Chemoenzymatic collective synthesis of optically active hydroxyl(methyl)tetrahydronaphthalene-based bioactive terpenoids

Article abstract of DOI:10.1039/c5ob01740h

Starting from succinic anhydride and 2-methylanisole, a chemoenzymatic collective formal/total synthesis of several optically active tetrahydronaphthalene based bioactive natural products has been presented via advanced level common precursors; the natural product and antipode (-)/(+)-aristelegone B. Regioselective benzylic oxidations, stereoselective introduction of hydroxyl groups at the α-position of ketone moiety in syn-orientation, efficient enzymatic resolutions with high enantiomeric purity, stereoselective reductions, samarium iodide induced deoxygenations and tandem acylation-Wittig reactions without racemization and/or eliminative aromatization were the key features. An attempted diastereoselective synthesis of (±)-vallapin has also been described.

Full text of DOI:10.1039/c5ob01740h

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Chemoenzymatic collective synthesis of optically
active hydroxyl(methyl)tetrahydronaphthalene-
based bioactive terpenoids†
Cite this: DOI: 10.1039/c5ob01740h
Ramesh U. Batwal and Narshinha P. Argade*
Starting from succinic anhydride and 2-methylanisole, a chemoenzymatic collective formal/total syn-
thesis of several optically active tetrahydronaphthalene based bioactive natural products has been pre-
sented via advanced level common precursors; the natural product and antipode (−)/(+)-aristelegone
B. Regioselective benzylic oxidations, stereoselective introduction of hydroxyl groups at the α-position of
ketone moiety in syn-orientation, efficient enzymatic resolutions with high enantiomeric purity, stereo-
selective reductions, samarium iodide induced deoxygenations and tandem acylation-Wittig reactions
without racemization and/or eliminative aromatization were the key features. An attempted diastereo-
selective synthesis of ( )-vallapin has also been described.
Received 19th August 2015,
Accepted 15th September 2015
DOI: 10.1039/c5ob01740h
www.rsc.org/obc
Introduction
A large number of hydroxyl(methyl)tetrahydronaphthalene and
methoxy(methyl)tetrahydronaphthalene classes of natural pro-
ducts with a broad range of biological activities are known
(Fig. 1).1 Nature designs them starting from either farnesyl
pyrophosphate or geranyl pyrophosphate via intramolecular
cyclizations involving 1,2- and 1,3-hydride shifts followed by a
regioselective oxidation pathway.2 A postulated biogenetic
transformation of farnesyl pyrophosphate to the potential pre-
cursor 7-hydroxycalamene with an appropriate fixing of posi-
tions of both methyl and hydroxyl/methoxy groups has been
depicted in Scheme 1. In a biogenetic process the fifteen
carbon, bearing crucial intermediate 7-hydroxycalamene,
further undergoes several requisite functional group trans-
formations in a stereoselective fashion with or without the loss
of the isopropyl group, thus delivering a variety of enantio-
merically pure bioactive natural products bearing twelve/
fifteen carbon skeletons (Scheme 1). The (+)-aristelegone A,
(−)-aristelegone B and (−)-aristelegone D have been isolated
from Aristolochia elegans; while (+)-methylaristelegone
A (antispasmodic) has been isolated from Aristolochia con-
stricta.3 The (+)-heritonin (toxic to fish), (+)-heritol (toxic to
fish) and (−)-vallapin (pesticide) have been isolated from
Heritiera littoralis and (+)-mutisianthol (antitumor) has been
isolated from Mutisia homoeantha.1e,4 The (−)-7-methoxy-1,2-
Fig. 1 Hydroxyl/methoxy(methyl)tetrahydronaphthalene based bio-
active natural products.
dihydrocadalene and (−)-7-methoxycalamenene have been iso-
lated from a Heteroscyphus planus culture.5 Several elegant
product specific racemic as well as enantioselective total syn-
theses of the above specified natural products have been
reported;6–10 except for the aristelegone D, 7-methoxy-1,2-di-
hydrocadalene and vallapin. The science of the collective total
synthesis of bioactive natural products is very important for
the structure activity relationship studies from the lead optim-
ization and drug discovery point of view.11 The substituted
methoxy(methyl)tetrahydronaphthalene based compounds
have a very high propensity towards instantaneous oxidation,
elimination and enolization processes due to the facile stabi-
lity driven aromatizations and hence the synthesis of such type
of target compounds is a challenging task.12 A concise retro-
synthetic analysis of natural products portrayed in Scheme 1
revealed that the 7-methoxy-6-methyltetralone would be a
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008,
India. E-mail: np.argade@ncl.res.in
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
and HPLC data. See DOI: 10.1039/c5ob01740h
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 1 Postulated brief biogenesis and proposed retrosynthetic precursors of the selected bioactive terpenoids.
potential precursor to accomplish both racemic and chemo-
enzymatic collective total synthesis of all selected target com-
pounds. In continuation with our studies on both cyclic
anhydrides and derivatives to bioactive natural products13 and
efficient enzymatic resolutions,14 we herein report the collec-
tive formal/total synthesis of nine optically active natural pro-
ducts (Schemes 1–4) and an attempted diastereoselective
synthesis of ( )-vallapin via an alternatively designed β-hydro-
xytetralone intermediate (Scheme 5).
Results and discussion
The 2-methylanisole (1) in a Friedel–Crafts acylation with suc-
cinic anhydride (2) followed by Clemmensen reduction and
acid-promoted intramolecular cyclization provided the desired
tetralone 3 in a 62% yield over 3-steps (Scheme 2).9a Tetralone
3 in a Wittig reaction exclusively formed the exo-methylene
product 4 in a 74% yield which in a catalytic hydrogenation
over palladium on charcoal delivered the reduced product ( )-5
in quantitative yield. KMnO4/FeCl3 promoted regioselective
benzylic oxidation of ( )-tetrahydronaphthalene 5 furnished
Scheme 3 Collective synthesis of optically pure terpenoids from
(−)-aristelegone B (7).
the ( )-methylaristelegone A (6) in a 73% yield. Hypervalent a desired major product (74%, dr = 6 : 1, by 1H NMR). As
iodine reagents are known to afford α-ketols with the represented in Table 1, we systematically studied the lipase
α-hydroxyl group attached to the more sterically hindered face Amano PS catalyzed stereoselective acylation of ( )-aristelegone
of an enolate and mechanistically it takes place via the B (7) using vinyl acetate (VA) as an acyl donor, and obtained
inversion of configuration.7 Accordingly, the base induced the optically active natural product (−)-aristelegone B (7) in a
stereoselective α-hydroxylation of ( )-tetralone 6 with (bis(tri- 54% yield (94% ee, by HPLC) and (+)-acylaristelegone B (8) in a
fluoroacetoxy)iodo)benzene resulted in ( )-aristelegone B (7) as 46% yield (96% ee, by HPLC). The obtained stereochemical
Scheme 2 Diastereoselective synthesis of the common precursor ( )-aristelegone B (7) and its efficient enzymatic resolution.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
The free hydroxyl group in (−)-aristelegone B (7) was
initially protected as –OTBS to avoid its direct interaction with
aluminium from DIBAL-H and also to increase the steric bulk
of β-face to favor a hydride attack from an anticipated less hin-
dered α-face (Scheme 3). TBS-protected (−)-hydroxytetralone
9 on DIBAL-H reduction directly delivered the natural product
(−)-aristelegone D (10) in an 84% yield. TLC results of the
above reaction clearly indicate that O-desilylation takes place
during the workup procedures. The analytical and spectral
data obtained for the synthetic product was in complete agree-
ment with the reported data for the natural product3a and the
chemoenzymatic first synthesis of (−)-aristelegone D (10) was
accomplished in ten steps with an 8% overall yield.
