Application of intramolecular carbonyl-ene reaction towards the synthesis of idarubicinone scaffold

Article abstract of DOI:10.24820/ark.5550190.p009.921

Intramolecular aromatic carbonyl-ene reaction (ICE)has been combined with a modified Hauser annulation to offer a facile access to the tetracyclic idarubicinone core. The required key dihydroxyanthraquinone aldehyde precursor was assembled in one step by

Full text of DOI:10.24820/ark.5550190.p009.921

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Arkivoc 2018, part iii, 257-269
Organic Chemistry
Application of intramolecular carbonyl-ene reaction towards the synthesis of
idarubicinone scaffold
Shyam Basak, Sutapa Ray, and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
E-mail: dmal@chem.iitkgp.ernet.in
Received 11-02-2017
Accepted 03-20-2018
Published on line 04-16-2018
Abstract
Intramolecular aromatic carbonyl-ene reaction (ICE)† has been combined with a modified Hauser annulation to
offer a facile access to the tetracyclic idarubicinone core. The required key dihydroxyanthraquinone aldehyde
precursor was assembled in one step by modified Hauser annulation of a functionalized benzoquinone. Its ene
reaction in the presence of SnCl4·5H2O directly led to the formation of idarubicinone core. Also described are
an unprecedented thermal cascade involving a thermal ICE en route to α-naphthols, and exploratory studies
on model elaboration of anthracycline A rings.
†
By “aromatic carbonyl-ene reaction” we mean those reactions in which an aromatic ring is embedded in the transition state of a
carbonyl-ene reaction.
O
O
O
OH
O
O
OH
OH
SPh
O
SnCl4·5H2O
DCM, rt
O
OTHP
89%
CHO
O
OH OH
Keywords: Intramolecular, carbonyl-ene, tetralin, anthracyclines
DOI: https://doi.org/10.24820/ark.5550190.p009.921
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Introduction
The type-II intramolecular carbonyl-ene reaction (ICE) shown as eqn. 1 in Scheme 1 is an established process in
the organic synthesis.1–2 It has allowed total synthesis of many bioactive natural products.3–8 However, its
aromatic version (eqn. 2, Scheme 1) discovered in 1983 by Hauser and Mal in conjunction with their work on
the total synthesis of (±)-γ-citromycinone, has been limited to anthracyclines.9–15 It is a significant
advancement in the area of ICE, in view of its success despite the conformational constraint imposed by a
benzene ring. Furthermore, the placement of the benzylic hydroxyl group in the product obviates the
problems of benzylic bromination under radical conditions on a large scale.16,17 However, its application to
simple naphthalenes and anthracenes are problematic due to the susceptibility of the incipient ene products
to aromatization. In a recent report18 from our laboratory, we have demonstrated that the ICE can be
manoeuvred to prevent aromatization of the ene products, thus permitting synthesis of non-aromatized ene
products i.e. hydroaromatic products. We also included development of a synthesis of ortho
methallylbenzaldehydes based upon Suzuki coupling reactions.
Scheme 1. Type II carbonyl-ene reaction.
In seeking an application of the aromatic ICE in developing a simpler route to anthracyclines 1–5 (Figure 1),
the most widely used anticancer drugs19–22, we chose to assemble the tetracycline framework of idarubicinone
(3) as shown in Scheme 2. The salient features of the retrosynthesis are i) modified Hauser annulation of 6 and
7 to assemble dihydroxy intermediate 8 and ii) its direct use as the ene substrate to produce tetracyclic
intermediate 9. It may be mentioned that the reactivity of the 1,4-dimethoxy analog of quinone 8, prepared by
Claisen rearrangement, was examined towards the aromatic ICE.23 No further elaboration was attempted
probably due to the problem with deprotection of the aromatic methoxy groups without affecting the A-ring.
In devising the synthesis of 3, we, therefore, envisioned investigations with dihydroxy intermediate 8. It was
anticipated that the corresponding ene product i.e. 9 would be sufficiently stable due to intramolecular
hydrogen bonding for further elaborations without resorting to a deprotection.
In this study, the potential of the aromatic ICE approach in creating an asymmetric centre at C7 position of
anthracyclines is proposed. Asymmetric epoxidations or hydroxylations or nucleophilic additions can be
invoked for further elaborations, as indicated in Scheme 2. Asymmetric dihydroxylation of the ene product 9 is
proposed to give 10 and then 3. In the second approach, tetracycle 11 is expected to produce compounds 12
and 13 and 3 (Scheme 2).
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Figure 1. Selected clinically used anthracyclines.
Scheme 2. Retrosynthetic analysis of idarubicinone (3).
Results and Discussion
To perform a model study of idarubicinone (3) utilizing Hauser annulation, we first decided to synthesize the
Michael acceptor 14 (cf 7, Scheme 2) (Scheme 3). This proposal stemmed from our previous study on the
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Hauser annulation of p-quinones for straightforward generation of 1,4-dihydroxyanthraquinone moieties.24
Accordingly, O-methallyl substrate 15 was prepared by selective O-methallylation of methyl 2,5-
dihydroxybenzoate with methallyl bromide in the presence of K2CO3 in acetone. Claisen rearrangement of 15
in boiling DMF gave two products 16 and 17 in 1:1 ratio. Appearance of a 2H singlet at δ 2.98 and a 6H singlet
at δ 1.50 indicated the formation of 17, which was confirmed by its acetylation to compound 18. Quinol 16
was methylated to 19 by reaction with Me2SO4-K2CO3 in acetone. Compound 19 was then reduced to alcohol
2025 by lithium aluminium hydride.
