Access to orthogonal protected phenols - Synthesis of a silylated quinol

Article abstract of DOI:10.1515/znb-2003-0413

Herein we describe the synthesis of t-butyldimethylsilyl protected quinol (9), using an oxidation/reduction sequence to create the desired orthogonality. The title compound acts as a synthetic equivalent for a quinone, required in the total synthesis of E

Full text of DOI:10.1515/znb-2003-0413

Access to Orthogonal Protected Phenols – Synthesis of a Silylated Quinol
Shahzad A. Siddiqi and Thilo J. Heckrodt
Institut fu¨r Organische Chemie, Universita¨t Wien, Wa¨hringer Straße 38, A-1090 Wien, Austria
Reprint requests to Dipl.-Chem. Thilo J. Heckrodt. Fax +43 (1) 4277-9521.
E-mail: thilo.heckrodt@univie.ac.at
Z. Naturforsch. 58b, 328 – 331 (2003); received September 25, 2002
Herein we describe the synthesis of t-butyldimethylsilyl protected quinol (9), using an oxida-
tion/reduction sequence to create the desired orthogonality. The title compound acts as a synthetic
equivalent for a quinone, required in the total synthesis of Elisabethin A. It contains a masked quinone
and therefore is a suitable precursor for the quinone moiety of this diterpenoid.
Key words: Orthogonal Protected Phenols, Quinol, Total Synthesis, Elisabethin A
Introduction
In the course of studies towards the total synthesis of
Elisabethin A (1), it was necessary to elaborate a syn-
thetic strategy for a quinol which is protected orthogo-
nally to a methylether. Elisabethin A is a natural prod-
uct which was isolated from the Caribbean gorgonian
Pseudopterogorgia elisabethae (Octocorallia) [1]. Ma-
rine natural products are among the most promising
sources of new biologically active molecules. Cer-
tain diterpenoid secondary metabolites possess a broad
spectrum of biological activities. Elisabethin type nat-
ural products were found to have antitumor and anti-
tuberculosis activity [2]. Keeping in mind the biolog-
ically scope of Elisabethin A (1), we intended to syn-
thesise this molecule. The retrosynthetic disconnection
implies an intramolecular Diels-Alder reaction of an
(E,Z)-diene to a p-benzoquinone. A possible precursor
(compound 9) for this quinone moiety is described in
this report. It contains a masked quinone and a highly
reactive aldehyde function.
Elisabethin A (1)
ing phenol 5 with CAN in acetonitrile. Quinone 6
was reduced by sodium dithionite to produce hydro-
quinone 7 [5] in 85% yield. After several unsuccess-
ful attempts the twice o,p-activated position was regio
selectively formylated by refluxing compound 7 with
hexamethylene-tetra amine and acetic acid to yield 8
[6] in 40% crude yield. The free hydroxyl groups were
protected as silylethers to furnish the desired aldehyde
9 in 45% yield (Scheme 1).
Experimental Section
All moisture sensitive reactions were carried out under
Argon. Anhydrous solvents were obtained as follows: Et2O
distilled from LiAlH4; acetone, CH2Cl2 and DMF distilled
from P2O5. All other solvents were HPLC grade. Column
chromatography was performed with Merck silica gel (240 –
400 mesh). TLC was carried out with E. Merck silica gel 60-
F254 plates. NMR spectra were recorded on either Bruker
Avance DPX 250 MHz or Bruker Avance DRX 400 MHz.
All NMR spectra were measured in CDCl3 solutions and ref-
erenced to the residual CHCl3 signal (1H, δ = 7.26; 13C, δ =
77.0). Mass spectra were measured on a Micro Mass, Trio
200 Fisions Instrument. HRMS were taken with a Finnigan
MAT 8230 with a resolution of 10000.
