Towards the synthesis of chiral isochromanquinones. The use of Corey-Bakshi-Shibata reductions

Article abstract of DOI:10.1016/S0040-4039(02)00759-1

(1R,3R,4S)-3,4-Dihydro-4-hydroxy-6-methoxy-1,3-dimethylisochroman-5,8-dione has been synthesized in 65% ee from (1R,3R,4S)-5-benzyloxy-3,4-dihydro-4-hydroxy-6-methoxy-1,3-dimethylisochroman by catalytic hydrogenolysis followed by Fremy's salt oxidation of

Full text of DOI:10.1016/S0040-4039(02)00759-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4199–4201
Towards the synthesis of chiral isochromanquinones. The use of
Corey–Bakshi–Shibata reductions
Charles B. de Koning,a Robin G. F. Giles,b Ivan R. Greenc,* and Nazeem M. Jahedc
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, South Africa
bDepartment of Chemistry, Murdoch University, Murdoch, WA 6150, Australia
cDepartment of Chemistry, University of the Western Cape, Private Bag X17, Bellville 7530, South Africa
Received 7 February 2002; revised 9 April 2002; accepted 17 April 2002
Abstract—(1R,3R,4S)-3,4-Dihydro-4-hydroxy-6-methoxy-1,3-dimethylisochroman-5,8-dione has been synthesized in 65% ee from
(1R,3R,4S)-5-benzyloxy-3,4-dihydro-4-hydroxy-6-methoxy-1,3-dimethylisochroman by catalytic hydrogenolysis followed by Fre-
my’s salt oxidation of the derived phenol. The latter isochroman was synthesized from a mercury(II) mediated oxidative
cyclization of (R)-3-benzyloxy-4-methoxy-1-(1%-hydroxyethyl)-2-prop-1%-enylbenzene which in turn was obtained in 75% ee from
the chiral reduction of 1-acetyl-3-benzyloxy-4-methoxy-2-prop-1%-enylbenzene with borane–methylsulfide complex in the presence
of the Corey–Bakshi–Shibata catalyst. © 2002 Elsevier Science Ltd. All rights reserved.
Recently the synthesis of the chiral diol 1, characterized
as the more stable diacetate 2, has been described.1 This
was achieved employing titanium tetraisopropoxide and
ultrasonication on the phenolic aldehyde 3. By this
judicious choice of chelating metal ion used during the
ring closure, selective synthesis of chiral 4-hydroxy-
In this paper we wish to report our preliminary findings
on an alternative approach towards the synthesis of
chiral isochromanquinones in which the introduction of
the first stereogenic centre is generated by the use of the
Corey–Bakshi–Shibata (CBS) reduction.
isochromanquinone
4
was accomplished.2 Related
Allylation of the phenolic group of isovanillin followed
by pyrolysis at 180°C afforded phenol 6. This was
alkylated employing the appropriate alkyl halide in hot
(80°C) dimethylformamide containing potassium
carbonate to produce 7, 8 and 9 in yields of 77–
80%. Treatment of these aldehydes with methylmagne-
sium iodide followed by oxidation with manganese(IV)
oxide in boiling benzene gave the corresponding
ketones 10, 11 and 12 in yields of about 70% over two
steps.
methodology has resulted in the synthesis of bromo-
quinone 5 and its subsequent Diels–Alder reaction with
1-methoxy-1,3-trimethylsilyloxy-1,3-butadiene has pro-
vided an entry into the synthesis of chiral
naphthopyranquinones.3
OCH3
OCH3
O
O
OR
OR
OH
O
Initial attempts to reduce ketones 10, 11 and 12 using
borane dimethyl–sulfide complex and the Corey–Bak-
shi–Shibata catalysts4 under a variety of conditions
afforded the desired chiral alcohols in yields of only
7–8%. The major products isolated resulted from unde-
sired addition to the olefin and were similar to those
previously described by us.5 This was overcome by
conjugation of the olefinic bond of the allyl substituent
in these ketones using PdCl2(MeCN)2.6 Chiral reduc-
tion of these conjugated products as described above
afforded the (R)-alcohols 13, 14 and 15 in average
yields of 58% and with ee values of 74–75% (Scheme
1).7
1, R=H; 2, R=Ac
3
O
O
Br
O
O
O
OH
O
OH
4
5
Keywords: chiral reduction; mercury(II) mediated oxidative cyclisa-
tion; isochromanquinones.
* Corresponding author. Tel.: +27-21-959-2262; fax: +27-21-959-3055;
e-mail: igreen@uwc.ac.za
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00759-1

