A new strategy for the synthesis of 4,6-di-tert-butyl-2,2-dipentyl-2,3- dihydro-5-benzofuranol (BO-653), a potent antiatherogenic antioxidant

Article abstract of DOI:10.1016/j.tetlet.2010.07.035

An efficient alternative route to 4,6-di-tert-butyl-2,2-dipentyl-2,3- dihydro-5-benzofuranol (BO-653), a potent antiatherogenic antioxidant, has been developed by the application of the base-promoted dienone- phenol rearrangement reaction. A decisive effect of MgBr2 in the reaction of Grignard reagents is also described.

Full text of DOI:10.1016/j.tetlet.2010.07.035

Tetrahedron Letters 51 (2010) 4950–4952
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A new strategy for the synthesis
of 4,6-di-tert-butyl-2,2-dipentyl-2,3-dihydro-5-benzofuranol (BO-653),
a potent antiatherogenic antioxidant
*
Masatoshi Murakata , Masahiro Kimura
API Process Development Department, Chugai Pharmaceutical Co., Ltd, 5-5-1 Ukima, Kita-Ku, Tokyo 115-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient alternative route to 4,6-di-tert-butyl-2,2-dipentyl-2,3-dihydro-5-benzofuranol (BO-653), a
potent antiatherogenic antioxidant, has been developed by the application of the base-promoted die-
none-phenol rearrangement reaction. A decisive effect of MgBr2 in the reaction of Grignard reagents is
also described.
Received 26 May 2010
Revised 28 June 2010
Accepted 7 July 2010
Available online 18 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
4,6-Di-tert-butyl-2,2-dipentyl-2,3-dihydro-5-benzofuranol (BO-653)
1 is found to be the most promising candidate as an antiatherogen-
ic antioxidant among a series of 4,6-di-tert-butyl-2,3-dihydro-5-
benzofuran derivatives which were designed and synthesized in
Chugai Pharmaceutical (Fig. 1).1 It has been reported that this com-
pound 1 shows radical scavenging activities against lipid peroxida-
tion and the inhibitory action on LDL oxidation.1b,c The mobility of
kyl group to furnish excellently the phenol (hydroquinone) 7 upon
exposure to potassium tert-buthoxide in DMF. We thought that
this without employing acidic conditions indicates a facile acquisi-
tion of our target molecule provided an appropriately functional-
ized hydroxyl-dienone precursor could be prepared (Scheme 2).2
the LDL incubated with 1 lM of this compound 1 in the case of
CuSO4 oxidation is similar to that of native LDL. However, the syn-
thesis of 1 we previously established required nine steps of reac-
tions to attain 10% overall yield which is far less than satisfactory
for its practical production (Scheme 1).1a
As outlined in Scheme 1, although the synthesis allowed using
an inexpensive readily accessible starting material 2 already carry-
ing the requisite two tert-butyl substituents, it required rather te-
dious and extra steps including protection–deprotection steps for
the installation of the 2,2-gem-substituted dihydrobenzofuran
moiety of the target molecule. Namely, it necessitates a sequence
of six steps of reactions to introduce the 3-formyl group to give 3
which further requires three steps including the acidic conditions
often inducing rearrangement and removal of the tertiary butyl
group to reach the final product 1 in 10% overall yield from the
starting material 2 (Scheme 1).
Figure 1. The structure of BO-653.
We, therefore, turned our attention to the way of more efficient
and shorter construction of the dihydrofuran moiety on the aro-
matic ring carrying the requisite functionalities without employing
strong acidic conditions. To this end, a base-induced dienone-phe-
nol type rearrangement reported by Nishinaga et al. in 1976
seemed to be the most promising. As appeared it was reported that
the hydroxy-dienone (quinol) 6, generated from the phenol 5 by
oxidation (O2, KOH), brought about the selective 1,2-shift of an al-
Scheme 1. Reagents: (a) H2SO4, Ac2O; (b) TMSI, CH2Cl2; (c) HOCH2NHCOCH2Cl,
H2SO4, Ac2O; (d) c-HCl, EtOH; (e) hexamethylenetetramine, AcOH, H2O; (f) HCl (aq);
(g) (Pen)2CHMgBr; (h) BF3OEt2, CH2Cl2; (i) LiAlH4, THF.
* Corresponding author. Tel.: +81 3 3968 4836; fax: +81 3 3968 8340.
E-mail address: murakatamst@chugai-pharm.co.jp (M. Murakata).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.035