(−)-Aristelegone B (7) underwent a smooth tandem acylation-
Wittig reaction under the recently reported Matsuo and
Shindo conditions8b and furnished an aimed product
(−)-heritonin (11) in a 74% yield (93% ee, by HPLC) via intra-
molecular cyclization. The above mentioned tandem acylation-
Wittig reaction was moisture sensitive. Therefore freshly dried
reagents were used under perfectly anhydrous reaction con-
ditions to obtain the desired product in a very good yield. It is
noteworthy that the starting material, α-hydroxyketone, in situ
formed a corresponding α-acylated-ketone intermediate and
the obtained product γ-lactone all three bear a sufficiently
acidic methine proton; however the reaction was very clean
and delivered the final product (−)-heritonin (11) without any
racemization. The obtained analytical and spectral data for
(−)-heritonin (11) was in complete agreement with reported
data8b,c and it was synthesized in nine steps with an 8% overall
yield. AlCl3 induced transformation of (−)-heritonin (11) to
(−)-heritol (12) with an 80% yield is known.8c The α-hydroxyl
group was diastereoselectively introduced on ( )-methyl-
aristelegone A (6) to use it as a handle for efficient enzymatic
Scheme 4 Synthesis of (−)-7-methoxy-1,2-dihydrocadalene (15), (−)-7-
methoxycalamenene (16) and (+)-heritonin (11).
outcome was further confirmed by comparison with the
reported analytical and spectral data for the natural product
(−)-7.3a Typically, syntheses of a natural product starting from
a natural product belonging to same genesis are more concise,
efficient and involve the minimum protection–deprotection
steps. The twelve carbon skeleton of naturally occurring ariste-
legone B bears well placed substituents and essential func-
tional groups; hence it was planned to use ( )/(+)/(−)-7/8 as
pivotal building blocks to accomplish the racemic/chiral pool
based/stereoselective collective synthesis of target compounds
from Scheme 1.
Scheme 5 Attempted diastereoselective synthesis of vallapin (27).
Table 1 Lipase Amano PS catalyzed resolution of ( )-aristelegone B (7)
Entry
Solvent
Temp. (time)a
(−)-7: % yield (ee)b
(+)-8: % yield (ee)b
E
1
2
3
4
5
Benzene
Benzene–PE (1 : 1)
Acetone
Acetone
Acetone
25 °C (48 h)
25 °C (48 h)
25 °C (24 h)
25 °C (36 h)
25 °C (48 h)
42 (77)
51 (67)
67 (65)
54 (94)
49 (97)
48 (68)
49 (50)
33 (96)
46 (96)
51 (91)
12.0
5.8
96.7
175.8
89.0
a Reactions were monitored by HPLC. b Chiral HPLC.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
resolution and also as an appropriate functional group. and obtained the optically active products (+)-18 in a 44% yield
Samarium iodide caused post-resolution detachment of the (92% ee, by HPLC) and (+)-19 in a 56% yield (89% ee, by
hydroxyl group in (−)-aristelegone B (7) via the corresponding HPLC). Tentative stereochemical assignment of (+)-18 and
acetate formed (+)-methylaristelegone A (6) in a 65% yield. (+)-19 was done on the basis of known Amano PS selectivity.14
(+)-Methylaristelegone A (6) on treatment with BBr3 provided Anticipating the high propensity of such type of substituted
(+)-aristelegone A (13) in a 74% yield. Starting from (+)-methyl- tetralone systems to aromatize and also from starting material
aristelegone A (6), a three-step synthesis of (−)-heritonin (11) availability point of view; it was essential to first standardize
via the Reformatsky reaction and the five-step synthesis of all reaction conditions and complete the diastereoselective
(+)-mutisianthol (14) via thallium(III) trinitrate catalyzed ring synthesis of our target compound. Hydrolysis of acetate ( )-18
contraction pathways are well known.8c,9a
to the corresponding alcohol ( )-19 followed by TBDPS-protec-
At this stage it was also decided to use the second enantio- tion provided silyl ether ( )-20 in a 78% yield over two steps.
merically pure building block (+)-8 obtained in enzymatic Diastereoselective reduction of the exocyclic carbon–carbon
resolution for the synthesis of natural products. The samarium double bond in compound ( )-20 delivered the syn-disubsti-
iodide influenced detachment of the acetoxy group in com- tuted tetrahydronaphthalene ( )-21 in ∼100% isolated yield
pound (+)-8 furnished (−)-methylaristelegone A (6) in an 84% (dr = 9 : 1, by 1H NMR). The bulk of the –OTBDPS group in
yield (Scheme 4). The reaction of isopropylmagnesium ( )-20 directs π-lobes adsorption on the palladium catalyst
bromide with (−)-methylaristelegone A (6) followed by acid from the opposite face to form the desired cis-isomer as a
catalyzed in situ dehydration of the formed intermediate ter- major product. Regioselective CrO3 oxidation of the benzylic
tiary alcohol yielded another natural product, (−)-7-methoxy- methylene group in tetrahydronaphthalene ( )-21 furnished
1,2-dihydrocadalene (15), in a 92% yield. The analytical and the expected tetralone ( )-22 in a 66% yield. Fortunately
spectral data obtained for the synthetic product was in com- during the course of CrO3 oxidation in acetic acid we did
plete agreement with the reported data for the natural not notice any desilylation and concomitant aromatization.
product5 and the chemoenzymatic first synthesis of The studied Wittig reaction of tetralone ( )-22 to obtain
(−)-7-methoxy-1,2-dihydrocadalene (15) was accomplished in product ( )-24 and Reformatsky reaction of tetralone ( )-22 to
ten steps with an 8% overall yield. An enantioselective obtain ( )-25 were unfortunately not successful (Fig. 2). An
reduction of the actually isolated natural product (−)-15 to attempted Reformatsky reaction on ( )-22, instead formed the
form yet another natural product (−)-7-methoxycalamenene corresponding aromatized product 23 in a 68% yield. An
(16) is known.5 Base-induced de-acylation of compound (+)-8 attempted desilylation of ( )-22 also resulted in the formation
to form (+)-aristelegone B (7) followed by its similarly per- of the same aromatized product 23 with a 63% yield plausibly
formed tandem acylation-Wittig reaction provided the natural via the corresponding unstable β-hydroxyketone intermediate.
product (+)-heritonin (11) in a 71% yield.
Selective introduction of the oxygen function on tetralone
In the next part of the study, the chemoenzymatic total ( )-22 by using KMnO4/CH3CH2COOH in refluxing benzene
synthesis of (−)-vallapin (27) was initially planned again from offered the expected product ( )-26 but in a less than 10%
the same common precursor tetralone 3. Tetralone 3, on treat- yield. The well functionalized product ( )-26 was very unstable
ment with KMnO4/AcOH15 in refluxing benzene, furnished the and hence we could cautiously characterize an isolated crude
1
required α-acetoxyketone ( )-17 in a 70% yield (Scheme 5). The product only by using H NMR and HRMS data. We feel that
ketone ( )-17 on the Wittig reaction exclusively formed yet much milder reaction conditions will be required to transform
another exo-methylene product ( )-18 in a 67% yield. As rep- tetralone ( )-22 or other similar type of intermediates to
resented in Table 2, we also systematically studied the lipase the desired target compound ( )-vallapin and it remains as a
Amano PS catalyzed stereoselective hydrolysis of acetate ( )-18 synthetic challenge.
Table 2 Lipase Amano PS catalyzed resolution of ( )-acetate 18
Temp.
(time)a
(+)-18:
(+)-19:
Entry
% yield (ee)b
% yield (ee)b
E
1
2
3
4
35 °C (96 h)
40 °C (72 h)
45 °C (24 h)
45 °C (48 h)
55 (79)
55 (80)
54 (88)
44 (92)
45 (95)
45 (100)
46 (100)
56 (89)
94.6
497.0
590.3
56.2
Fig. 2 Expected products from tetralone ( )-22 for the synthesis of val-
lapin (27).
a Reactions were monitored by HPLC. b Chiral HPLC.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
diluted with ethyl acetate (100 mL) and the organic layer was
washed with water, brine and dried over Na2SO4. The concen-
Conclusions
In summary, we have described the facile chemoenzymatic col- tration of the organic layer in vacuo followed by silica gel
lective total synthesis of several tetrahydronaphthalene based (60–120 mesh) column chromatographic purification of the
optically active terpenoids. The late stage efficient enzymatic resulting residue using ethyl acetate–petroleum ether (1 : 19)
resolution provides access to both (+)/(−)-isomers as potential as an eluent afforded product 4 as a viscous oil (1.83 g, 74%).
