yl)-3- reaction was heated under reflux for 36 h. After completion of
methylbutan-1-one (25): To a magnetically stirred solution of reaction indicated by TLC, the reaction was quenched by saturated
compound 23 (574 mg, 1.59 mmol) in acetone (10 mL) was added Na2CO3 solution then extracted with ethyl acetate (2 × 10 mL).
Na2CO3 (562 mg, 6.69 mmol). The reaction mixture was then cooled Evaporation of the solvent and residue was purified by silica gel
to 0 °C and stirred for 10 min. Then, a solution of oxone (3.0 g, 4.94 column chromatography using EtOAc− hexane (1:49) as an eluent
mmol) (prepared by dissolving oxone in 12 mL water) was added furnished the product 6 (13 mg, 50%) as a yellow foam; Rf = 0.70
28
drop wise. The reaction continued at the same temperature for an (EtOAc−hexane 1:4); [α]D = −43.5 (c = 0.13, MeOH); IR (neat):
additional 30 min and then was slowly allowed to come to 30 °C. νmax/cm-1 2925, 2956, 2853, 1622, 1584, 1492, 1464, 1386, 1248,
After completion of reaction, indicated by TLC, the reaction mixture 1160, 1090, 977, 815; 1H NMR (500 MHz, CDCl3) δ 13.52 (s, 1H),
was concentrated under reduced pressure and then extracted with 6.01 (s, 1H), 5.87 (d, J = 6.2 Hz, 1H), 4.76 (d, J = 7.0 Hz, 1 H), 3.80 (s,
ethyl acetate (2 × 30 mL). Evaporation of the solvent and residue 3H), 3.09 (dd, J = 7.0, 11.0 Hz, 1H), 2.93 (dd, J = 7.0, 15.0 Hz, 1H),
was purified by silica gel column chromatography using EtOAc− 2.82 (dd, J = 7.0, 15.0 Hz, 1H), 2.23 − 2.17 (m, 1H), 2.03 (dt, J = 16.9,
hexane (1:11) as an eluent furnished the product 25 (300 mg, 50%) 4.0 Hz, 1H), 1.92 (s, 3H), 1.82 − 1.76 (m, 2H), 1.45 (tt, J = 4.0, 11.0
28
as a yellow foam; Rf = 0.55 (EtOAc−hexane 1:4); [α]D = −30.1 (c = Hz, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.90 (d, J =
0.16, CHCl3); IR (neat): νmax/cm-1 3453 (br.), 2957, 2870, 1629, 1596, 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
1502, 1464, 1443, 1386, 1368, 1299, 1270, 1123, 1082, 997, 885, 204.7, 166.0, 162.5, 162.3, 129.7, 128.7, 110.0, 102.8, 92.3, 86.7,
1
702; H NMR (400 MHz, CDCl3) δ 13.42 (s, 1H), 6.02 (s, 1H), 4.13 55.3, 51.7, 42.2, 41.2, 27.1, 25.5, 23.4, 22.9, 22.8, 22.0, 20.7, 16.3;
(dd, J = 1.2, 5.5 Hz, 1H), 3.80 (s, 3H), 3.09 (dd, J = 5.5, 11.0 Hz, 1H), HRMS: m/z calcd for C22H31O4 [M+H]+: 359.2222; found: 359.2227.
2.85 (d, J = 6.7 Hz, 2H), 2.17 (td, J = 6.7, 13.4 Hz, 1H), 1.87 − 1.76 (m, (−)-Viminalin N (7): To a magnetically stirred solution of compound
2H), 1.70 - 1.65 (m, 1H), 1.49 (br. s, 1H), 1.47 (s, 3H), 1.41 (dt, J = 27 (50 mg, 0.13 mmol) in toluene (5 mL) was added p-
3.4, 9.9 Hz, 2H), 1.09 −1.04 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.95 (d, J toluenesulfonic acid monohydrate (47 mg, 0.27 mmol). Then
= 6.9 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H); 13C reaction was heated under reflux for 36 h. After completion of
NMR (100 MHz, CDCl3) δ 204.5, 165.6, 161.8, 161.7, 113.2, 103.0, reaction indicated by TLC, the reaction mixture was extracted with
92.9, 92.3, 69.4, 55.5, 51.6, 46.7, 39.6, 35.4, 28.4, 27.2, 25.7, 22.8, ethyl acetate (2 × 10 mL). Evaporation of the solvent and residue
22.8, 21.8, 17.3, 15.5; HRMS: m/z calcd for C22H33O5 [M+H]+: was purified by silica gel column chromatography using EtOAc−
377.2328; found: 377.2325.