M. Murakata, M. Kimura / Tetrahedron Letters 51 (2010) 4950–4952
4951
Table 1
Additions of Grignard reagents to dienone-ester 9a
Entry
Reagent
Temp. (°C)
Yieldb (%)
Conversionc (%)
1
2
3
4
5
6
Bu2Mg
PenMgBr
PenMgBr
PenMgBr–MgBr2
PenMgBr–MgBr2
PenMgBr–MgBr2
À25
À78 to rt
À25
À20
À50
0
Trace
35
46
81
88
55
86
78
99
97
99
62
a
b
c
All reactions were carried out with 3 equiv of reagents in Et2O for 18 h.
Determined by crude NMR spectra with anthracene as an internal standard.
Conversion: ratio of target material to starting material.
To visualize our intention of developing a new synthesis of BO-
653 1 by application of ‘the dienone-phenol rearrangement’ reac-
tion, the benzoquinone 8, bearing two tert-butyl groups and avail-
able in bulk, was chosen for the starting material. Thus, 8 was
treated with the lithium enolate generated in situ by treating
methyl acetate with lithium hexamethyldisilazide (LiHMDS) in
THF at À78 °C to yield regioselectively the dienone-ester 9 in an
excellent yield producing neither regioisomer nor double-addition
product.3 The gem-pentyl group was installed at this stage to yield
the bis-tertiary alcohol 10 (Scheme 3).
Scheme 2. Base-induced dienone-phenol type rearrangement.
At first, the ester 9 was treated with 3 equiv of pentylmagnesium
bromide in ether. The expected reaction occurred both at À78 and
À25 °C to give the desired dienone 10 both in moderate yields, both
accompaniedby a complex mixture of unidentifiedby-products, and
the starting material 9 (entries 2 and 3). Under these conditions, the
dienone carbonyl group of 9 was found to be intact presumably due
to the interference of the adjacent two tertiary butyl groups.4 Since it
is knownthata Grignardreagentisin a Schlenkequilibriumbetween
diorganomagnesium and MgBr2,5 we next examined the reaction in
thepresenceof thesameequivalentofMgBr2 totheGrignardreagent
as the additive so as to shift the equilibrium to the Grignard reagent
side. In precedence to the addition experiment, we treated the ester
9 with dibutylmagnesium at À25 °C in ether in order to confirm the
effect of the additive.6 Virtually, no desired reaction occurred to give
a trace of the target product after consumption of half of the starting
material (entry 1). In contrast, when MgBr2 was present, the desired
reaction readily occurred to give the tertiary alcohol 10, in yields of
81% at À20 °C and 88% at À50 °C, respectively, without the genera-
Scheme 3. Synthesis of bis-tertiary alcohol 10.
Scheme 4. Formation of BO-653 (1) by a base-promoted dienone-phenol rearrangement reaction followed by an acid-treatment.