Scheme 3. Preparation of alcohol 20.
For an alternative route to 20, we examined the possibility of Claisen rearrangement of a related aldehyde
precursor, and for the model study we chose aldehyde 2126 (Scheme 4).
Scheme 4. Thermal rearrangement of aldehyde 21.
When it was heated in refluxing DMF, the desired Claisen product was not obtained. Instead, the reaction
resulted in formation of three products 22 (4%), 23 (7%) and 2427 (23%) (Scheme 4). Formation of the
naphthol 22 is accounted for by Claisen rearrangement of 21 to intermediate 25 followed by thermal ICE of 25
through 26 to 27, its dehydration and isomerization. The formation of 23 is very striking in that its formation
must involve a reduction, since there is a decrease in the oxidation level.28 The probable mechanism is shown
in Scheme 5, where DMF acts as the hydride donor. The structure of 23 is further confirmed by transforming it
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into its acetate. It may be noted that the product 23 was not obtained when the reaction was carried out in
1,2-dichlorobenzene. Formation of 24 is explicable in terms of its Claisen rearrangement of 21 followed a 5-
exo-trig cyclization of 25.
Scheme 5. Proposed mechanism for the transformation of 21 to 23.
In view of the problems with above Claisen rearrangement methodology, the synthesis of quinone 14 was
started from the known aldehyde 28.18 It was converted into quinone 14 in two steps. NaBH4 reduction of 28
gave alcohol 20 in 86% yield, which was oxidized with CAN to give 14 in 66% yield. It was then converted into
THP ether 29 by treatment with DHP in dry DCM in the presence of a catalytic amount of PPTS (Scheme 6).
O
O
O
O
DHP, cat. PPTS
dry DCM
CAN, CH3CN
H2O, rt, 12 h
NaBH4
MeOH-THF, rt
96%
CHO
66%
86%
O
O
OH
O
OH
O
OTHP
28
20
14
29
Scheme 6. Alternative synthesis of alcohol 20 and acceptor 29.
Both the quinones 14 and 29 were subjected to Hauser annulations with phthalide 3029. In the presence of
LiOBu-t, the annulation24 of 30 with 14 gave annulation product 31, but in only 10% yield. Assuming that the
free –OH in 14 interfered the annulation, we examined its protected form i.e. 29. Annulation of phthalide
sulfide 30 with 29 under similar conditions gave dihydroxyanthraquinone 32 in 68% yield. Deprotection of 32
with PPTS-MeOH provided alcohol 31 in 76% yield. PCC oxidation of 31 furnished aldehyde 33 in 69% yield.
This was then subjected to ICE under a variety of conditions. Gratifyingly, we obtained tetracycle 11 as the sole
product representing the core structure of idarubicinone (3) on treatment with SnCl4·5H2O. It was sufficiently
stable to be purified by chromatography on silica gel (Scheme 7).
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Scheme 7. Synthesis of the tetracycle core of idarubicinone (3).
In parallel with the synthesis of the tetracycle 11, we performed few exploratory studies designed for
functionalization of the A ring with model ene derivative 3418 obtained from our previous work. Its NMO-
mediated dihydroxylation afforded triol 35 in 64% yield along with diols 36 (15%). Trans stereochemistry of 35
was confirmed by analysis of coupling constants of C1 hydrogen and comparing them with those for similar
compounds.23 For 1,3-cis dihydroxy analogs, the corresponding coupling constants are less than 5 Hz. It is
noteworthy that the dihydroxylation produced only one diastereomer. Ozonolysis of the ene product 34
followed by treatment with triphenylphosphine did not furnish product 37. Instead, it produced aromatized
product β-naphthol (38). But, its silyl derivative 39, prepared by silylation with TBSCl/imidazole gave 40 in 65%
yield on ozonolysis. It is sufficiently stable for a chromatographic purification (Scheme 8).
Scheme 8. Model study for functionalization of tetralin skeleton of anthracyclines.
Conclusions
The modified Hauser annulation i.e. annulation of phenylthiophthalides with 1,4-quinones was combined with
aromatic carbonyl-ene reaction to pave a simple entry to tetracyclic core of anthracyclines. Noteworthy is the
fact that tetracycle 11 with free phenolic –OH group is not very sensitive to aromatization, and it should be
amenable to selective dihydroxylation.
Experimental Section
General. All reactions utilizing moisture-sensitive reagents were performed under an inert atmosphere. All
solvents namely DMF, DCM, THF, MeOH etc. were dried prior to use, according to the standard protocols.
Melting points were determined in open capillary tubes and are reported as uncorrected. TLC was carried out
on precoated plates (silica gel 60 F254), and the spots were visualized with UV and fluorescent lights. Column
chromatography was performed on silica gel (60–120 or 230–400 mesh). NMR spectra for all the compounds
were recorded at 200/400/600 and 50/100/150 MHz (Bruker AVANCE 200, Bruker UltrashieldTM 400, AscendTM
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600), respectively. IR spectra were recorded with a Perkin–Elmer FTIR instrument using a KBr pellet. HRMS
spectra were obtained on XEVO-G2QTOF machine. The phrase “usual work-up” or “worked up in the usual
manner” refers to washing of the organic phase with water (2 x 1/4 of the volume of the organic phase) and
brine (1 x 1/4 of the volume of the organic phase), drying (Na2SO4), filtration, and concentration under
reduced pressure.