1-((5aR,6R,9R,9aS)-3,6-dihydroxy-9-isopropyl-1-methoxy-6-
methyl-5a,6,7,8,9,9a
hexane (1:49) as eluent furnished the product 7 (24 mg, 51%) as a
28
yellow solid; Rf = 0.70 (EtOAc−hexane 1:4); mp = 90-92 °C; [α]D
=
hexahydrodibenzo[b,d]furan-4-yl)-2- −46.1 (c = 0.027, MeOH); IR (neat): νmax/cm-1 2959, 2928, 2870,
methylpropan-1-one (27): To a magnetically stirred solution of 2855, 1626, 1602, 1505, 1464, 1455, 1367, 1352, 1269, 1248, 1166,
compound 26 (750 g, 2.16 mmol) in acetone (15 mL) was added 1081, 966, 886, 777; 1H NMR (400 MHz, CDCl3) δ 13.54 (s, 1 H), 6.01
Na2CO3 (964 mg, 9.10 mmol). The reaction mixture was then cooled (s, 1H), 5.86 (d, J = 5.5 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 3.80 (s, 3H),
to 0 °C and stirred for 10 min. Then, a solution of oxone (4.09 g, 3.71 (m, 1H), 3.09 (dd, J = 7.3, 11.0 Hz, 1H), 2.02 (td, J = 4.4, 17.4 Hz,
6.71 mmol) was added drop wise. After completion of reaction, the 1H), 1.89 (s, 3H), 1.82 − 1.73 (m, 2H), 1.45 (m, 1H), 1.17 (d, J = 7.0
reaction mixture was concentrated under reduced pressure and Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.86 (d, J =
then extracted with ethyl acetate (2 × 30 mL). Evaporation of the 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.0, 166.3, 162.4, 161.9,
solvent and residue was purified by silica gel column 129.8, 128.5, 110.1, 101.8, 92.4, 86.7, 55.4, 42.2, 41.1, 38.7, 27.0,
chromatography using EtOAc− hexane (1:11) as an eluent furnished 23.4, 22.0, 20.6, 19.1, 18.8, 16.2; HRMS: m/z calcd for C21H29O4
the product 27 (380 mg, 48%) as a yellow foam; Rf = 0.55 [M+H]+: 345.2066; found: 345.2061.
28
(EtOAc−hexane 1:4); [α]D = −3.4 (c = 0.58, CHCl3); IR (neat):
νmax/cm-1 3459 (br.), 2959, 2936, 2871, 1629, 1602, 1505, 1464,
1443, 1384, 1368, 1269, 1247, 1174, 1127, 1099, 978, 888, 777; H
NMR (400 MHz, CDCl3) δ 13.43 (s, 1H), 6.03 (s, 1H), 4.12 (d, J = 5.5
Conflicts of interest
There are no conflicts to declare
1
Hz, 1H), 3.79 (s, 3H), 3.65 (quin, J = 6.7 Hz, 1H), 3.09 (dd, J = 5.5,
11.0 Hz, 1H), 1.82 (dd, J = 2.7, 7.0 Hz, 1H), 1.76 (d, J = 1.8 Hz, 1H),
1.69 − 1.58 (m, 2H), 1.45 (s, 3H), 1.42 (s, 1H), 1.40 (d, J = 3.7 Hz, 2H),
1.16 (d, J = 6.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 7.0 Hz,
3H), 0.82 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.7,
165.9, 161.7, 161.3, 113.2, 101.9, 93.0, 92.2, 69.4, 55.5, 46.8, 46.8,
Acknowledgements
We thank Dr. Rohan D. Erande, Dr. Balu D. Dherange and Dr.
Samarpita Mahapatra for their kind help in improving the
manuscript A.K.N. thanks IIT Kanpur for the award of research
fellowship is gratefully acknowledged.
References:
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Graphical Abstract