1
building blocks. Remarkably, stereoselective reactions were IR (CHCl3) νmax 1612 cm−1; H NMR (CDCl3, 200 MHz) δ 1.79
performed to accomplish the synthesis of several natural pro- (quintet, J = 6 Hz, 2H), 2.12 (s, 3H), 2.40–2.50 (m, 2H), 2.68 (t,
ducts from one single common precursor, aristelegone J = 6 Hz, 2H), 3.77 (s, 3H), 4.85 (s, 1H), 5.35 (s, 1H), 6.81 (s,
B. Multistep total synthesis of both (+)- and (−)-heritonin have 1H), 7.00 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ 15.9, 24.1, 29.5,
been accomplished and all synthetic pathways described 33.3, 55.3, 105.0, 106.6, 126.9, 129.3, 131.2, 132.8, 143.8, 156.0;
herein will also synthesise their respective antipodes. Unfortu- ESIMS (m/z) 189 [M + H]+; HRMS (ESI) calcd for C13H17O
nately all our attempts to complete first total synthesis of 189.1274, found 189.1272.
( )-vallapin met with failure due to the inherent instability of
the advanced β-hydroxytetralone intermediate.
( )-7-Methoxy-1,6-dimethyl-1,2,3,4-tetrahydronaphthalene
(5). To a stirred solution of compound 4 (1.50 g, 7.97 mmol)
in ethyl acetate (25 mL), 10% Pd/C (50 mg) at 25 °C was added
and the reaction mixture was subjected to hydrogenation
under balloon pressure for 4 h. The reaction mixture was fil-
tered through a Celite bed and washed with ethyl acetate. The
concentration of the filtrate in vacuo furnished the pure
Experimental section
General information
The melting points are uncorrected. The IR spectra were product ( )-5 as a viscous oil (1.51 g, ∼100%). IR (CHCl3)
1
1
recorded on an FT-IR spectrometer. The H NMR spectra were νmax 1615 cm−1; H NMR (CDCl3, 200 MHz) δ 1.31 (d, J = 8 Hz,
recorded on 200 MHz NMR, 400 MHz NMR, 500 MHz NMR 3H), 1.40–2.00 (m, 4H), 2.18 (s, 3H), 2.68 (t, J = 6 Hz, 2H), 2.90
and 700 MHz NMR spectrometers using TMS as an internal (sextet, J = 6 Hz, 1H), 3.83 (s, 3H), 6.68 (s, 1H), 6.85 (s, 1H);
standard. The 13C NMR spectra were recorded on 200 NMR 13C NMR (CDCl3, 100 MHz) δ 15.7, 20.6, 23.0, 29.0, 31.6, 32.6,
(50 MHz), 400 NMR (100 MHz), 500 NMR (125 MHz) and 55.4, 109.6, 124.0, 128.3, 131.1, 140.3, 155.8; ESIMS (m/z) 213
700 MHz NMR (175 MHz) spectrometers. Mass spectra were [M + Na]+.
taken on an MS-TOF mass spectrometer. HRMS (ESI) were
( )-Methoxy-4,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one
taken on Orbitrap (quadrupole plus ion trap) and a TOF mass (6). To a stirred solution of ( )-5 (1.50 g, 7.88 mmol) in
analyzer. Column chromatographic separations were carried acetone (30 mL), KMnO4 (12.46 g, 78.80 mmol) and FeCl3
out on silica gel (60–120 mesh and 230–400 mesh). Commer- (3.20 g, 19.70 mmol) were added and the reaction mixture was
cially available 2-methylanisole, methyltriphenylphosphonium stirred at −78 °C under an argon atmosphere for 1 h. The reac-
iodide, PhI(OCOCF3)2, vinyl acetate, TBSCl, DIBAL-H, mole- tion mixture was allowed to warm gradually to 25 °C and
cular sieves 4 Å, OXONE®, samarium diiodide solution (0.10 further stirred for 10 h. The resulting suspension was diluted
M in THF), boron tribromide solution (1 M in DCM), acetic with dichloromethane (30 mL), filtered and the residue was
anhydride, TBDPSCl, ethyl 2-bromopropionate, tetrabutyl- washed with dichloromethane (10 mL × 2). The concentration
ammonium fluoride solution and Zn metal were used. Amano of the organic layer in vacuo followed by silica gel
PS enzymes form Amano Enzyme Japan and Sigma-Aldrich (60–120 mesh) column chromatographic purification of the
were used.
7-Methoxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one (3). an eluent afforded product ( )-6 as a white solid (1.17 g, 73%).
Mp 54–55 °C; IR (CHCl3) νmax 1668, 1610 cm−1 1H NMR Mp 108–109 °C; IR (CHCl3) νmax 1667, 1599 cm−1 1H NMR
resulting residue using ethyl acetate–petroleum ether (1 : 9) as
;
;
(CDCl3, 200 MHz) δ 2.10 (quintet, J = 6 Hz, 2H), 2.25 (s, 3H), (CDCl3, 200 MHz) δ 1.40 (d, J = 6 Hz, 3H), 1.75–2.00 (m, 1H),
2.60 (d, J = 8 Hz, 1H), 2.64 (d, J = 6 Hz, 1H), 2.86 (t, J = 6 Hz, 2.10–2.35 (m, 1H), 2.20 (s, 3H), 2.40–2.85 (m, 2H), 2.95–3.15
2H), 3.86 (s, 3H), 7.02 (s, 1H), 7.44 (s, 1H); 13C NMR (CDCl3, (m, 1H), 3.90 (s, 3H), 6.68 (s, 1H), 7.83 (s, 1H); 13C NMR
50 MHz) δ 16.4, 23.5, 28.7, 38.7, 55.3, 106.6, 130.7, 131.2, (CDCl3, 50 MHz) δ 15.7, 20.8, 30.7, 33.0, 35.8, 55.4, 107.6,
133.6, 136.9, 156.5, 198.1; ESIMS (m/z) 191 [M + H]+.
124.8, 125.4, 129.6, 149.4, 162.2, 197.4; ESIMS (m/z) 205
7-Methoxy-6-methyl-1-methylene-1,2,3,4-tetrahydronaphtha- [M + H]+; HRMS (ESI) calcd for C13H17O2 205.1223, found
lene (4). To a stirred solution of methyltriphenylphosphonium 205.1224.
iodide (8.01 g, 19.72 mmol) in anhydrous THF (35 mL), a solu-
( )-2-Hydroxy-6-methoxy-4,7-dimethyl-3,4-dihydronaphtha-
tion of n-BuLi (12.33 mL, 19.72 mmol, 1.60 M in hexane) was len-1(2H)-one (aristelegone B, 7). A solution of the ketone
added in dropwise fashion at 0 °C under an argon atmosphere ( )-6 (1.10 g, 5.39 mmol) and KOH (3.02 g, 53.90 mmol) in
and the reaction mixture was stirred for 30 min. A solution of MeOH (25 mL) was stirred at 0 °C under an argon atmosphere
compound 3 (2.50 g, 13.14 mmol) in THF (10 mL) was added for 10 min and PhI(OCOCF3)2 (2.78 g, 6.47 mmol) was added
to the above reaction mixture at 0 °C and it was further stirred to the reaction mixture. It was stirred at the same temperature
for 10 h. The reaction was quenched with saturated NH4Cl for 1 h and at 25 °C for 2 h. The reaction mixture was concen-
solution and concentrated in vacuo. The obtained residue was trated under reduced pressure and the obtained residue was
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
dissolved in diethyl ether (50 mL). The organic layer was (d, J = 8 Hz, 3H), 1.94 (q, J = 12 Hz, 1H), 2.19 (s, 3H), 2.29 (td,
washed with sat. NaHCO3, brine and dried over Na2SO4. The J = 12 and 8 Hz, 1H), 3.12 (septet, J = 8 Hz, 1H), 3.89 (s, 3H),
obtained product was purified by silica gel (230–400 mesh) 4.35 (dd, J = 12 and 4 Hz, 1H), 6.73 (s, 1H), 7.84 (s, 1H); 13C
column chromatography using ethyl acetate–petroleum ether NMR (CDCl3, 100 MHz) δ −5.4, −4.3, 15.7, 18.6, 20.7, 25.9,
(1 : 9) as an eluent to afford the major product ( )-7 as a white 32.4, 42.0, 55.4, 74.9, 106.7, 124.4, 125.8, 129.9, 147.9, 162.2,
solid (0.75 g, 63%). Mp 102–103 °C; IR (CHCl3) νmax 3466, 197.0; ESIMS (m/z) 357 [M + Na]+; HRMS (ESI) calcd for
1674, 1606 cm−1
8 Hz, 3H), 1.76 (dd, J = 26 and 14 Hz, 1H), 2.22 (s, 3H), 2.49
;
1H NMR (CDCl3, 200 MHz) δ 1.46 (d, J = C19H31O3Si 335.2037, found 335.2031.
