A further improved synthesis of a dibenzodioxocinone CETP inhibitor

Article abstract of DOI:10.1055/s-0029-1217757

A newly improved synthesis of a dibenzodioxocinone CETP inhibitor is described. Key features of the synthetic route include a chiral ligand induced alkyl addition to aldehyde and the use of triethylborane for improved selective alkylation of brominated ph

Full text of DOI:10.1055/s-0029-1217757

2688
LETTER
A Further Improved Synthesis of a Dibenzodioxocinone CETP Inhibitor
D
ibenzodioxoci
h
none Synthe
i
sis -Hua Sun,*a,b Guo-Qiang Lin,b Erkang Fan*a
a
Department of Biochemistry, University of Washington, Seattle, WA 98155, USA
Fax +1(206)6857002; E-mail: erkang@u.washington.edu; E-mail: sungaris@gmail.com
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, P. R. of China
b
Received 27 April 2009
duction of the chiral functional group and borane-based
alkylation to reach an overall yield of 4.5%.
Abstract: A newly improved synthesis of a dibenzodioxocinone
CETP inhibitor is described. Key features of the synthetic route in-
clude a chiral ligand induced alkyl addition to aldehyde and the use
of triethylborane for improved selective alkylation of brominated
phenyl ring.
The overall synthetic route is described in Scheme 1.
Starting from 2, aldehyde 3 can be obtained in seven steps
with an overall yield of 24.2%, following the procedures
described before.8,9 Of these seven steps, the first three
steps to arrive at 3-benzyloxy-5-methylsalicylic acid are
identical to the original route developed by Bayer Health-
Care AG.8 However, in our hand, we performed the reac-
tions at kg scale and achieved a combined yield of 61.3%
as compared to a 18.3% yield at gram scale reported in the
original patent.8 The desired chlorine atom was intro-
duced during this stage,9 marking a difference between
our work and the original route.
Key words: total synthesis, asymmetric synthesis, natural prod-
ucts, inhibitors, drugs
The natural product penicillide {11-hydroxy-3-[(1S)-1-
hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-di-
benzo[b,g][1,5]dioxocin-5-one, Figure 1} is a dibenzo-
dioxocinone first reported by Sassa et al.1 Derivatives of
penicillide were reported to have a variety of biological
activities including lipid lowering,2 ACAT inhibition,3
oxytocin antagonism,4 and antihypertensive potential.5
Recently, certain derivatives of dibenzodioxocinone were
found to be a new class of CETP (cholesterol ester transfer
protein) inhibitors.6 Inhibition of CETP can lead to an in-
creased level of high-density lipoprotein cholesterol
(HDL-C) and is an alternative way to prevent coronary
heart disease as opposed to lowering the level of low-
density lipoprotein cholesterol (LDL-C).7 In particular,
compound 1 was reported to be a promising candidate for
in vivo study with an IC50 of 15 nM toward CETP inhibi-
tion and long plasma stability.6
In our previous work, alkyl addition to aldehyde 3 was
carried out in a racemic manner. As a consequence, chiral
separation of intermediate enantiomers is required at
Table 1 Chiral Amino Alcohol Induced Asymmetric Addition
Amino alcohol 4
Isolated yield of 5 (%)
ee (%)
NMe2
64
92
OH
4a
NMe2
66
86
OH
O
O
OH
O
4b
OH
O
O
NMe2
Cl
O
O
O
O
60
58
>99
95
OH
O
4c
Ph
OH
HO
N
H
penicillide
1
Ph
4d
Figure 1
Ph
OH
The original synthesis of 1 was a 17-step protocol with an
overall yield of 0.1%, starting from 5-methylsalicylic
acid.8 We previously developed an 15-step route with a
much better overall yield of 1.6%.9 In this work, we report
a further improved procedure that combines early intro-
N
Ph
50
46
96
82
Ph
4e
OH
Ph
N
SYNLETT 2009, No. 16, pp 2688–2690
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1217757; Art ID: S04209ST
© Georg Thieme Verlag Stuttgart · New York
Ph
4f