Methyl 2-hydroxy-5-(2-methylallyloxy)benzoate (15). To a stirred solution of methyl 2,5-dihydroxybenzoate
(4 g, 23.8 mmol) in acetone (10 mL) potassium carbonate (3.2 g, 23.8 mmol) was added and stirred for 15 min.
To this mixture methylallyl bromide (3.6 mL, 35.7 mmol) was added and stirred for 2.5 h. After the completion
of the reaction, the mixture was concentrated under vacuum to remove excess acetone. The reaction mixture
was then diluted with water and extracted with ethyl acetate (2 × 100 mL). The combined extracts were
washed successively with water (50 mL), saturated aqueous solution of sodium thiosulfate (20 mL), brine (50
mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. Column chromatography of
1
the residue afforded ester 15 as oil (4.5 gm, 87%). Rf (1:5 EA(ethyl acetate)/hexane) 0.75; H NMR (400 MHz,
CDCl3): δ 10.38 (s, 1H), 7.31 (d, J 3.2 Hz, 1H), 7.11 (dd, J 3.2, 8.8 Hz, 1H), 6.91 (d, J 8.8 Hz, 1H), 5.09 (s, 1H), 4.99
13
(s, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 1.83 (s, 3H); C NMR (100 MHz, CDCl3): δ 170.3, 156.1, 151.1, 140.8, 124.7,
118.5, 113.3, 112.9, 11.9, 72.5, 52.4, 19.5; IR (KBr): ν̃
3220, 2954, 2362, 1683, 1488, 1218, 771 cm-1; HRMS
(ESI): m/z calculated for C11H11O3: requires: 191.0708 for [M-OMe]+; found: 191.0706.
Methyl 3,6-dihydroxy-2-(2-methylprop-2-enyl)benzoate (16). Compound 15 (4 g, 18.0 mmol) was dissolved in
DMF (7 mL) and heated at reflux for 10 h. After completion of the reaction the reaction mixture was diluted
with water (10 mL) and extracted with ethyl acetate (2 × 100 mL). The combined extracts were washed
successively with water (50 mL), brine (50 mL), dried (anhydrous Na2SO4), filtered and concentrated under
reduced pressure. Column chromatography of the residue afforded ester 16 as white solid but in impure form.
Since this compound was susceptible to aerial decomposition and could not be purified, it was directly
subjected to methylation. Rf (1:3 EA/hexane) 0.4; mp 80 °C; 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 7.01 (d,
J 8.8 Hz, 1H), 6.91 (d, J 8.8 Hz, 1H), 4.83 (s, 1H), 4.53 (s, 1H), 3.95 (s, 3H), 3.68 (s, 2H),1.82 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 171.3, 156.2, 147.6, 144.4, 126.3, 123.6, 116.8, 113.2, 110.6, 52.3, 36.1, 23.0; IR (KBr): ν̃ 3496,
2954, 1681, 1497, 1178, 1027, 890, 825 cm-1; HRMS (ESI): m/z calculated for C11H11O3: requires: 191.0708 for
[M – OMe] +; found: 191.0709.
Methyl 3,6-dimethoxy-2-(2-methylprop-2-enyl)benzoate (19). Dihydroxy compound 16 (0.67 g, 3.0 mmol)
was dissolved in dry acetone (20 mL) under N2-atmosphere. To this solution were added dry K2CO3 (2.1 g, 15
mmol) and Me2SO4 (0.57 mL, 6 mmol; freshly washed with cold water (10 mL), saturated NaHCO3 solution (15
mL), brine (15 mL) and dried over anhydrous K2CO3). After 2 h of reflux, on completion of the reaction, the
inorganic salts were filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate (15
mL), treated with Et3N (6 mmol) at room temperature and stirred for 30 min. The reaction mixture was then
diluted with ethyl acetate (50 mL), washed with water (15 mL) and 5% aq. HCl solution (15 mL) then subjected
to usual work-up (drying over anhydrous Na2SO4 and concentrating under reduced pressure) to obtain a crude
residue. The crude product was purified by column chromatography on silica gel to furnish pure oil 19 in 36%
1
yield over two steps. Rf (1:3 EA/hexane) 0.6; H NMR (400 MHz, CDCl3): δ 6.86 (d, J 8.8 Hz, 1H), 6.76 (d, J 8.8
Hz, 1H), 4.72 (s, 1H), 4.48 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.34 (s, 2H), 1.70 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 168.2, 151.8, 150.1, 143.7, 127.1, 125.4, 112.4, 110.7, 109.7, 56.3, 56.3, 52.0, 34.6, 22.6; IR
(KBr): ν
219.1021 for [M-OMe]+; found: 219.1016.
̃
2925, 1733, 1560, 1457, 1263, 1066, 773 cm-1; HRMS (ESI): m/z calculated for C13H15O3: requires:
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5,8-Dihydroxy-3,3-dimethylisochroman-1-one (17). Compound 17 was obtained along with 16 in 40% yield as
a white solid from 15 as described above. Rf (1:3 EA/hexane) 0.37; IR (KBr): ν̃ 3307, 2364, 1646, 1479, 1226,
1
1114, 883, 819, 686 cm-1; H NMR (400 MHz, CDCl3): δ 10.74 (s, 1H), 6.99 (d, J 8.8 Hz, 1H), 6.79 (d, J 8.8 Hz,
13
1H), 2.98 (s, 2H), 1.50 (s, 6H); C NMR (100 MHz, CDCl3): δ 169.5, 156.2, 144.4, 124.3, 123.4, 116.0, 107.9,
+
82.3, 32.9, 27.6, 27.6; HRMS (ESI): m/z calculated for C11H13O4: requires: 209.0814 for [M + H] ; found:
209.0812.