4952
M. Murakata, M. Kimura / Tetrahedron Letters 51 (2010) 4950–4952
Komuro, E.; Kato, Y.; Tamura, K.; Cynshi, O.; Kodama, T.; Niki, E. Arch. Biochem.
Biophys. 1997, 342, 236; (c) Noguchi, N.; Okimoto, Y.; Tsuchiya, J.; Cynshi, O.;
Kodama, T.; Niki, E. Arch. Biochem. Biophys. 1997, 347, 141.
tion ofa substantialamount oftheby-product mixture(entries4 and
5).7 However, the yield of 10 was diminished considerably when the
reaction was carried out at 0 °C (Table 1, entry 6).8,9
2. (a) Nishinaga, A.; Itahara, T.; Matsuura, T.; Berger, S.; Henes, G.; Rieker, A. Chem.
Ber. 1976, 109, 1530; rearrangement of quinol catalysed by bases or acids has
reported, see: (b) Abe, Y. Bull. Chem. Soc. Jpn. 1943, 18, 93; (c) Although this type
of rearrangement in the present paper should be called ‘quinol-hydroquinone
rearrangement’, we use the term ‘dienone-phenol rearrangement’ as a well-
known expression.
Having establishedthe reaction conditions suitable for the gener-
ation of the desired dienone intermediate 10, its rearrangement to
the penultimate hydroquinone 13 was then examined under basic
conditions. Upon exposure of 10 to 3 equiv of potassium tert-butox-
ide in DMF at room temperature, the expected ‘dienone-phenol rear-
rangement’ did really occur to furnish the hydroquinone 13,10 which
was immediately treated with methanesulfonic acid to yield the tar-
get molecule, BO-653 1, directly, in 65% yield, with neither initiation
of rearrangement nor removal of tertiary butyl moiety.11 Although
the exact mechanism for the generation of the hydrofuran moiety
of 1 from the hydroquinone intermediate 13 is not clear, it is pre-
sumed to take place only under acidic conditions through either a
substitution pathway (via 13) or an addition–elimination pathway
(via 13–11–12)10a as 1 was not detected under the basic conditions
initiating the rearrangement. Overall yield of 1 from the starting
benzoquinone 8 was 53% in four steps without including any se-
quence of the protection–deprotection steps (Scheme 4).
In conclusion, we have established an alternative procedure
capable of producing 4,6-di-tert-butyl-2,2-dipentyl-2,3-dihydro-5-
benzofuranol (BO-653) 1, a potent antiathrogenic antioxidant, in
53% overall yield starting from a readily accessible starting material
8 through a sequence of four steps of reactions by the application of
the base-promoted dienone-phenol rearrangement reaction in the
key step.
3. Compound 9: 1H NMR (CDCl3) d 1.22 (18H, s), 2.63 (2H,s), 3.58 (1H, s), 3.72 (3H,
s), 6.61 (2H, s).
4. Precedents of the reactions between benzoquinones and nucleophiles. For ester
enolates, see: (a) Fischer, A.; Henderson, G. N. Tetrahedron Lett. 1983, 24, 131.
and references cited therein; For alkyllithiums and alkylmagnesium bromides,
see: (b) Liotta, D.; Saindane, M.; Barnum, C. J. Org. Chem. 1981, 46, 3369. and
references cited therein.
5. (a) Schlenk, W.; Schlenk, W., Jr. Chem. Ber. 1929, 62, 920; (b) Wakefield, B. J.
Organomagnesium Methods in Organic Synthesis; Academic Press: London, 1995;
(c)Grignard Reagents New Developments; Richey, H. G., Jr., Ed.; Wiley: New York,
2000.
6. Bu2Mg in place of Pen2Mg was used for the preliminary examination because of
commercial availability.
7. General procedure is as follows: Under an argon atmosphere, to a suspension of
Mg (10.71 mmol) in Et2O (10 mL) under vigorous stirring was added dropwise
1,2-dibromoethane (10.71 mmol) keeping a gentle reflux and the stirring was
continued at rt for 1.5 h. To the resulting suspension was added a solution of
PenMgBr in Et2O (4.31 mL, 8.62 mmol) at rt. The resulting clear solution was
added dropwise to
a solution of the ester 9 in Et2O (2.85 mmol) at the
temperature described in Table 1, and the stirring was continued for 18 h at the
same temperature described. After the addition of aqueous NH4Cl, the mixture
was extracted with Et2O. The organic extract was washed with saturated
aqueous NaCl, and dried over MgSO4. Compound 10: 1H NMR (CDCl3) d 0.89
(6H, t, J = 6.8 Hz), 1.10–1.60 (16H, m), 1.23 (18H, s), 1.79 (2H, s), 4.34 (1H, s),
6.75 (2H, s). The conversions were estimated through the ratio of the
integration of an olefinic proton in starting material 9 [d 6.61 (2H, s)] and an
olefinic proton in target material 10 [d 6.75 (2H, s)]. The yields were
determined with anthracene as an internal standard.
Acknowledgments
8. Representative examples regarding the use of MgBr2, see: (a) Swain, C. G.;
Boyles, H. B. J. Am. Chem. Soc. 1951, 73, 870; (b) Wotiz, J. H.; Hollingsworth, C.
A.; Dessy, R. E. J. Org. Chem. 1956, 21, 1063; (c) Holm, T. Acta Chem. Scand. 1967,
21, 2753; (d) Ashby, E. C.; Chao, L.-C.; Neumann, H. M. J. Am. Chem. Soc. 1973,
95, 4896; (e) Yamazaki, S.; Yamabe, S. J. Org. Chem. 2002, 67, 9346. and
references cited therein; for MgCl2: e.g. (f) Sobota, P.; Duda, B. J. Organomet.
Chem. 1987, 332, 239; Concentration and solvents used have also influence on
Schlenk equilibrium, see: (g) Smith, M. B.; Becker, W. E. Tetrahedron 1966, 22,
3027.
M.M. thanks Dr. Kunio Ogasawara, Professor Emeritus, Tohoku
University, for helpful suggestions for this study and preparation
of the manuscript. Thanks are also due to Dr. Masahiro Kato, Dep-
uty Department Manager of API Process Development Department,
Mr. Toshiro Kozono, Department Manager of API Process Develop-
ment Department, and Dr. Hidetoshi Ushio, General Manager of
Pharmaceutical Technology Division of Chugai Pharmaceutical
Co., Ltd, for their support of this work.
9. MgBr2 in Et2O was a suspension, however, it became a clear solution as
PenMgBr was added indicating that a mixed aggregation of PenMgBr–MgBr2
would take place in Et2O.
10. The structure of compound 13 was deduced from a 1H NMR analysis of its
crude product: 1H NMR (CDCl3) d 0.87 (6H, t, J = 6.5 Hz), 1.2–1.5 (16H, m), 1.42
(s, 9H), 1.57 (s, 9H), 3.3(2H, s), 4.8(OH, 1H, s), 6.82 (1H, s).
References and notes
11. Related cyclization of hydroquinone or its keto tautomer, see: (a) Cohen, N.;
Lopresti, R. J.; Neukom, C. J. Org. Chem. 1981, 46, 2445; (b) The reaction could
proceed under aqueous acidic conditions (e.g., a solution of citric acid) to give
the desired product though capriciously perhaps due to bi-phase reactions.
1. (a) Tamura, K.; Kato, Y.; Ishikawa, A.; Kato, Y.; Himori, M.; Yoshida, M.;
Takashima, Y.; Suzuki, T.; Kawabe, Y.; Cynshi, O.; Kodama, T.; Niki, E.; Shimizu,
M. J. Med. Chem. 2003, 46, 3083; (b) Noguchi, N.; Iwaki, Y.; Takahashi, M.;