LETTER
Dibenzodioxocinone Synthesis
2689
OH
O
O
O
O
O
O
O
O
OH
O
O
H
O
chiral amino
alcohol 4c
O
7 steps
TsOH
HO
O
O
Cl
O
O
Cl
i-PrOH, H2O
Zn
5, 60% >99% ee
2
3, overall 24.2%
OH
O
O
OH
O
O
I–
OH
O
O
O
OH
Cl
OH OH
N+
Cl
O
O
O
O
Cl
KOH
H2, Pd/C
O
O
Cl
MeOH
Et3N
EtOAc, EtOH
O
6, 75%
7, 95%
8, 80%
O
Cl
OH
O
O
O
O
OH
O
O
O
OH
O
O
CsOAc, Et3B
Pd(dppf)Cl2
NBS
Cl
O
O
1
NaH
99.6%
Cl
O
Cl
9, 95%
HO
10, 88%
HO
HO
11, 65%
overall 4.5%
Br
Scheme 1 Improved synthetic route for compound 1
some stage before reaching the final product 1. This draw- lized the Stille coupling13 with a 22% yield.8 The forma-
back not only wastes starting material and lowers the tion of the target compound 1 was finally achieved after a
overall yield, but also makes it much harder to adapt the 99.6% acylation step.
procedure for potential large-scale production. Therefore,
we decided to explore asymmetric alkyl addition condi-
tions in hope to discover protocols that can produce the
desired S-enantiomer in high yield and avoid chiral sepa-
In summary, compound 1 as a potent CETP inhibitor was
prepared starting from 2 with a significantly improved
overall yield of 4.5% over previous methods.8,9 With a
highly enantioselective protocol for asymmetric alkyla-
tion of aldehyde 3, our synthetic route avoids chiral sepa-
ration procedures.
We explored a variety of chiral amino alcohols 4 to induce ration of intermediates. Combined with other
asymmetric addition of 2,2-dimethylpropyl zinc to alde- improvements to optimize individual reaction steps, this
hyde 3. The results are summarized in Table 1. It is grati- improved synthetic sequence opens up the opportunity to
fying to find that 4c can induce the formation of 5 large-scale production of 1 or its analogues.
exclusively with an acceptable yield of 60%.10 Figure 2
shows the optical purity of 5 by chiral chromatography.
References and Notes
From 5 to 10, the procedures are identical to our previous
(1) Sassa, T.; Niwa, G.; Unno, H.; Ikeda, M.; Miura, Y.
work.9 It is worth noting that in spite of the presence of the
Tetrahedron Lett. 1974, 45, 3941.
(2) Taisho Pharmaceutical Ltd.; WO 1994012175, 1994.
(3) Tomoda, H.; Nishida, H.; Masuma, R.; Cao, J.; Okuda, S.;
Omura, S. J. Antibiot. 1990, 44, 136.
(4) Salituro, G. M.; Pettibone, D. J.; Clineschmidt, B. V.;
Williamson, J. M.; Zink, D. L. Bioorg. Med. Chem. Lett.
1993, 3, 337.
chlorine atom, the benzyl protection can be efficiently re-
moved using Pd/C-catalyzed hydrogenation in EtOAc and
EtOH to afford 9 with a high yield of 95%, a substantial
improvement over the original protocol using FeCl3 with
a 65% yield.8
From compound 10, introduction of the ethyl group was
achieved using triethylborane and Pd(dppf)2Cl2 to afford
11 with a yield of 65%.11 This is improved over our previ-
ous protocol that utilized the Negishi coupling12 with a
40% yield,9 as well as the original Bayer protocol that uti-
(5) (a) Bayer AG; DE 4039860, 1992. (b) Bayer AG; EP
0411268, 1995.
(6) Bruckner, D.; Hafner, F.-T.; Li, V.; Schmeck, C.; Telser, J.;
Valalopoulos, A.; Wirtz, G. Bioorg. Med. Chem. Lett. 2005,
15, 3611.
Synlett 2009, No. 16, 2688–2690 © Thieme Stuttgart · New York