8-Hydroxy-3,3-dimethyl-1-oxoisochroman-5-yl acetate (18). Et3N (0.06 mL, 0.77 mmol) was added to a
solution of 17 (80 mg, 0.38 mmol) in dry CH2Cl2 (3 mL) and stirred for 10 min. Acetyl chloride (0.05 mL, 0.77
mmol) was drop-wise added to this mixture at 0 °C and allowed to stir for 2.5 h at room temperature. The
reaction was quenched with water (5 mL) and extracted with CH2Cl2 (50 mL). The combined extracts were
successively washed with water (10 mL), brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated
under reduced pressure. Column chromatography of the residue afforded 18 as a white solid (80 mg, 83%). Rf
(1:3 EA/hexane) 0.4; mp 92 °C; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 7.19 (d, J 8.8 Hz, 1H), 6.91 (d, J 8.8
13
Hz, 1H), 2.81 (s, 2H), 2.32 (s, 3H), 1.48 (s, 6H); C NMR (100 MHz, CDCl3): δ 169.1, 168.8, 160.0, 139.4, 130.2,
129.8, 116.7, 107.7, 82.0, 33.6, 27.3, 27.3, 20.6; IR (KBr): ν
cm-1.
̃ 3448, 2985, 1756, 1670, 1475, 1226, 1112, 902, 804
[3,6-Dimethoxy-2-(2-methylprop-2-enyl)phenyl]methanol (20).25 To a stirred solution of 19 (1.0 gm, 4 mmol)
in dry ether (7 mL) under nitrogen atmosphere, cooled to 0 °C, lithium aluminium hydride (380 mg, 10 mmol)
was added and stirred for 3 h at room temperature. After completion of the reaction, it was cooled and
quenched by dropwise addition of saturated sodium sulfate until a white precipitate separated. This was
filtered through celite and concentrated under reduced pressure. Column chromatography of the residue
1
afforded pure 20 (700 mg, 79%) as colorless liquid. Rf (1:1 EA/hexane) 0.5; H NMR (400 MHz, CDCl3): δ 6.81
(d, J 8.8 Hz, 1H), 6.76 (d, J 8.8 Hz, 1H), 4.74 (s, 1H), 4.65 (s, 2H), 4.33 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.46 (s,
2H), 1.81 (s, 3H).
4-Methoxy-3-(2-methallyloxy)benzaldehyde (21).26 To a stirred solution of isovanillin (8.8 g, 57.9 mmol) in dry
acetone (300 mL) was added solid K2CO3 (8.0 g, 57.9 mmol) at 0 °C followed by addition of methallyl bromide
(8.8 mL, 86.9 mmol). The reaction mixture was stirred for 24 h and filtered. The filtrate was concentrated and
extracted with ethyl acetate (250 mL). Organic layer was washed with H2O (3 x 100 mL) and brine (100 mL).
Combined organic layer was dried over Na2SO4 and evaporated under vacuum to afford the crude material. It
was purified by performing flash column chromatography on silica gel with 1:5 ethyl acetate/hexane solvent
to afford 21 (10.9 g, 52.7 mmol) in 91% yield. Yellow oil; 1H NMR (200 MHz, CDCl3) δ 9.75 (s, 1H), 7.41–7.32 (m,
13
2H), 6.91 (d, J 8.2 Hz, 1H), 5.06 (s, 1H), 4.94 (s, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 1.77 (s, 3H); C NMR (50 MHz,
CDCl3) δ 190.8 (CH), 154.9, 148.7, 140.1, 130.0, 126.7 (CH), 113.2 (CH2), 111.2, 110.8 (CH), 72.5 (CH2), 56.1
(CH3), 19.3 (CH3); IR (KBr): ν
642 cm-1.
̃ =3422, 2936, 1686, 1611, 1582, 1508, 1438, 1270, 1220, 1162, 1134, 1017, 905,
Compound 21 (1.1 g, 5.33 mmol) was dissolved in DMF (5 mL) or 1, 2-dichlorobenzene and heated to reflux at
250 °C. Expected product was not obtained. From 1, 2-dichlorobenzene, products were 22 (0.245 g, 1.3 mmol,
25%), 23 (0.200 g, 1.00 mmol, 19%). From DMF, yields were 22 (0.035 g, 0.19 mmol, 4%), 23 (0.070 g, 0.37
mmol, 7%), 24 (0.255 g, 1.24 mmol, 23%).