(−)-(1R,2S,4R)-6-Methoxy-4,7-dimethyl-1,2,3,4-tetrahydro-
(ddd, J = 12, 4 and 4 Hz, 1H), 3.16 (septet, J = 6 Hz, 1H), 3.92 naphthalene-1,2-diol (aristelegone D, 10). To a stirred solu-
(s, 3H), 3.95 (d, J = 2 Hz, 1H), 4.34 (ddd, J = 14, 4 and 2 Hz, tion of (−)-9 (50 mg, 0.15 mmol) in THF (4 mL) DIBAL
1H), 6.78 (s, 1H), 7.84 (s, 1H); 13C NMR (CDCl3, 100 MHz) solution (0.16 mL, 0.16 mmol, 1 M in hexane) was added in
δ 15.7, 20.5, 31.6, 40.8, 55.5, 72.9, 107.0, 121.7, 126.1, 129.7, dropwise fashion at −10 °C and the reaction mixture was
149.0, 162.9, 198.5; ESIMS (m/z) 243 [M + Na]+.
stirred under an argon atmosphere for 2 h. The reaction was
Amano PS catalyzed resolution of ( )-2-hydroxy-6-methoxy- quenched with saturated NH4Cl solution and the reaction
4,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (7). To mixture was concentrated in vacuo. The obtained residue was
a
stirred solution of ( )-2-hydroxy-6-methoxy-4,7-dimethyl-3,4- diluted with ethyl acetate (20 mL) and the organic layer was
dihydronaphthalen-1(2H)-one (7) (700 mg, 3.18 mmol) and washed with water, brine and dried over Na2SO4. The concen-
vinyl acetate (1.35 g, 15.90 mmol) in acetone (20 mL), the tration of organic layer in vacuo followed by silica gel (60–120)
enzyme Amano PS (50 mg, Sigma-Aldrich) was added. The column chromatographic purification of the resulting residue
resulting reaction mixture was stirred at 25 °C for 36 h with using ethyl acetate–petroleum ether (2 : 3) as an eluent
monitoring of the reaction progress by HPLC. The reaction afforded the pure product (−)-10 as a white solid (28 mg,
mixture was filtered through a Celite bed and washed with 84%). Mp 124–125 °C [lit. 126–127 °C];3a [α]D25 −67.8
ethyl acetate (30 mL). The concentration of the organic layer (c 0.27 CHCl3) {lit. [α]2D5 −70.6 (c 0.017 CHCl3)};3a IR (CHCl3)
1
in vacuo followed by silica gel (60–120 mesh) column chroma- νmax 3430, 1642 cm−1; H NMR (CDCl3, 200 MHz) δ 1.39 (d, J =
tographic purification of the resulting residue using ethyl 8 Hz, 3H), 1.72 (q, J = 12 Hz, 1H), 1.85–2.05 (m, 1H), 2.00–2.60
acetate–dichoromethane (1 : 99) as an eluent, affording the (br s, 2H), 2.20 (s, 3H), 2.90 (septet, J = 2 Hz, 1H), 3.84 (s, 3H),
pure product (+)-8 as a viscous oil (383 mg, 46%) and (−)-7 as 3.89 (td, J = 12 and 4 Hz, 1H), 4.63 (d, J = 2 Hz, 1H), 6.75 (s,
a white solid (378 mg, 54%).
1H), 7.13 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.7, 21.4, 32.5,
(+)-8: [α]2D5 +30.6 (c 0.20 CHCl3, 96% ee); IR (CHCl3) νmax 35.0, 55.3, 69.7, 70.2, 107.7, 125.4, 127.8, 132.7, 139.9, 158.2;
1
1741, 1688, 1607 cm−1; H NMR (CDCl3, 200 MHz) δ 1.47 (d, ESIMS (m/z) 245 [M + Na]+; HRMS (ESI) calcd for C13H17O3
J = 6 Hz, 3H), 2.00 (dd, J = 26 and 12 Hz, 1H), 2.21 (s, 3H), 2.23 221.1172, found 221.1172.
(s, 3H), 2.37 (td, J = 12 and 8 Hz, 1H), 3.24 (septet, J = 6 Hz,
(−)-(3aS,5R)-7-Methoxy-1,5,8-trimethyl-4,5-dihydronaphtho-
1H), 3.92 (s, 3H), 5.52 (dd, J = 12 and 8 Hz, 1H), 6.75 (s, 1H), [2,1-b]furan-2(3aH)-one (heritonin, 11). To a stirred solution
7.83 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.7, 20.5, 20.9, of the (−)-aristelegone B (7) (88 mg, 0.40 mmol) in toluene
32.1, 38.0, 55.5, 74.0, 106.7, 124.0, 126.1, 130.0, 147.7, 162.7, (4 mL), Cu(II) catalyst (5 mol%), Wittig reagent (272 mg,
170.4, 192.2; ESIMS (m/z) 263 [M + H]+; HRMS (ESI) calcd for 0.60 mmol), molecular sieves 4 Å (200 mg, 500 mg mmol−1
)
C15H19O4 263.1278, found 263.1273.
and OXONE® (369 mg, 1.20 mmol) were added under an
(−)-Aristelegone B (7). Mp 103–104 °C [lit. 103 °C];8g [α]2D5 argon atmosphere. The reaction mixture was stirred at 60 °C
−28.9 (c 0.14 CHCl3, 94% ee); the obtained spectroscopic data for 12 h until the disappearance of the starting material, then
was identical with the data for ( )-7.
xylene (6 mL) was added to the reaction mixture and the whole
(−)-(2S,4R)-2-((tert-Butyldimethylsilyl)oxy)-6-methoxy-4,7- reaction mixture was stirred at 138 °C for 1 h. The reaction
dimethyl-3,4-dihydronaphthalen-1(2H)-one (9). To a stirred mixture was allowed to reach 25 °C, filtered through a Celite
solution of alcohol (−)-7 (50 mg, 0.22 mmol) in dichloro- bed and the filtrate was evaporated under reduced pressure.
methane (5 mL), imidazole (18 mg, 0.26 mmol) and TBSCl The obtained residue was purified by silica gel (60–120)
(40 mg, 0.26 mmol) were added at 0 °C under an argon atmos- column chromatographic purification using ethyl acetate–pet-
phere. The reaction mixture was allowed to reach 25 °C and roleum ether (1 : 19) as an eluent to afford the pure product
was further stirred for 4 h. The reaction mixture was concen- (−)-11 as a white solid (76 mg, 74%). Mp 110–112 °C [lit.