Results and Discussion
The synthesis of masked quinol 9 started from
the commercially available 2,6-dimethoxy toluene (2)
which was acetylated using acetyl chloride and ti-
tanium chloride as Lewis acid to give a quantita-
tive yield of acetophenone 3 [3]. Bayer-Villiger ox-
idation of 3 with MCPBA gave the desired ester 4
[4] which was hydrolysed with aq. KOH to furnish
phenol 5 in 83% yield. The oxidation to the benzo-
quinone 6 [5] was achieved in 94% yield by treat-
c
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S. A. Siddiqi – T. J. Heckrodt · Synthesis of a Silylated Quinol
329
Scheme 1. Reagents and con-
ditions: a) TiCl4 (2.0 equiv),
AcCl (2.0 equiv), C6H6, 0 ◦C,
30 min, 100%; b) MCPBA (2.0
equiv), TsOH-H2O (0.03 equiv),
CH2Cl2, 16 h, rt, 85%; c) KOH
(2.0 equiv), MeOH/H2O, 3 h,
100 ◦C, 83%; d) CAN (2.5
equiv), CH3CN, H2O, 45 min, rt,
94%; e) Na2S2O3 (3.85 equiv),
Et2O, H2O, 30 min, rt, 85%; f)
hexamethylene-tetra◦amine (10.0
equiv), AcOH, 80 C, 30 min,
40%; g) TBSCl (6.0 equiv), im-
idazole (6.0 equiv), DMF, rt,
16 h, 45%. MCPBA = m-chloro-
perbenzoic acid, TsOH-H2O =
p-toluenesulphonic acid hydrate,
CAN = cerium ammonium ni-
trate.
1-(2,4-Dimetoxy-3-methyl-phenyl)-ethanone (3)
(23.0 g, 151 mmol) in benzene (100 ml) was transferred
dropwise into the flask under argon over a period of
15 min. Stirring was continued for half an hour. The so-
lution was quenched by the cautious addition of aq. HCl
(5%). Phases were separated and the H2O layer was ex-
tracted with ether (5 × 100 ml), dried over MgSO4 and
solvent was removed under reduced pressure. After purifi-
cation by column chromatography (hexane / EtOAc 8:2),
Titanium chloride (57.3 g, 302 mmol) and acetyl chlo-
ride (23.7 g, 302 mmol) was placed in a three necked
flask equipped with reflux condensor, mechanical stirrer
◦
and a dropping funnel and cooled to 0 C. After 15 min
this solution solidified and the colour changed from yel-
low to orange. A solution of 2,6-dimethoxy- toluene 2
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330
S. A. Siddiqi – T. J. Heckrodt · Synthesis of a Silylated Quinol
the product 3 was isolated in 100% (29.4 g) yield as a 8.9 Hz, 1 H, ArH), 5.63 (br s, 1 H, OH), 3.78 (s, 6 H, OMe),
brown oil.
Rf 0.53 (SiO2, hexane/EtOAc 6:4). 1H NMR (250 MHz,
2.19 (s, 3 H, ArMe). 13C NMR (62.9 MHz, CDCl3): δ =
151.8, 145.9, 142.8, 119.9, 111.7, 106.7, 60.7, 55.9, 9.2. MS
(EI, 70 eV): m/z = 168 (100) [M]+, 153 (83) [M-CH3]+, 125
(45), 65 (40), 53 (36). HRMS (20 ◦C, 70 eV): m/z = calcd for
C9H12O3, 168.0786; found, 168.0791.
CDCl3): δ = 7.54 (d, J = 8.7 Hz, 1 H, ArH), 6.59 (d,
J = 8.7 Hz, 1 H, ArH), 3.79 (s, 3 H, OMe), 3.67 (s, 3 H,
OMe), 2.54 (s, 3 H, COMe), 2.09 (s, 3 H, ArMe). 13C NMR
(62.9 MHz, CDCl3): δ = 198.4, 161.9, 159.1, 128.7, 119.9,
105.6, 61.5, 55.4, 29.9, 8.6. MS (EI, 70 eV): m/z = 194 (22)
[M]+, 178 (100) [M-CH3]+, 136 (12) [M- CH3-COCH3]+,
2-Methoxy-3-methyl-1,4-benzoquinon (6)
◦
To a solution of phenol 5 (20.0 g, 119 mmol) in CH3CN
(250 ml) was added under rapid stirring cerium ammonium
nitrate (163.3 g, 298 mmol) in H2O (325 ml) at r.t. over a
period of 10 min. Stirring was continued for 45 min then
the mixture was extracted with CH2Cl2 (5 × 250 ml). The
combined organic extracts were washed with H2O (250 ml),
10% NaHCO3 (2 × 250 ml), H2O (250 ml) and then brine
(250 ml). The organic layer was dried over MgSO4 and the
solvent was evaporated in vacuo. Quinone 6 was isolated as
a yellow oil (17.0 g, 94%).