1
2-Methoxy-7-methylnaphthalen-1-ol (22). Yellow liquid; H NMR (200 MHz, CDCl3) δ 8.06 (d, J 0.6, 1H), 7.73
(d, J 8.4 Hz, 1H), 7.42 (d, J 9.0, 1H), 7.28 (d, d, J 8.4, 1.6 Hz, 1H), 7.21 (d, J 9.0 Hz, 1H), 6.24 (bs, 1H), 3.97 (s, 3H),
2.60 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 141.5, 139.3, 135.2, 128.1, 127.5 (CH), 126.8 (CH), 124.3, 120.1 (CH),
119.5 (CH), 112.4 (CH), 57.1 (CH3), 22.0 (CH3); IR (KBr): ν̃ 3422, 2927, 1741, 1608, 1459, 1275, 1220, 1051, 678
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cm-1. HRMS (ESI): m/z calculated for C12H12O2: requires: 187.0759 for [M-H]+, 188.0837 for [M], 189.0916
[M+H], 191.1072 [M+3H]; found: 187.0749, 188.0837, 189.0893, 191.1068.
2-Methoxy-7-methyl-7,8-dihydronaphthalen-1-ol (23). Yellow liquid; 1H NMR (200 MHz, CDCl3) δ 6.66 (d, J 8.0
Hz, 1H), 6.58 (d, J 8.0 Hz, 1H), 6.35 (dd, J 2.8, 9.6 Hz, 1H), 5.70 (s, 1H), 3.88 (s, 3H), 3.06–3.01 (m, 1H), 2.56-2.51
(m, 1H), 2.47–2.41 (m, 1H), 1.13 (d, J 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 146.1, 142.6, 133.2 (CH), 128.2,
126.5 (CH), 120.7, 117.5 (CH), 107.9 (CH), 56.2 (CH3), 28.6 (CH2), 28.4 (CH), 20.7 (CH3); IR (KBr): ν̃ 3454, 2956,
1636, 1491, 1275, 1079, 806, 772 cm-1; HRMS (ESI): m/z calculated for C12H14O2: requires: 191.1072 for
[M+H]+; found: 191.1085.
2-Methoxy-7-methyl-7,8-dihydro-naphthalen-1-yl acetate. 1H NMR (600 MHz, CDCl3) δ 6.88 (d, J 8.3 Hz, 1H),
6.73 (d, J 8.2 Hz, 1H), 6.35 (dd, J 2.2, 9.6 Hz, 1H), 5.75 (dd, J 3.3, 9.8 Hz, 1H), 3.81 (s, 3H), 2.77 (dd, J 6.6, 15.7
Hz, 1H), 2.51 (qd, J 3.4, 6.8 Hz, 1H), 2.35 (s, 4H), 1.09 (d, J 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.1,
150.6, 137.5, 133.1, 128.7, 127.8, 126.1, 123.9, 109.4, 56.1, 29.6, 28.3, 20.7, 20.5. IR (KBr): ν̃ 2921, 2851, 1764,
1463, 1275, 1219, 1191, 1077 cm-1. HRMS (ESI): m/z calculated for C14H16O3: requires: 233.1178 for [M+H]+;
found: 233.1193.
7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-4-carbaldehyde (24).27 1H NMR (200 MHz, CDCl3) δ 9.85 (s,
13
1H), 7.27 (d, J 8.4 Hz, 1H), 6.83 (d, J 8.4 Hz, 1H), 3.91 (s, 3H), 3.35 (s, 2H), 1.49 (s, 6H); C NMR (50 MHz,
CDCl3): δ 191.6 (CH), 149.5, 148.2, 128.6, 127.3 (CH), 126.9, 110.4 (CH), 89.3, 56.2 (CH3), 43.4 (CH2), 28.5 (2 x
CH3); IR (KBr): ν̃
2972, 1686, 1611, 1582, 1508, 1438, 1270, 1220, 1162, 1134, 1017, 905, 642 cm-1; HRMS (ESI):
m/z calculated for C12H14O3: requires: 207.1021 for [M+H]+; found: 207.1038.
[3,6-Dimethoxy-2-(2-methallyl)-phenyl]methanol (20).25 To a stirred solution of compound 28 (0.44 g, 2
mmol) in THF (10 mL) and MeOH (3 mL) at 0 °C was added NaBH4 (84 mg, 2.2 mmol) in portions. The resulting
mixture was stirred at rt for overnight. Then it was quenched with saturated NH4Cl (3 mL). Extraction of the
reaction mixture with EA (3 x 10 mL) followed by drying over Na2SO4 and removal of solvent gave a residue.
Flash column chromatography of the residue on silica gel with 1:2 EA/hexane solvent afforded product 20
(0.38 g, 1.72 mmol) as colorless liquid in 86% yield.
2-Hydroxymethyl-3-(2-methylprop-2-enyl)-1,4-benzoquinone (14). To a stirred solution of 20 (280 mg, 1.26
mmol) in acetonitrile (7 mL), solution of cerric ammonium nitrate (2.07 gm, 3.78 mmol) in water (7 mL) was
added drop-wise and stirred for 1 h. Then the reaction mixture was extracted with ethyl acetate (2 x 50 mL).
The combined extracts were washed successively with water (25 mL), brine (25 mL), dried (anhydrous Na2SO4),
filtered and concentrated under reduced pressure. Column chromatography of the residue afforded 14 (160
mg, 66%). Yellow solid; Rf (1:1 EA/hexane) 0.4; 1H NMR (400 MHz, CDCl3): δ 6.74 (d, J 10 Hz, 1H), 6.70 ( d, J 10
13
Hz, 1H), 4.73 (s, 1H), 4.47 (s, 2H), 4.45 (s, 1H), 3.21 (s, 2H), 2.46 (brs, 1H), 1.71 (s, 3H); C NMR (100 MHz,
CDCl3): δ 188.7, 187.0, 142.8, 142.2, 141.9, 136.8 (CH), 136.3 (CH), 111.9 (CH2), 57.4 (CH2), 32.7 (CH2), 23.2
(CH3); IR (KBr): ν̃
3448, 2933, 1654, 1297, 1018, 850 cm-1.