trated in vacuo and the obtained residue was diluted with ethyl 115–116 °C];8c [α]D25 −299.2 (c 0.25 CHCl3, 93% ee) {lit. [α]2D5
acetate (10 mL). The organic layer was washed with water, −312.97 (c 1.3 CHCl3)};8c IR (CHCl3) νmax 1738, 1651,
brine and dried over Na2SO4. The concentration of the organic 1611 cm−1; 1H NMR (CDCl3, 700 MHz) δ 1.46 (d, J = 7 Hz, 3H),
layer in vacuo followed by silica gel (60–120) column chromato- 1.48 (q, J = 14 Hz, 1H), 2.14 (s, 3H), 2.25 (s, 3H), 2.64 (dt, J = 14
graphic purification of the resulting residue using ethyl and 7 Hz, 1H), 3.14 (septet, J = 7 Hz, 1H), 3.89 (s, 3H), 4.92
acetate–petroleum ether (1 : 19) as an eluent afforded the pure (dd, J = 14 and 7 Hz, 1H), 6.86 (s, 1H), 7.43 (s, 1H); 13C NMR
product (–)-9 as viscous oil (66 mg, 87%). [α]2D5 −64.1 (CDCl3, 175 MHz) δ 9.9, 16.0, 21.7, 32.0, 38.7, 55.3, 78.1, 108.4,
(c 0.10 CHCl3); IR (CHCl3) νmax 1689, 1608 cm−1
;
1H NMR 115.9, 120.7, 125.7, 129.6, 142.2, 156.7, 159.6, 175.6; HRMS
(CDCl3, 400 MHz) δ 0.12 (s, 3H), 0.23 (s, 3H), 0.95 (s, 9H), 1.44 (ESI) calcd for C16H19O3 259.1329, found 259.1326.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
(+)-(R)-6-Methoxy-4,7-dimethyl-3,4-dihydronaphthalen-1(2H)- [lit. 115–116 °C];9a [α]D25 −22.4 (c 0.25 CHCl3) {lit. [α]D25 −18.4 (c
one (methylaristelegone A, 6). To a stirred solution of (−)-aris- 1.18 CHCl3)};9a the obtained spectroscopic data was identical
telegone B (7) (50 mg, 0.22 mmol) in THF (2 mL), acetic anhy- with the data for ( )-6.
dride (45 mg, 0.44 mmol) was added followed by a solution of
(−)-(S)-4-Isopropyl-7-methoxy-1,6-dimethyl-1,2-dihydronaphtha-
samarium diiodide (8.80 mL, 0.88 mmol, 0.10 M in THF) in a lene (15). To a stirred solution of (−)-methylaristelegone A (6)
dropwise fashion at 0 °C and the reaction mixture was stirred (50 mg, 0.24 mmol) in THF (4 mL), a solution of isopropyl-
under an argon atmosphere for 2 h. The reaction was magnesium chloride (0.14 mL, 0.28 mmol, 2 M in THF) was
quenched with saturated NH4Cl solution and concentrated added in a dropwise fashion at 0 °C and the reaction mixture
in vacuo. The obtained residue was diluted with ethyl acetate was stirred at the 25 °C under an argon atmosphere for 6 h.
(10 mL) and the organic layer was washed with water, brine The reaction was quenched with 2 N HCl and stirred for
and dried over Na2SO4. The concentration of the organic layer 30 min. The reaction mixture was concentrated in vacuo and
in vacuo followed by silica gel (60–120) column chromato- the obtained residue was diluted with ethyl acetate (10 mL).
graphic purification of the resulting residue using ethyl The organic layer was washed with water, brine and dried over
acetate–petroleum ether (1 : 9) as an eluent afforded the pure Na2SO4. The concentration of the organic layer in vacuo fol-
product (+)-6 as a white solid (30 mg, 65%). Mp 109–110 °C lowed by silica gel (60–120) column chromatographic purifi-
[lit. 107–108 °C];6b [α]D25 +21.3 (c 0.25 CHCl3) {lit. [α]1D2 +26.5 cation of the resulting residue using ethyl acetate–petroleum
(c 2.4 CHCl3)};6b the obtained spectroscopic data was identical ether (1 : 49) as an eluent afforded the pure product (−)-15 as a
with the data for ( )-6.
viscous oil (52 mg, 92%). [α]2D5 −57.8 (c 0.37 CHCl3); IR (CHCl3)
(+)-(R)-6-Hydroxy-4,7-dimethyl-3,4-dihydronaphthalen-1(2H)- νmax 1603 cm−1; H NMR (CDCl3, 400 MHz) δ 1.16 (d, J = 8 Hz,
one (aristelegone A, 13). To a stirred solution of (+)-methyl- 3H), 1.19 (d, J = 8 Hz, 3H), 1.22 (d, J = 8 Hz, 3H), 2.07 (dt, J = 16
aristelegone A (6) (25 mg, 0.12 mmol) in DCM (2 mL), a solu- and 8 Hz, 1H), 2.24 (s, 3H), 2.37–2.46 (m, 1H), 2.81 (sextet, J =
tion of boron tribromide (0.30 mL, 0.30 mmol, 1 M in DCM) 8 Hz, 1H), 2.95 (septet, J = 8 Hz, 1H), 3.87 (s, 3H), 5.67 (t, J = 4
was added in a dropwise fashion at −78 °C and the reaction Hz, 1H), 6.72 (s, 1H), 7.14 (s, 1H); 13C NMR (CDCl3, 100 MHz)
mixture was stirred under argon atmosphere for 1 h. The reac- δ 16.1, 19.9, 22.0, 22.4, 28.1, 30.9, 32.6, 55.4, 108.6, 116.8,
tion mixture was allowed to reach 25 °C and stirred further for 123.4, 125.4, 126.5, 141.1, 141.5, 156.3; HRMS (ESI) calcd for
12 h. The reaction was quenched with ice cold water and C16H23O 231.1743, found 231.1743.
1
stirred for 30 min. The reaction mixture was extracted with
(+)-(2R,4S)-2-Hydroxy-6-methoxy-4,7-dimethyl-3,4-dihydro-
DCM (7 mL × 2) and the organic layer was washed with water, naphthalen-1(2H)-one (aristelegone B, 7). To a stirred solu-
brine and dried over Na2SO4. The concentration of the organic tion of acetoxy ketone (+)-8 (200 mg, 0.76 mmol) in methanol
layer in vacuo followed by silica gel (60–120) column chromato- (5 mL), K2CO3 (5 mg) was added at 0 °C and the reaction
graphic purification of the resulting residue using ethyl mixture was further stirred under an argon atmosphere for
acetate–petroleum ether (1 : 2) as an eluent afforded the pure 1 h. The reaction mixture was concentrated in vacuo and the
product (+)-13 as a white solid (17 mg, 74%). Mp 148–150 °C obtained residue was diluted with ethyl acetate (20 mL). The
[lit. 150–151 °C];3a [α]D25 +13.6 (c 0.28 CHCl3) {lit. [α]2D5 +15.4 organic layer was washed with water, brine and dried over
(c 0.24 CHCl3)};3a IR (CHCl3) νmax 3218, 1651, 1585 cm−1 1H Na2SO4. The concentration of the organic layer in vacuo fol-
;
NMR (CDCl3, 500 MHz) δ 1.36 (d, J = 5 Hz, 3H), 1.82–1.90 (m, lowed by silica gel (60–120) column chromatographic purifi-
1H), 2.16–2.24 (m, 1H), 2.26 (s, 3H), 2.57 (ddd, J = 20, 10 and cation of the resulting residue using ethyl acetate–petroleum
5 Hz, 1H), 2.76 (ddd, J = 20, 10 and 5 Hz, 1H), 2.99 (sextet, J = ether (1 : 9) as an eluent afforded the pure product (+)-7 as a
10 Hz, 1H), 6.64 (br s, 1H), 6.75 (s, 1H), 7.87 (s, 1H); 13C NMR white solid (137 mg, 82%). Mp 102–103 °C [lit. 103 °C];8g [α]2D5
(CDCl3, 125 MHz) δ 15.3, 20.5, 30.8, 32.6, 36.2, 112.8, 123.0, +29.2 (c 0.18 CHCl3, 92% ee); the obtained spectroscopic data
124.9, 130.6, 149.7, 159.5, 198.4; HRMS (ESI) calcd for was identical with the data for ( )-7.
C12H15O2 191.1067, found 191.1070.