4200
C. B. de Koning et al. / Tetrahedron Letters 43 (2002) 4199–4201
On the other hand, treatment of the isopropoxy and
CHO
(ii), (iii)
H3CO
benzyloxy alcohols 14 and 15 with mercury(II) acetate
in the presence of oxygen10 afforded the two
diastereoisomeric pairs of the 4-hydroxy analogues 21
and 22 in yields of 40 and 63%, respectively.
O
H3CO
OR
OR
10, R=CH3; 11, R=iPr;
(i)
(i)
(i)
7, R=CH3
8, R=iPr
9, R=Bn
6 R=H
12, R=Bn.
(iv), (v)
H
O
O
H3CO
H3CO
OH
R
OR
OH
OR
OH
13, R=CH3; 14, R=iPr;
15, R=Bn.
H3CO
21b, R=iPr;
22b, R=Bn.
21a, R=iPr;
22a, R=Bn.
OR
O
O
Scheme 1. Reagents and conditions; (i) RBr, K2CO3, DMF,
80°C, 24 h, 77–80%; (ii) CH3MgI, Et2O, 25°C, 40 min,
80–93%; (iii) MnO2, benzene, reflux, 45 min, 57–60%; (iv)
PdCl2(CH3CN)2, CH2Cl2, 35°C, 72 h, 81–94%; (v)
BH3·(CH3)2S, THF, CBS catalyst, 25°C, 30 min, 55–61%,
74–75% ee.
O
23, R=H;
24, R=Ac.
H3CO
OR
Catalytic hydrogenolysis of the mixture 22a and 22b
using the same conditions as described for 18 afforded
the corresponding phenols which were oxidized with
Fremy’s salt to yield a stereoisomeric mixture from
which one optically enriched enantiomer, (1R,3R,4S)
23, was isolated in 26% yield. The quinone 23 was also
converted into its acetate 24. The ee value of 24 was
determined as 65% on the addition of 10 mol% of the
asymmetric lanthanide shift reagent Eu(hfc)3 and
Cyclisation of the chiral alcohols 13, 14 and 15 was
effected using a mercury(II) mediated protocol.8 In this
way isochromans 16, 17 and 18 were obtained as 1:1
separable mixtures of (1R,3S) and (1R,3R)
diastereoisomers in average yields of 60%. Catalytic
hydrogenolysis of the diastereoisomeric mixture of 18
over Pd/C in ethyl acetate containing a drop of concen-
trated HCl afforded the corresponding phenolic mix-
tures 19 in 97% yield.
1
observing separation of signals in the H NMR spec-
trum. In particular, the acetate signal at l 2.08 was
deshielded and split into two signals at l 2.86 and 2.79.
Oxidation of this mixture with Fremy’s salt9 afforded
the two chiral quinones 20a (26%) and 20b (28%) with
ee values of 70% (Scheme 2).
In summary, an alternative protocol is being developed
for the synthesis of chiral isochromanquinones making
use of the CBS reduction of an aromatic ketone func-
tional group. There are not many examples of CBS
reductions on systems containing ortho-substituents11
and this study represents the first example of ortho-
vinyl acetophenones undergoing partially enantioselec-
tive CBS reductions. Methods to improve both yields
and ee’s are currently under investigation.
O
O
H3CO
H3CO
OR
OR
16a, R=CH3; 17a, R=iPr; 16b, R=CH3; 17b, R=iPr;
18a, R=Bn.
For 18
18b, R=Bn.
For 18
(i)
(i)
Acknowledgements
O
This work was supported by the National Research
Foundation, Pretoria, The University of the Western
Cape and the University of the Witwatersrand.
O
H3CO
H3CO
19a
19b
OH
O
OH
O
(ii)
(ii)
References
O
O
1. Giles, R. G. F.; Joll, C. A. Tetrahedron Lett. 1995, 36,
1125.
2. Giles, R. G. F.; Joll, C. A. J. Chem. Soc., Perkin Trans.
H3CO
H3CO
20a
O
20b
O
1 1999, 3039.
3. Giles, R. G. F.; Green, I. R.; Oosthuizen, F. J.; Taylor,
C. P. Tetrahedron Lett. 2001, 42, 5753.
4. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986 and references cited therein.
Scheme 2. Reagents and conditions; (i) H2, Pd/C c. HCl (one
drop) EtOAc, 25°C, 15 h, 97% 19a and 19b; (ii) K(SO3)2NO,
methanol/phosphate buffer, 25°C, 15 h, 26% 20a, 28% 20b.

C. B. de Koning et al. / Tetrahedron Letters 43 (2002) 4199–4201
4201
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6. Giles, R. G. F.; Lee Son, V. R.; Sargent, M. V. Aust. J.
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7.32 (1H, d, J 8.4, H-6), and 7.38 (5H, m, Ph); lC (50
MHz, CDCl3) 19.2 (CH3CH[OH]), 24.4 (C-3%), 56.0
(OCH3), 66.5 (CH[OH]), 74.6 (CH2Ph), 111.1 (C-2%), 120.8
(C-6), 123.7 (C-5), 128.3 (3×ArC), 128.4 (2×ArC), 131.1
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and 152.1 (C-4).
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7. The CBS catalyst (0.1 ml, 0.05 mmol) in 0.5 M toluene
was introduced under nitrogen into an oven dried three
necked flask. The borane:dimethyl sulphide complex in
THF (0.33 ml, 0.33 mmol) was added dropwise to this
reagent, and the mixture stirred at 25°C for 5 min. The
ketone (3.31 mmol) in THF (2 ml) was then introduced
by syringe through one neck while additional
borane:dimethyl sulphide complex in THF (1.99 ml, 1.99
mmol) was added simultaneously by syringe through the
other neck over a period of 10 min. After stirring for an
additional 30 min, methanol (1 ml) was added and stir-
ring was continued for a further 10 min. The reaction
mixture was extracted with dichloromethane and the
residue purified by gravity silica gel column chromatogra-
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the desired products.
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reduced with CBS. (a) Schmalz, H.-G.; Hollander, J.;
Arnold, M.; Durner, G. Angew. Chem., Int. Ed. Eng.
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In this way alcohol 15 was obtained as a pale yellow oil,
(61%) with the following spectroscopic data. [h]D=
+21.9°, (c=0.755, CH2Cl2, 25°C), ee 74% (from euro-
pium shift reagent); wmax (film)/cm−1 3396 cm−1 (OH); lH
(200 MHz, CDCl3) 1.46 (3 H, d, J 6.2, CH3CH[OH], 1.89
(3H, dd, J 6.6 and 1.8, CHꢀCHCH3), 3.87 (3H, s, OCH3),
4.88 (2H, s, OCH2Ph), 5.11 (1H, q, J 6.2, CH3CH[OH]),