2-(2-Methylprop-2-enyl)-3-(tetrahydropyran-2-yloxymethyl)-1,4-benzoquinone (29). To a stirred solution of
14 (40 mg, 0.21 mmol) in dry dichloromethane (5 mL) were added dihydropyran (0.04 mL, 0.42 mmol) and a
catalytic amount of PPTS and stirred for 3 h. Then the reaction mixture was extracted with ethyl acetate (50
mL). The combined extracts were washed successively with water (10 mL), brine (10 mL), dried (anhydrous
Na2SO4), filtered and concentrated under reduced pressure. Column chromatography of the residue afforded
1
29 (55 mg, 96%). Yellow semisolid; Rf (1:3 EA/hexane) 0.65; H NMR (400 MHz, CDCl3): δ 6.78 (s, 2H), 4.79 (s,
1H), 4.60 (d, J 10.8 Hz, 1H), 4.52 (s, 1H), 4.33 (d, J 10.8 Hz, 1H), 3.87 (t, J 9.6 Hz, 1H), 3.40–3.60 (m, 2H), 3.34 (s,
2H), 1.80 (s, 3H), 1.40–1.79 (m, 6H); IR (KBr): ν̃
2942, 1656, 1440, 1297, 1120, 1025, 771 cm-1; HRMS (ESI): m/z
calculated for C16H20O4: requires: 175.0759 for [M-OTHP]+; found: 175.0761.
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1,4-Dihydroxy-2-(2-methylprop-2-enyl)-3-(tetrahydropyran-2-yloxymethyl) anthraquinone (32). A solution of
30 (242 mg, 1 mmol) in dry THF (5 mL) was added to suspension of LiOBu-t (240 mg, 3 mmol) in dry THF at -60
°C under an inert atmosphere. The resulting solution was stirred at -60 °C for 30 min after which a solution of
29 (331 mg, 1.2 mmol) in dry THF (5 mL) was added to it. The reaction was stirred for another 30 min at -60 °C
followed by 6-8 h at room temperature. The reaction was then quenched with saturated ammonium chloride
solution and THF was removed under reduced pressure. The residue was then extracted with ethyl acetate (3
x 20 mL). The combined extracts were washed with brine (3 x 1/3 vol), dried (Na2SO4) and concentrated to
provide crude product. The crude product was purified by column chromatography to furnish quinone 32. Red
1
solid; Rf (1:3 EA/hexane) 0.7; mp 125–127 °C; H NMR (400 MHz, CDCl3): δ 13.62 (s, 1H), 13. 50 (s, 1H), 8.34–
8.40 (m, 2H), 7.70–7.90 (m, 2H), 4.88 (d, J 10.8 Hz, 1H), 4.80 (s, 1H), 4.65 (d, J 10.8 Hz, 1H), 4.39 (s, 1H), 3.98 (t,
13
J 8.4 Hz, 1H), 3.67 (s, 2H), 3.50–3.65 (m, 2H), 1.89 (s, 3H), 1.50–1.83 (m, 6H); C NMR (100 MHz, CDCl3): δ
186.9, 186.5, 157.5, 156.8, 143.1, 142.2, 137.1, 134.3 (CH), 134.2 (CH), 133.6, 133.5, 126.9 (CH), 126.9 (CH),
111.8, 111.1, 110.9 (CH2), 98.9 (CH), 62.2 (CH2), 59.4 (CH2), 33.5 (CH2), 30.5 (CH2), 25.4 (CH2), 23.4 (CH3), 19.3
(CH2); IR (KBr): ν̃
2927, 2372, 1623, 1401, 1265, 1024, 773 cm-1. HRMS (ESI): m/z calculated for C24H24O6:
requires: 431.1471 for [M+Na]+, 409.1651 for [M+H], 391.1546 for [M-H2O+H]+, 325.1076 for [M-DHP+H]+,
307.0970 for [M-DHP-H2O+H]+; found: 431.1483, 409.1667, 391.1545, 325.1082, 307.0992.
1,4-Dihydroxy-2-hydroxymethyl-3-(2-methylprop-2-enyl)anthraquinone (31). To a stirred solution of 32 (100
mg, 0.25 mmol) in methanol (5 mL), a catalytic amount of PPTS was added and stirred for 1 h. Then the
reaction mixture was extracted with ethyl acetate (50 mL). The combined extracts were washed successively
with water (10 mL), brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced
pressure. Column chromatography of the residue afforded quinone 31 (60 mg, 76%). Red solid; mp 117–118
1
°C; Rf (1:3 EA/hexane) 0.6; H NMR (400 MHz, CDCl3): δ 13.68 (s, 1H), 13.51 (s, 1H), 8.35–8.40 (m, 2H), 7.90–
7.70 (m, 2H), 4.83 (s, 1H), 4.79 (s, 2H), 4.45 (s, 1H), 3.63 (s, 2H), 2.70 (brs, 1H), 1.88 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 186.9, 186.9, 157.0, 156.9, 143.7, 139.9, 139.6, 139.6, 134.6 (CH), 134.5 (CH), 133.6, 133.5, 127.2
(CH), 127.0 (CH), 111.5, 111.4 (CH2), 57.3 (CH2), 33.4 (CH2), 23.3 (CH3); IR (KBr): ν̃ 3426, 2923, 2370, 1587,
1401, 1263, 1020, 798 cm-1; HRMS (ESI): m/z calculated for C19H16O5: requires: 325.1076 for [M+H]+, 307.0970
for [M-H2O+H]+; found: 325.1082, 307.0956.