(+)-(3aR,5S)-7-Methoxy-1,5,8-trimethyl-4,5-dihydronaphtho-
(−)-(S)-6-Methoxy-4,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one [2,1-b]furan-2(3aH)-one (heritonin, 11). To a stirred solution
(methylaristelegone A, 6). To a stirred solution of acetoxy of the (+)-aristelegone B (7) (88.0 mg, 0.40 mmol) in toluene
ketone (+)-8 (100 mg, 0.38 mmol) in THF (4 mL), a solution of (4 mL), Cu(II) catalyst (5 mol%), Wittig reagent (272 mg,
samarium diiodide (7.60 mL, 0.76 mmol, 0.10 M in THF) was 0.60 mmol), molecular sieves 4 Å (200 mg, 500 mg mmol−1
)
added in a dropwise fashion at 0 °C and the reaction mixture and OXONE® (369 mg, 1.20 mmol) were added under an
was stirred under an argon atmosphere for 2 h. The reaction argon atmosphere. The reaction mixture was stirred at 60 °C
was quenched with saturated NH4Cl solution and concentrated for 12 h until the disappearance of the starting material, then
in vacuo. The obtained residue was diluted with ethyl acetate xylene (6 mL) was added to the reaction mixture and the whole
(10 mL) and the organic layer was washed with water, brine reaction mixture was stirred at 138 °C for 1 h. The reaction
and dried over Na2SO4. The concentration of the organic layer mixture was allowed to reach 25 °C, filtered through a Celite
in vacuo followed by silica gel (60–120) column chromato- bed and the filtrate was evaporated under reduced pressure.
graphic purification of the resulting residue using ethyl The obtained residue was purified by silica gel (60–120)
acetate–petroleum ether (1 : 9) as an eluent afforded the pure column chromatographic purification using ethyl acetate–pet-
product (−)-6 as a white solid (65 mg, 84%). Mp 109–111 °C roleum ether (1 : 19) as an eluent to afford the pure product
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
(+)-11 as a white solid (72 mg, 71%). Mp 111–113 °C [lit. water, brine and dried over Na2SO4. The concentration of the
115–116 °C];4a [α]D25 +298.1 (c 0.32 CHCl3); the obtained spec- organic layer in vacuo was followed by a silica gel (60–120)
troscopic data was identical with the data for (−)-11.
column chromatographic purification of the resulting residue
( )-7-Methoxy-6-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen- using ethyl acetate–petroleum ether (1 : 4) as an eluent
2-yl acetate (17). A solution of KMnO4 (1.25 g, 78.84 mmol) in afforded the pure product (+)-18 as a white solid (2.99 g, 44%)
benzene–acetic acid (10 : 1, 250 mL) was stirred under reflux and (+)-19 also as a white solid (329 mg, 56%).
(Dean–Stark apparatus) until the purple color of KMnO4
turned brown (30–45 min). To this solution compound 3 troscopic data was identical with the data for ( )-18.
(5.00 g, 26.28 mmol) was added and reflux was continued. The
(+)-19: [α]2D5 +3.2 (c 0.40 CHCl3, 89% ee); the obtained spec-
reaction was monitored by TLC and after 6 h it was diluted troscopic data was identical with the data for ( )-19.
with diethyl ether and neutralized with aq. NaHCO3. The ( )-7-Methoxy-6-methyl-1-methylene-1,2,3,4-tetrahydronaphtha-
(+)-18: [α]2D5 +2.8 (c 1.75 CHCl3, 92% ee); the obtained spec-
resulting organic phase was dried over Na2SO4 and concen- len-2-ol (19). To a stirred solution of acetate ( )-18 (1.50 g,
trated in vacuo. The crude product was purified by silica gel 6.08 mmol) in methanol (10 mL), K2CO3 (20 mg) was added at
(60–120) column chromatographic purification using ethyl 0 °C and the reaction mixture was further stirred under an
acetate–petroleum ether (1 : 3) as an eluent to afford the pure argon atmosphere for 1 h. The reaction mixture was concen-
product ( )-17 as a viscous oil (4.56 g, 70%). IR (CHCl3) νmax trated in vacuo and the obtained residue was diluted with ethyl
1775, 1746, 1692, 1611 cm−1 1H NMR (CDCl3, 200 MHz) acetate (20 mL). The organic layer was washed with water,
;
δ 2.10–2.42 (m, 2H), 2.21 (s, 3H), 2.23 (s, 3H), 2.86–3.18 (m, brine and dried over Na2SO4. The concentration of the organic
2H), 3.83 (s, 3H), 5.49 (dd, J = 12 and 6 Hz, 1H), 7.00 (s, 1H), layer in vacuo followed by silica gel (60–120) column chromato-
7.38 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ 16.5, 20.8, 27.0, 29.4, graphic purification of the resulting residue using ethyl
55.4, 74.5, 107.0, 130.2, 130.6, 134.5, 135.6, 156.7, 170.2, 192.7; acetate–petroleum ether (1 : 2) as an eluent afforded the pure
ESIMS (m/z) 271 [M + Na]+; HRMS (ESI) calcd for C14H17O4 product ( )-19 as a white solid (1.05 g, 85%). Mp 85–87 °C; IR
249.1121, found 249.1120.
( )-7-Methoxy-6-methyl-1-methylene-1,2,3,4-tetrahydronaphtha- 200 MHz) δ 1.69 (br s, 1H), 1.85–2.15 (m, 2H), 2.20 (s, 3H),
len-2-yl acetate (18). To stirred solution of methyl- 2.68–3.07 (m, 2H), 3.86 (s, 3H), 4.51 (dd, J = 8 and 4 Hz, 1H),
(CHCl3) νmax 3430, 1644, 1604 cm−1 1H NMR (CDCl3,
;
a
triphenylphosphonium iodide (8.10 g, 19.93 mmol) in 5.27 (s, 1H), 5.55 (s, 1H), 6.91 (s, 1H), 7.05 (s, 1H); 13C NMR
anhydrous THF (40 mL), a solution of n-BuLi (12.45 mL, (CDCl3, 50 MHz) δ 16.0, 25.4, 31.7, 55.4, 70.9, 105.6, 107.2,
19.93 mmol, 1.60 M in hexane) was added in a dropwise 127.5, 128.1, 131.0 (2 C), 146.6, 156.3; HRMS (ESI) calcd for
fashion at 0 °C under an argon atmosphere and the mixture C13H17O2 205.1223, found 205.1224.
was stirred for 30 min. A solution of compound ( )-17 (4.50 g,
18.12 mmol in 20 ml THF) was added to the above reaction hydronaphthalen-2-yl)oxy)diphenylsilane (20). To
( )-tert-Butyl((7-methoxy-6-methyl-1-methylene-1,2,3,4-tetra-
stirred
a
mixture at 0 °C and it was further stirred for 10 h. The reaction solution of alcohol ( )-19 (1.00 g, 4.89 mmol) in dichloro-
was quenched with saturated NH4Cl solution and concentrated methane (20 mL), imidazole (366 mg, 5.38 mmol) and
in vacuo. The obtained residue was diluted with ethyl acetate TBDPSCl (1.48 g, 5.38 mmol) were added at 0 °C under an
(150 mL), washed with water, brine and dried over Na2SO4. argon atmosphere. The reaction mixture was allowed to reach
The concentration of the organic layer in vacuo followed by 25 °C and further stirred for 6 h. The reaction mixture was con-
silica gel (60–120) column chromatographic purification of the centrated in vacuo and the obtained residue was diluted with
resulting residue using ethyl acetate–petroleum ether (1 : 4) as ethyl acetate (40 mL). The organic layer was washed with
an eluent afforded the product ( )-18 as a white solid (2.99 g, water, brine and dried over Na2SO4. The concentration of the
67%). Mp 52–54 °C; IR (CHCl3) νmax 1736, 1613 cm−1; 1H NMR organic layer in vacuo followed by silica gel (60–120 mesh)
(CDCl3, 200 MHz) δ 1.95–2.18 (m, 2H), 2.09 (s, 3H), 2.21 (s, column chromatographic purification of the resulting residue
3H), 2.70–3.05 (m, 2H), 3.86 (s, 3H), 5.25 (s, 1H), 5.61 (s, 1H), using ethyl acetate–petroleum ether (1 : 49) as an eluent
5.66 (dd, J = 6 and 4 Hz, 1H), 6.92 (s, 1H), 7.04 (s, 1H); 13C afforded the pure product ( )-20 as a white solid (1.99 g, 92%).