2690
Z.-H. Sun et al.
LETTER
15 min, the temperature was lowered to –78 °C, followed by
the addition of a toluene solution (10 mL) of compound 3
(10.4 g, 18.8 mmol). The mixture was allowed to slowly
warm to 0 °C, and stirred for another 6 h. The reaction was
slowly quenched by a sat. solution of NH4Cl, and then
extracted three times with EtOAc. The combined organic
phase was washed by H2O and brine, dried over anhyd
MgSO4, filtered and concentrated. The product 5 was
purified using silica gel chromatography (CH2Cl2–EtOAc,
50:1). Yield 7.06 g, 60%, [a]D20 +22.5 (c 1.0, CHCl3; >99%
ee, as analyzed by chiral HPLC, see Figure 2). ESI-MS:
m/z = 627.1 [M + H]+. 1H NMR (400 MHz, CD3Cl): d = 1.01
(s, 9 H), 1.20–1.70 (m, 8 H), 2.02 (s, 1 H), 2.37 (s, 3 H), 3.45
(m, 1 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 4.50 (dd, 1 H), 4.65 (m,
1 H), 4.93 (dd, 1 H), 5.02 (s, 2 H), 5.08 (m, 1 H), 6.38 (d, 1
H), 6.90 (s, 1 H), 7.18–7.35 (m, 6 H) ppm. 13C NMR (100
MHz, CD3Cl): d = 20.4, 20.5, 25.4, 27.1, 30.1 (3 C), 30.5,
51.5, 52.4, 58.6, 62.3, 63.3, 66.5, 71.1, 114.5, 116.9, 118.8,
121.3, 123.6, 127.1 (2 C), 127.6, 128.9 (2 C), 131.0, 131.6,
131.8, 136.7, 138.3, 142.3, 144.1, 151.1, 154.2, 168.2 ppm.
(11) Under argon, compound 10 (18.0 g, 36 mol), CsOAc (35.2
g, 108 mmol), and Pd(dppf)2Cl2 (0.54 g, 0.72 mmol) was
dissolved in dry THF. To this was added a solution of Et3B
(1 M, 108 mL, 108 mmol) in THF. The mixture was heated
to reflux for 4 h. Then it was cooled to 0 °C, and the reaction
was quenched with 10% NaOH and 30% H2O2. After stirring
at r.t. for 30 min, the mixture was neutralized with diluted
HCl, followed by extraction with EtOAc for three times. The
combined organic phase was washed with brine, dried over
anhyd MgSO4, and concentrated. Purification using silica
gel chromatography (PE–EtOAc, 8:1 to 1:1) afforded 11.
Yield 10.5 g (65%). HRMS (MALDI/DHB): m/z = 471.1550
[M + Na]+. 1H NMR (400 MHz, CD3Cl): d = 1.03 (s, 9 H),
1.15 (t, 3 H), 1.57 (m, 1 H), 1.61 (m, 1 H), 1.93 (d, 1 H), 2.31
(s, 3 H), 2.77 (q, 2 H), 3.99 (s, 3 H), 5.16 (m, 1 H), 5.37 (dd,
1 H), 5.48 (dd, 1 H), 6.26 (s, 1 H), 6.84 (d, 1 H), 6.95 (s, 1
H), 7.59 (d, 1 H) ppm. 13C NMR (100 MHz, CD3Cl): d =
13.3; 16.2; 20.7, 30.1 (3 C), 30.8, 52.4, 62.3, 65.9, 66.6,
116.9, 118.8, 121.3, 123.6, 131.0, 131.6, 131.8, 138.3,
142.3, 144.1, 151.1, 154.2, 167.4 ppm.
Figure 2 Optical purity of 5 analyzed using a Chiralpak AD-H
column, mobile phase: n-hexane–EtOH (80:20). Top: compound 5;
bottom: mixture of 5 and a racemic sample based on our previous
work.9
(7) (a) Dullaart, R. P. F.; Dallinga-Thie, G. M.; Wolffenbuttel,
B. H. R.; van Tol, A. Eur. J. Clin. Invest. 2007, 37, 90.
(b) Linsel-Nitschke, P.; Tall, A. R. Nature Rev. Drug
Discov. 2005, 4, 193.
(8) Bayer HealthCare AG; WO 2004039453, 2004.
(9) Fudan University; CN 101066967, 2007.
(10) Experimental Procedure
(12) (a) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc.,
Chem. Commun. 1977, 683. (b) Handbook of Organo-
palladium Chemistry for Organic Synthesis, Part III, Vol. 1;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002.
(13) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
To a stirred solution of 4c (74.1 mg, 0.4 mmole) in dry
toluene at 15 °C under argon, a solution of 2,2-dimethyl-
propyl zinc (4.76 g, 23 mmole) in toluene was added. After
Synlett 2009, No. 16, 2688–2690 © Thieme Stuttgart · New York