1,4-Dihydroxy-3-(2-methyl-allyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxaldehyde (33). PCC (213 mg,
0.99 mmol) was added to a stirred solution of 31 (108 mg, 0.33 mmol) in DCM (5 mL) and stirring was
continued for 3 h at rt. Solvent was evaporated and slurried with basic alumina. Column chromatography was
done with basic alumina and 1:20 ethyl acetate/haxane solvent. Compound 33 (73 mg, 0.23 mmol) was
1
obtained in 69% yield. Yellow solid; mp 100 °C; Rf (1:1 EA/hexane) 0.7; H NMR (400 MHz, CDCl3): δ 13.69 (s,
1H), 13. 27 (s, 1H), 10.68 (s, 1H), 8.41–8.30 (m, 2H), 7.90–7.86 (m, 2H), 4.75 (s, 1H), 4.33 (s, 1H), 3.88 (s, 2H),
13
1.90 (s, 3H). ); C NMR (100 MHz, CDCl3): δ 190.6 (CH), 186.7, 186.5, 159.3, 155.8, 143.7, 143.3, 134.9 (CH),
134.8 (CH), 133.0, 133.0, 131.0, 131.0, 127.3 (CH), 127.0 (CH), 112.0, 110.4 (CH2), 32.6 (CH2), 23.6 (CH3); IR
(KBr): ν̃
3375, 2372, 1585, 1218, 1052, 771 cm-1. HRMS (ESI): m/z calculated for C19H14O5: requires: 322.0841
for [M]+, 321.0763 for [M-H]+, 293.0814 for [M-HCHO+H]+; found: 322.0809, 321.0775, 293.0820.
6,7,11-Trihydroxy-9-methylene-7,8,9,10-tetrahydronaphthalene-5,12-dione (11). A stirred solution of 33
(0.145 g, 0.45 mmol) in dry DCM (4.5 mL) was treated with SnCl4·5H2O (0.079 g, 0.23 mmol) in stoppered
reaction flask. After completion of the reaction, as monitored by TLC, it was quenched with saturated solution
of sodium bicarbonate (2.5 mL/mmol). The reaction mixture was then extracted with DCM (3 x 5 mL). The
combined extracts were washed with brine (3 x 1/3 vol), dried (Na2SO4) and concentrated to provide crude
product. After flash column chromatography by silica gel with 1:2 ethyl acetate/hexane solvent compound 11
(0.129 g, 0.40 mmol) was obtained in 89% yield. Rf (1:1 EA/hexane) 0.65; 1H NMR (400 MHz, CDCl3): δ 13.72 (s,
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1H), 13.37 (s, 1H), 8.40–8.32 (m, 2H), 7.80–7.88 (m, 2H), 5.30 (brs, 1H), 5.16 (s, 1H), 5.12 (s, 1H), 3.63 (ABd, J
13
20.4, 2H), 3.52 (ABd, J 20.4 Hz, 2H), 2.91 (brs, 1H), 2.71 (d, J 4.4 Hz, 2H); C NMR (100 MHz, CDCl3): δ 186.8,
186.7, 156.6, 156.0, 138.8, 138.3, 137.7, 134.4 (CH), 134.4 (CH), 133.5, 133.4, 127.0 (CH), 127.0 (CH), 113.4
(CH2), 110.5, 63.8, 38.7, 32.1 (one quaternary carbon is missing); IR (KBr): ν̃ 3450, 2370, 1583, 1403, 1222,
1024 cm-1; HRMS (ESI): m/z calculated for C19H14O5: requires: 323.0920 for [M+H]+; found: 323.0925.
Dihydroxylation of 34. To a stirred solution of compound 34 (192 mg, 1.2 mmol) in THF (36 mL) and H2O (18
mL) were added OsO4 (2.4 mL 0.05 M solution in toluene, 0.12 mmol) and NMO (422 mg, 3.6 mmol). The
reaction vessel was wrapped by a black paper and stoppered well. Reaction mixture was stirred for 15 h at rt.
After the starting material disappeared, the reaction was quenched by adding sodium bisulfite. Then usual
work-up was done with ethyl acetate. Crude material was subjected to column chromatography packed with
basic alumina to give product 35 (149 mg, 0.77 mmol, 64%), 36 (35 mg, 0.18 mmol, 15%).