1
NMR (CDCl3, 50 MHz) δ 15.9, 21.4, 25.1, 28.7, 55.3, 72.8, 105.4, Mp 108–109 °C; IR (CHCl3) νmax 1609 cm−1; H NMR (CDCl3,
109.9, 127.6, 127.8, 130.8, 130.9, 141.5, 156.3, 170.5; HRMS 200 MHz) δ 1.06 (s, 9H), 1.65–2.00 (m, 2H), 2.17 (s, 3H),
(ESI) calcd for C15H18O3Na 269.1148, found 269.1147.
2.45–2.65 (m, 1H), 2.80–3.00 (m, 1H), 3.84 (s, 3H), 4.48 (dd, J =
Amano PS catalyzed resolution of ( )-7-methoxy-6-methyl-1- 8 and 4 Hz, 1H), 5.15 (s, 1H), 5.37 (s, 1H), 6.82 (s, 1H), 6.96 (s,
methylene-1,2,3,4-tetrahydronaphthalen-2-yl acetate (18). To a 1H), 7.25–7.50 (m, 6H), 7.62 (dd, J = 8 and 2 Hz, 2H), 7.72 (dd,
stirred solution of allyl acetate ( )-18 (1.00 g, 4.05 mmol) in a J = 8 and 2 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 16.0, 19.4,
mixture of petroleum ether and benzene (1 : 2, 30 mL), the 26.1, 27.0, 32.7, 55.4, 72.5, 105.9, 107.1, 126.9, 127.4, 127.6,
phosphate buffer (pH 7, 20 mL) and enzyme Amano PS 128.0, 129.5, 129.6, 130.8, 132.2, 134.0, 134.6, 135.9 (2 C),
(50 mg, Amano Enzyme Japan) were successively added. The 146.4, 156.1; HRMS (ESI) calcd for C29H33O2Si 441.2244, found
resulting reaction mixture was stirred at 45 °C for 48 h with 441.2245.
monitoring of the reaction progress by HPLC. The reaction
( )-tert-Butyl((7-methoxy-1,6-dimethyl-1,2,3,4-tetrahydronaphtha-
mixture was filtered through a Celite bed and washed with len-2-yl)oxy)diphenylsilane (21). To a stirred solution of com-
ethyl acetate (50 mL). The organic layer was washed with pound ( )-20 (1.50 g, 3.38 mmol) in ethyl acetate (25 mL), 10%
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
Pd/C (25 mg) was added at 25 °C and the reaction mixture was fluoride (0.23 mL, 0.23 mmol, 1 M in THF) was slowly added at
subjected to hydrogenation under balloon pressure for 8 h. 0 °C. The reaction mixture was further stirred for 5 h at the
The reaction mixture was filtered through a Celite bed and same temperature and quenched with saturated NH4Cl solu-
washed with ethyl acetate. The concentration of the filtrate tion. The reaction mixture was concentrated in vacuo and the
in vacuo furnished a diastereomeric mixture of compound obtained residue was diluted with ethyl acetate (20 mL). The
( )-21 as a white solid with ∼9 : 1 ratio (by 1H NMR) (1.51 g, organic layer was washed with water, brine and dried over
∼100%). Mp 110–113 °C; IR (CHCl3) νmax 1602 cm−1; major Na2SO4. The concentration of the organic layer in vacuo fol-
isomer: 1H NMR (CDCl3, 200 MHz) δ 1.10 (s, 9H), 1.32 (d, J = 8 lowed by silica gel (60–120) column chromatographic purifi-
Hz, 3H), 1.55–1.70 (m, 1H), 1.80–2.05 (m, 1H), 2.11 (s, 3H), cation of the resulting residue using ethyl acetate–petroleum
2.28–2.55 (m, 1H), 2.57–2.75 (m, 1H), 2.83–3.00 (m, 1H), 3.77 ether (1 : 4) as an eluent afforded the pure product 23 as an
1
(s, 3H), 4.04–4.17 (m, 1H), 6.48 (s, 1H), 6.73 (s, 1H), 7.25–7.50 orange oil (27 mg, 63%). IR (CHCl3) νmax 3415, 1599 cm−1; H
(m, 6H), 7.65–7.80 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 15.7, NMR (CDCl3, 200 MHz) δ 2.43 (s, 3H), 2.58 (s, 3H), 3.99 (s,
17.4, 19.4, 26.6, 27.0, 27.5, 39.6, 55.4, 71.8, 110.5, 124.5, 126.3, 3H), 5.37 (br s, 1H), 6.59 (d, J = 8 Hz, 1H), 7.07 (d, J = 8 Hz,
127.47, 127.54, 129.5, 129.6, 130.5, 134.3, 134.8, 135.8, 139.9 (2 1H), 7.11 (s, 1H), 7.99 (s, 1H); 13C NMR (CDCl3, 100 MHz)
C), 155.9; ESIMS (m/z) 467 [M + Na]+; HRMS (ESI) calcd for δ 16.9, 19.1, 55.2, 101.3, 106.1, 119.3, 123.1, 125.0, 125.8,
C29H36O2NaSi 467.2377, found 467.2371.
127.2, 133.6, 149.5, 157.2; ESIMS (m/z) 203 [M + H]+; HRMS
( )-3-((tert-Butyldiphenylsilyl)oxy)-6-methoxy-4,7-dimethyl-3,4- (ESI) calcd for C13H15O2 203.1067, found 203.1066.
dihydronaphthalen-1(2H)-one (22). To a stirred solution of
( )-21 (1.00 g, 2.24 mmol) in acetic acid (20 mL), a solution of
CrO3 (292 mg, 2.92 mmol) in AcOH plus H2O (8 : 2, 8 mL) was
added in a dropwise fashion at 0 °C. The reaction mixture was
Acknowledgements
further stirred for 2 h, diluted with water and carefully neutral-
R. U. B. thanks UGC, New Delhi, for the award of a research
ized by the addition of a saturated solution of NaHCO3. The
fellowship. N. P. A. thanks the Department of Science and
reaction mixture was extracted with diethyl ether (25 mL × 3)
Technology, New Delhi, for financial support. We also grate-
and the organic layer was washed with water, brine and dried
fully acknowledge the financial support from CSIR-Network
over Na2SO4. The concentration of the organic layer in vacuo
Project. We thank Mrs S. S. Kunte from NCL, Pune, for the
followed by silica gel (60–120) column chromatographic purifi-
HPLC data.
cation of the resulting residue using ethyl acetate–petroleum
ether (1 : 9) as an eluent afforded the diastereomerically pure
product ( )-22 as viscous oil (680 mg, 66%). IR (CHCl3) νmax
1728, 1667, 1602 cm−1 1H NMR (CDCl3, 200 MHz) δ 1.09 (s,
;
Notes and references
9H), 1.37 (d, J = 8 Hz, 3H), 2.15 (s, 3H), 2.59 (dd, J = 18 and
6 Hz, 1H), 2.83 (dd, J = 18 and 12 Hz, 1H), 3.03 (quintet, J =
6 Hz, 1H), 3.86 (s, 3H), 4.32 (td, J = 12 and 4 Hz, 1H), 6.53 (s,
1H), 7.30–7.50 (m, 6H), 7.60–7.80 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 15.6, 19.2, 26.5, 26.9, 40.6, 42.7, 55.5, 69.8, 108.7,
124.1, 125.9, 127.7, 129.3, 129.6, 129.79, 129.83, 133.6, 133.7,
134.8, 135.7, 148.1, 162.5, 195.9; ESIMS (m/z) 481 [M + Na]+;
HRMS (ESI) calcd for C29H35O3Si 459.2350, found 459.2348.