91 (12). HRMS (20 C, 70eV): m/z = calcd for C11H14O3,
194.0943; found, 194.0937.
Acetic acid 2,4-dimethoxy-3-methyl-phenyl ester (4)
Acetophenone 3 (29.7 g, 153 mmol) was dissolved in
CH2Cl2 (100 ml) t◦ogether with p-toluensulfonic acid hy-
drate (1.50 g) at 0 C. m-Chloro-per-benzoic acid (68.6 g,
306 mmol) was added carefully under vigorous stirring over
◦
a period of about 1 h at 0 C. The colour of the solution
Rf 0.64 (SiO2, hexane/EtOAc 1:4). 1H NMR (250 MHz,
CDCl3): δ = 6.65 (d, J = 10.0 Hz, 1 H, ArH), 6.56 (d, J =
10.0 Hz, 1 H, ArH), 4.01 (s, 3 H, OMe), 1.94 (s, 3 H, ArMe).
13C NMR (100.6 MHz, CDCl3): δ = 187.7, 182.7, 155.2,
135.8, 134.3, 128.4, 60.3, 8.1. MS (EI, 70 eV): m/z = 152
(100) [M]+, 137 (7) [◦M-CH3]+, 122 (41), 109 (21), 84 (93),
66 (32). HRMS (50 C, 70 eV): m/z = calcd for C8H8O3,
152.0473; found 152.0477.
changed from yellow to orange. This mixture was stirred for
16 h at r.t., diluted with sat. NaHCO3 solution (100 ml) and
extracted with CH2Cl2 (4 × 100 ml). Solvents were evapo-
rated in vacuo from the organic layers and the solid residue
was shaken with sat. aq NaHCO3 solution (6 × 100 ml) to
remove the benzoic acid. After decanting, the residue was
dissolved in Et2O, passed through a plug of MgSO4, sol-
vents were evaporated and the crude product was further
purified by column chromatography (hexane/EtOAc 8:2) to
give 27.4 g (85%) of the desired ester 4.
Rf 0.53 (SiO2, hexane/EtOAc 6:4). 1H NMR (250 MHz,
CDCl3): δ = 6.86 (d, J = 8.9 Hz, 1 H, ArH), 6.59 (d, J =
8.9 Hz, 1 H, ArH), 3.80, 3.75 (2s, each 3 H, OMe), 2.32 (s,
3 H, COMe), 2.17 (s, 3 H, ArMe). 13C NMR (62.9 MHz,
CDCl3): δ = 169.5, 156.3, 150.4, 137.5, 121.0, 119.6, 105.5,
61.7, 55.6, 20.6, 9.0. MS (EI, 70 eV): m/z = 210 (12)
[M]+, 168 (100) [M-C2H2O]+, 153 (60), 125 (16). HRMS
(20 ◦C, 70 eV): m/z = calcd for C11H14O4, 210.0892; found,
210.0889.
2-Methoxy-3-methyl-benzene-1,4-diol (7)
To quinone 6 (17.0 g, 112 mmol) in Et2O (400 ml) was
added an aq solution of sodium dithionite (74.9 g, 430 mmol)
in H2O (350 ml) under rapid stirring in two portions. Af-
ter 30 min of stirring the two layers were separated and the
organic phase was dried over MgSO4. After evaporation of
solvents the desired hydroquinone 7 was obtained in 85%
(14.7 g) yield.
Rf 0.38 (SiO2, hexane/ EtOAc 3:2). 1H NMR (250 MHz,
CDCl3): δ = 6.66 (d, J = 8.7 Hz, 1 H, ArH), 6.64 (d, J =
8.7 Hz, 1 H, ArH), 5.24 (s, 1 H, OH), 4.50 (s, 1 H, OH), 3.77
(s, 3 H, OMe), 2.19 (s, 3 H, ArMe). 13C NMR (62.9 MHz,
CDCl3): δ = 147.6, 145.8, 142.7, 112.4, 112.4, 110.9, 60.8,
9.2. MS (EI, 70 eV): m/z = 154 (100) [M]+, 139 (83)
[M-CH3]+, 111 (53), 57 (47). HRMS (50 ◦C, 70 eV): m/z =
calcd for C8H10O3, 154.0630; found, 154.0624.