2,4-Dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl-oxonium (35). White solid; mp 98–100 °C; Rf (2:1
1
EA/hexane) 0.3; H NMR (400 MHz, CDCl3): δ 7.47 (d, J 7.2 Hz, 1H), 7.22–7.28 (m, 2H), 5.04 (t, J 5.4 Hz, 1H),
3.68 (d, J 11.2 Hz, 1H), 3.55 (d, J 11.2 Hz, 1H), 2.92 (d, J 16.8 Hz, 2H), 2.85 (d, J 16.8 Hz, 2H), 2.35 (bs, 2H), 2.21
(dd, J 5.2, 13.6 Hz, 1H), 2.05 (bs, 1H), 1.97 (dd , J 6.8, 13.6 Hz, 1H); 1H NMR (400 MHz, acetone-d6): δ 7.55 (d, J
7.2 Hz, 1H), 7.10–7.17 (m, 2H), 7.04 (d, J 7.6 Hz, 1H), 4.96 (d, J 3.6, 1H), 4.28 (s, 1H), 3.98 (bs, 1H), 3.59 (bs, 1H),
3.59 (s, 1H), 3.46 (s, 2H), 2.94 (s, 2H), 2.68 (d, J 16.8, 1H), 2.15–2.20 (m, 1H), 1.69–1.75 (m, 1H); 13C NMR (100
MHz, acetone-d6): δ 141.5, 135.6, 129.6 (CH), 127.5 (CH), 127.5 (CH), 126.5 (CH), 72.7, 71.2 (CH2), 67.2 (CH),
41.8 (CH2), 39.3 (CH2); IR (KBr): ν̃
3398, 2920, 1637, 1220, 1066 cm-1; HRMS (ESI): m/z calculated for C11H14O3:
requires: 129.0704 for [M-CH3OH-H2O2+H]+, 141.0704 for [M-3H2O+H]+, 159.0810 for [M-2H2O+H]+, 217.0841
for [M+Na]+; found: 129.733, 141.0746, 159.0839, 217.0913.
3-Hydroxy-3-hydroxymethyl-3,4-dihydro-2H-naphthalen-1-one (36). White solid; mp 43–45 °C; Rf (1:2
EA/hexane) 0.4; 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J 7.6 Hz, 1H), 7.52 (t, J 7.6 Hz, 1H), 7.34 (t, J 7.6 Hz), 7.28
(d, J 7.6 Hz, 1H), 3.61 (s, 2H), 3.18 (d, J 16.8 Hz, 1H), 3.12 (d, J 16.8 Hz, 1H), 2.86 (d, J 16.8 Hz, 1H), 2.75 (d, J
1
16.8 Hz, 1H), 2.54 (bs, 1H), 2.23 (bs, 1H); H NMR (400 MHz, acetone-d6): δ 7.90-7.92 (m, 1H), 7.50-7.54 (m,
1H), 7.29-7.32 (m, 2H), 4.18 (t, J 5.6 Hz), 3.87 (s, 1H), 3.54 (d, J 5.6 Hz, 2H), 3.32 (d, J 16.6 Hz, 1H), 2.98 (d, J
16.6 Hz, 1H), 2.84 (dd, J 2.0, 16.6 Hz, 1H), 2.64 (dd, J 2.0, 16.6 Hz, 1H); 13C NMR (100 MHz, acetone-d6): δ 197.4,
142.6, 134.3 (CH), 133.4, 130.8 (CH), 127.1 (CH), 126.8 (CH), 74.8, 70.2 (CH2), 48.1 (CH2), 39.0 (CH2); IR (KBr): ν
̃
3422, 2921, 1636, 1220 cm-1; HRMS (ESI): m/z calculated for C11H12O3: requires: 175.0759 for [M-H2O+H]+,
193.0865 for [M+H]+; found: 175.0786, 193.0891.
4-(tert-Butyl-dimethylsilanyloxy)-3,4-dihydro-1H-naphthalen-2-one (40).30 A stream of ozone was passed
through a stirred solution of 39 (550 mg, 2.0 mmol) in dry DCM (10 mL) at -78 °C until resulting solution
became blue-violet. The excess ozone was removed by passing a stream of oxygen followed by argon through
the solution. The resulting mixture was allowed to reach -50 °C and carefully quenched by addition of Ph3P
(630 mg, 2.4 mmol) in dry DCM (2.5 mL). After 24 h at rt the reaction mixture was concentrated and the
residue was subjected to chromatography on basic alumina and eluted with 1:30 ethyl acetate/hexane
1
solvent. Product 40 (359 mg, 1.3 mmol) was obtained in 65% yield. Yellow liquid; Rf (1:20 EA/hexane) 0.5; H
NMR (600 MHz, CDCl3) δ 7.38–7.33 (m, 1H), 7.30–7.26 (m, 2H), 7.18–7.12 (m, 1H), 5.06 (dd, J 3.8, 5.4 Hz, 1H),
3.77 (dd, 1H, J 1.0, 19.7 Hz), 3.51 (d, J 19.8 Hz, 1H), 2.75–2.63 (m, 2H), 0.86 (s, 9H), 0.13 (s, 3H), -0.05 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 208.6, 139.2, 133.1, 128.8 (CH), 128.4 (CH), 127.1 (CH), 126.5 (CH) , 70.0 (CH) ,
48.0 (CH2), 44.6 (CH2), 25.9 (3 x CH3), 18.3, -4.5 (CH3), -4.6 (CH3); IR (KBr): ν̃ 2930, 2857, 1702, 1256, 1219,
1081, 952, 836, 670 cm-1. HRMS (ESI): m/z calculated for C16H24O2Si: requires: 277.1624 for [M+H]+ ; found:
277.1636.
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Supplementary Materials
Analytical data (1H NMR, 13C NMR, single crystal X-ray diffraction) for all new compounds.
Acknowledgements
We gratefully acknowledge the Council of Scientific and Industrial Research (CSIR), New Delhi for financial
support, and the Department of Science and Technology, New Delhi for NMR instrumental facilities. S. B. and
S. R. thank CSIR for their research fellowships.
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