6-Methoxy-4,7-dimethylnaphthalen-1-ol (23). Method A: to a
stirred slurry of keto compound ( )-22 (100 mg, 0.21 mmol),
activated Zn (27 mg, 0.42 mmol) and a catalytic amount of
iodine in anhydrous diethyl ether (10 mL), a solution of ethyl
2-bromopropionate (76 mg, 0.42 mmol) in anhydrous diethyl
ether (2 mL) was slowly added at 25 °C under argon atmos-
phere. The reaction mixture was further refluxed for 12 h,
quenched with saturated NH4Cl solution and concentrated
in vacuo. The obtained residue was diluted with ethyl acetate
(20 mL). The organic layer was washed with water, brine and
dried over Na2SO4. The concentration of the organic layer
in vacuo followed by silica gel (60–120) column chromato-
graphic purification of the resulting residue using ethyl
acetate–petroleum ether (1 : 4) as an eluent afforded the pure
product 23 as an orange oil (30 mg, 68%). Method B: to a
stirred solution of keto compound ( )-22 (100 mg, 0.21 mmol)
in anhydrous THF (10 mL), a solution of tetrabutylammonium
1 (a) J.-X. Pu, X.-M. Gao, C. Lei, W.-L. Xiao, R.-R. Wang,
L.-B. Yang, Y. Zhao, L.-M. Li, S.-X. Huang, Y.-T. Zheng and
H.-D. Sun, Chem. Pharm. Bull., 2008, 56, 1143;
(b) C. F. Chyu, M. R. Ke, Y. S. Chang, S. C. Chien and
Y. H. Kuo, Helv. Chim. Acta, 2007, 90, 1514; (c) C.-H. Chao,
J.-C. Cheng, D.-Y. Shen and T.-S. Wu, J. Nat. Prod., 2014, 77,
22; (d) L. Long, S. K. Lee, H.-B. Chai, P. Rasoanaivo, Q. Gao,
H. Navarro, M. E. Wall, M. C. Wani, N. R. Farnsworth,
G. A. Cordell, J. M. Pezzuto and A. D. Kinghorn, Tetrahe-
dron, 1997, 53, 15663; (e) D. H. Miles, V. Chittawong,
D.-S. Lho, A. M. Payne, A. A. De la Cruz, E. D. Gomez,
J. A. Weeks and J. L. Atwood, J. Nat. Prod., 1991, 54, 286.
2 K. Nabeta, Y. Mototani, H. Tazaki and H. Okuyama, Phyto-
chemistry, 1994, 35, 915.
3 (a) T.-S. Wu, Y.-L. Tsai, A. G. Damu, P.-C. Kuo and P.-L. Wu,
J. Nat. Prod., 2002, 65, 1522; (b) Z. Gang, Isolation of Bio-
active Components from Ecuadorian Aristolochia Constricta,
Ph. D. Dissertation, Chiba University, Japan, 2010.
4 (a) D. H. Miles, A. M. Ly, V. Chittawong, A. A. De la Cruz
and E. D. Gomez, J. Nat. Prod., 1989, 52, 896;
(b) D. H. Miles, D. S. Lho, A. A. De la Cruz, E. D. Gomez,
J. A. Weeks and J. L. Atwood, J. Org. Chem., 1987, 52, 2930;
(c) F. Bohlmann, C. Zdero and N. Le Van, Phytochemistry,
1979, 18, 99.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
5 K. Nabeta, K. Katayama, S. Nakagawara and K. Katoh,
Phytochemistry, 1993, 32, 117.
6 (a) S. Serra, Nat. Prod. Commun., 2013, 8, 863; (b) S. Song,
S.-F. Zhu, S. Yang, S. Li and Q.-L. Zhou, Angew. Chem., Int.
Ed., 2012, 51, 2708.
Org. Lett., 2014, 16, 5612; (c) S. B. Markad and N. P. Argade,
Org. Lett., 2014, 16, 5470; (d) Y. Zheng, Y. Liu and Q. Wang,
J. Org. Chem., 2014, 79, 3348; (e) H. Li, X. Wang, B. Hong
and X. Lei, J. Org. Chem., 2013, 78, 800; (f) S. B. Jones,
B. Simmons, A. Mastracchio and D. W. MacMillan, Nature,
2011, 475, 183; (g) A. N. Flyer, C. Si and A. G. Myers, Nat.
Chem., 2010, 2, 886.
7 B.-C. Chen, P. Zhou, F. A. Davis and E. Ciganek, Org. React.,
2003, 62, 17.
8 (a) S. P. Chavan, S. Garai and U. R. Kalkote, Tetrahedron, 12 (a) D. G. Vanga and K. P. Kaliappan, Eur. J. Org. Chem.,
2012, 68, 8509; (b) K. Matsuo and M. Shindo, Org. Lett.,
2010, 12, 5346; (c) S. P. Chavan, M. Thakkar and
U. R. Kalkote, Tetrahedron Lett., 2007, 48, 643;
(d) C. C. Silveira, A. Machado, A. L. Braga and E. J. Lenardão,
Tetrahedron Lett., 2004, 45, 4077; (e) S. P. Chavan,
P. K. Zubaidha and N. R. Ayyangar, Tetrahedron Lett., 1992,
33, 4605; (f) P. K. Zubaidha, S. P. Chavan, U. S. Racherla and
2012, 2250; (b) C. Clausen, R. Wartchow and
H. Butenschön, Eur. J. Org. Chem., 2001, 93; (c) G. A. Kraus
and J. Shi, J. Org. Chem., 1990, 55, 4922; (d) J. M. Hornback,
M. L. Poundstone, B. Vadlamani, S. M. Graham,
J. Gabay and S. T. Patton, J. Org. Chem., 1988, 53,
5597; (e) J. R. Bethell and P. Maitland, J. Chem. Soc., 1962,
3751.
N. R. Ayyangar, Tetrahedron, 1991, 47, 5759; (g) H. Irie, 13 (a) P. S. Deore and N. P. Argade, J. Org. Chem., 2014, 79,
R. Matsumoto, M. Nishimura and Y. Zhang, Chem. Pharm.
Bull., 1990, 38, 1852.
9 (a) G. G. Bianco, H. M. C. Ferraz, A. M. Costa, L. V. Costa-
Lotufo, C. Pessoa, M. O. de Moraes, M. G. Schrems,
A. Pfaltz and L. F. Silva Jr., J. Org. Chem., 2009, 74, 2561;
2538; (b) P. S. Deore and N. P. Argade, Org. Lett., 2013, 15,
5826; (c) S. D. Vaidya and N. P. Argade, Org. Lett., 2013, 15,
4006; (d) P. Mondal and N. P. Argade, J. Org. Chem., 2013,
78, 6802; (e) R. M. Patel and N. P. Argade, Org. Lett., 2012,
15, 14. and references cited therein.
(b) H. M. C. Ferraz, A. M. Aguilar and L. F. Silva, Tetrahe- 14 (a) R. U. Batwal, R. M. Patel and N. P. Argade, Tetrahedron:
dron, 2003, 59, 5817; (c) T.-L. Ho, K.-Y. Lee and C.-K. Chen,
J. Org. Chem., 1997, 62, 3365.
Asymmetry, 2011, 22, 173; (b) S. Gogoi and N. P. Argade, Tet-
rahedron: Asymmetry, 2006, 17, 927; (c) S. Easwar and
N. P. Argade, Tetrahedron: Asymmetry, 2003, 14, 333;
(d) S. Easwar, S. B. Desai, N. P. Argade and K. N. Ganesh,
Tetrahedron: Asymmetry, 2002, 13, 1367; (e) S. B. Desai,
N. P. Argade and K. N. Ganesh, J. Org. Chem., 1999, 64,
8105; (f) S. B. Desai, N. P. Argade and K. N. Ganesh, J. Org.
Chem., 1996, 61, 6730.
10 (a) P. A. McDowell, D. A. Foley, P. O’Leary, A. Ford and
A. R. Maguire, J. Org. Chem., 2012, 77, 2035; (b) E. Brenna,
C. Dei Negri, C. Fuganti, F. G. Gatti and S. Serra, Tetrahe-
dron: Asymmetry, 2004, 15, 335; (c) M. Uemura, K. Isobe,
K. Take and Y. Hayashi, J. Org. Chem., 1983, 48, 3855.
11 (a) J.-C. Han, F. Li and C.-C. Li, J. Am. Chem. Soc., 2014,
136, 13610; (b) S.-Z. Jiang, T. Lei, K. Wei and Y.-R. Yang, 15 A. S. Demir and H. Findik, Tetrahedron, 2008, 64, 6196.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015