2,4-Dimethoxy-3-methyl phenol (5)
To a solution of ester 4 (27.3 g, 130 mmol) in MeOH
(100 ml) was added KOH (14.9 g, 260 mmol), dissolved
in a mixture of MeOH/ H2O at◦r.t. The solution was stirred
at r.t. for 30 min, heated at 50 C for 1 h and then refluxed
for 3 h. After the addition of H2O (200 ml), the solution was
acidified with aq HCl (15%), washed with brine (150 ml), ex-
tracted with Et2O (7 × 150 ml), dried over MgSO4 and liber-
ated from solvents in vacuo to give a brown crude oil. Purifi-
cation by column chromatography (hexane/EtOAc 19:1) fur-
nished the desired phenol 5 as a yellow oil in 83 % (18.2 g)
yield.
2,5-Dihydroxy-4-methoxy-3-methyl-benzaldehyde (8)
A solution of hydroquinone 7 (14.5 g, 94.1 mmol) and
hexamethylene- tetra amine (132 g, 940 mmol) in acetic acid
(600 ml) was heated at 80 ◦Cfor 30 min. The reaction mixture
was diluted with H2O (500 ml) and extracted with CH3Cl
Rf 0.55 (SiO2, hexane/EtOAc 8:2). 1H NMR (250 MHz, (4 × 300 ml). The combined extracts were washed with sat.
CDCl3): δ = 6.53 (d, J = 8.9 Hz, 1 H, ArH), 6.76 (d, J = NaHCO3 (400 ml). The organic phase was dried over MgSO4
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S. A. Siddiqi – T. J. Heckrodt · Synthesis of a Silylated Quinol
331
and solvents were evaporated in vacuo to give desired alde- 20 ml). Further purification by column chromatography (hex-
hyde 8 in 40% (6.85 g) crude yield.
ane/EtOAc 19:1) over silica gel furnished the title compound
9 in 45% (3.0 g) yield.
Rf 0.32 (SiO2, hexane/ EtOAc 3:1). 1H NMR (250 MHz,
CDCl3): δ = 9.70 (s, 1 H, CHO), 6.94 (s, 1 H, ArH), 5.79 (s,
1 H, OH), 3.86 (s, 3 H, OMe), 2.19 (s, 3 H, ArMe). MS (EI,
70 eV): m/z = 182 (100) [M]+, 167 (19) [M-CH3]+, 153 (7),
Rf 0.82 (SiO2, hexane/ EtOAc 8:2). 1H NMR (250 MHz,
CDCl3): δ = 10.18 (s, 1 H, CHO), 7.15 (s, 1 H, ArH),
3.82 (s, 3 H, OMe), 2.13 (s, 3 H, ArMe), 1.00, 1.05 (2s,
each 9 H, SiCMe3), 0.19, 0.14 (2s, each 6 H, SiMe2).
13C NMR (62.9 MHz, CDCl3): δ = 188.2, 155.9, 151.9,
143.5, 124.3, 123.5, 115.5, 59.3, 25.4, 18.3, 10.1, −4.2,
−4.0. MS (EI, 70 eV): m/z = 395 (3) [M-CH3]+, 353 (100)
[C17H29O4Si2]+, 281 (16), 224 (9). HRMS (80 ◦C, 70 eV):
m/z = calcd for C21H38O4Si2 —CH3, 395.2074; found,
395.2081.
◦
83 (53). HRMS (50 C, 70 eV): m/z = calcd for C8H10O4,
182.0579; found, 182.0577.
2,5-Bis-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-3-
methyl- benzaldehyde (9)
To a solution of crude aldehyde 8 (3.00 g, 16.0 mmol)
in dry DMF (20.0 ml) was added imidazole (7.00 g,
96.0 mmol) under constant stirring at r.t.. Then TBSCl
(14.5 g, 96.0 mmol) was added to the reaction mixture at
Acknowledgement
The authors would like to thank Prof. Dr. Johann Mulzer,
Institut fu¨r Organische Chemie, Universita¨t Wien, Austria for
providing facilities and helpful discussion. Financial support
by the Fonds der chemischen Industrie is gratefully acknow-
eledged (Kekule´-Fellowship for T. J. H.).
◦
0 C. The ice bath was removed and stirring was contin-
ued for 16 h at r.t.. The reaction mixture was diluted with
cold H2O (50 ml) and extracted with toluene (6 × 25 ml).
The combined toluene layers were washed with H2O (3 ×
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