Asymmetric allylboration for the synthesis of β-hydroxy-δ-lactone unit of statin drug analogs

Article abstract of DOI:10.1016/S0022-328X(01)00665-9

Acrylic esters of homoallylic alcohols prepared in 92-96% ee via the asymmetric allylboration of appropriate aldehydes with B-allyldiisopinocampheylborane, upon ring-closing metathesis in the presence of 10mol% of Grabbs' catalyst provided the correspondi

Full text of DOI:10.1016/S0022-328X(01)00665-9

Journal of Organometallic Chemistry 624 (2001) 239–243
www.elsevier.nl/locate/jorganchem
Asymmetric allylboration for the synthesis of b-hydroxy-d-lactone
unit of statin drug analogsꢀ
M. Venkat Ram Reddy, Herbert C. Brown* 1, P. Veeraraghavan Ramachandran* 2
Herbert C. Brown Center for Borane Research, 1393 H. C. Brown Laboratories of Chemistry, Purdue Uni6ersity, West Lafayette,
IN 47907-1393, USA
Received 16 October 2000; accepted 4 January 2001
Abstract
Acrylic esters of homoallylic alcohols prepared in 92–96% ee via the asymmetric allylboration of appropriate aldehydes with
B-allyldiisopinocampheylborane, upon ring-closing metathesis in the presence of 10 mol% of Grubbs’ catalyst provided the
corresponding 6-substituted dihydropyran-2-ones. These were diastereoselectively epoxidized and regioselectively reduced to
furnish optically pure analogs of statin drugs. This procedure allows for the development of a combinatorial library of analogs
of these drugs. © 2001 Elsevier Science B.V. All rights reserved.
Keywords: Asymmetric synthesis; Allylboration; Metathesis; Epoxidation; Reduction
(Lescol®) [9]. Of these, Lipitor® was second in the list of
most sold drugs in the USA in 1999 with Zocor® in
fifth place [10]. The enormous success of Lipitor® (Fig.
2) and Zocor® within a short time points to the poten-
1. Introduction
The discovery of compactin [1] and mevinolin [2]
(Fig. 1) as inhibitors of hydroxymethylglutaryl coen-
zyme A (HMG-CoA) reductase a quarter of a century
ago revolutionized research toward the treatment of
hypercholesterolemia, a condition that leads to coro-
nary artery disease (CAD), which is one of the leading
causes of death all over the world. These are members
of a series of drugs known as statin drugs available in
the market for the lowering of LDL-cholesterol [3]. For
example, mevinolin is also known as lovastatin, with a
brand name of Mevacor® [4]. Other statin drugs cur-
rently marketed in the USA that are analogs of mevino-
lin include: simvastatin (velostatin, Zocor®) [5],
pravastatin (eptastatin, Pravachol®) [6], atorvastatin
(Lipitor®) [7], cerivastatin (Baycol®) [8], and fluvastatin
Fig. 1.
ꢀ Contribution c10 from the Herbert C. Brown Center for
Borane Research. Preliminary work was presented during Aldrich
Chemical Company Pro-I Open House, Kohler, WI, October 15,
1999, and completed work was presented (FLUO c1) at the 219th
ACS National Meeting, San Francisco, CA, March 27, 2000.
1 *Corresponding author. Tel.: +1-765-494-5316; fax: +1-765-
494-0239; e-mail: hcbrown@purdue.edu
Fig. 2.
2 *Corresponding author.
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)00665-9

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M.V. Ram Reddy et al. / Journal of Organometallic Chemistry 624 (2001) 239–243
Scheme 2.
2. Results and discussion
Allylboration of 3-phenylpropionaldehyde (4a) with
(−)-B-allyldiisopinocampheylborane [17] ((−)-3) in
Et2O–pentane mixture at −100°C for 1 h, followed by
oxidation, provided a 76% yield [18] of (S)-1-phenyl-
hex-5-en-3-ol (5a) in 96% ee, as determined by HPLC
analysis using a Chiralcel® OD-H™ [19] column (Table
1). We used this product for further reactions without
rigorous purification. Since the additional product from
oxidation, isopinocampheol, did not interfere with our
reaction, we did not separate it until after the ring-clos-
ing metathesis reaction. Esterification of the product
mixture with acryloyl chloride provided an 80% yield
[18] of the corresponding acryloyl ester 6a, along with
isopinocampheyl acrylate. Treatment of the mixture of
esters with 10% of Grubbs’ ruthenium catalyst (7) [20]
in refluxing CH2Cl2 for 12 h provided, after column
chromatography, 8a in 84% isolated yield (Scheme 1).
The enantiomeric excess of 8a was not affected during
these processes.
Epoxidation of 8a with H2O2/NaOH in methanol
provided the corresponding trans-epoxide 9a in
diastereomerically pure form and 86% yield. High
diastereoselectivities in these types of epoxidations are
known [14b]. The regioselective 1,3-reduction of the
epoxide using diphenyldiselenide–sodium borohydride
in ethanol, in the presence of acetic acid, provided an
87% yield of the required b-hydroxy-d-lactone (Scheme
2). It is believed that this reduction proceeds via the
formation of PhSeH [21]. Crystallization of this
product provided optically pure material, as was deter-
mined by comparison of the optical rotation with that
reported in the literature [12a].
Scheme 1.
tial of statin drugs to become one of the most successful
classes of pharmaceuticals ever developed. Accordingly,
several more are under clinical investigation [3c].
Systematic study of the statin drugs has revealed that
the key pharmacophore necessary for the drug action is
the b-hydroxy-d-lactone unit [11]. Of the several
analogs that have been studied, d-2-phenylethyl-b-hy-
droxy-d-lactone (2a) [12], d-benzylidenemethyl-b-hy-
droxy-d-lactone (2b) [13], and d-benzyloxymethyl-b-
hydroxy-d-lactone (2c) [14](Figure 3) have received
most attention. Accordingly, various syntheses for 2a–c
have been reported in the literature [12–14]. One of the
most utilized procedures for the synthesis of the hy-
droxylactones is via the ring closing of 3,5-dihydroxy
esters that are obtained via the diastereoselective syn-
reduction of optically pure 5-hydroxy-3-ketoesters via a
boron-mediated intramolecular reduction with NaBH4
[15].
As an extension of our ongoing program involving
the synthesis of a-pyranone-containing molecules via an
asymmetric allylboration-ring-closing metathesis strat-
egy [16], we envisaged the synthesis of the hydroxylac-
tone moiety of statin drug analogs via a diastereo-
selective epoxidation and 1,3-reduction (Scheme 1). Our
successful results are described below.
To show the generality of our reaction sequence for
the synthesis of hydroxylactones, we prepared two
Table 1
Preparation of homoallylic alcohols
RCHO
No.
RCH(OH)CH2CHꢀCH2
R
No.
Yield (%)
% eea
Configurationb
4a
4b
4c
PhCH2CH2
PhCHꢀCH
PhCH2OCH2
5a
5b
5c
76
71
74
96
92
92
R
S
S
a % ee determined by the HPLC analysis of the alcohol on a Chiralcel OD-H™ column.
b Configuration is based on analogy of allylborations with 3.

M.V. Ram Reddy et al. / Journal of Organometallic Chemistry 624 (2001) 239–243
241
other frequently prepared statin analogs, 2b and 2c,
starting from cinnamaldehyde (4b) and bezyloxyac-
etaldehyde (4c) respectively. In both of these cases, the
corresponding homoallylic alcohols were obtained in
92% ee. Since 2b is a solid, it was upgraded to ]99%
ee by crystallization. The yields for each step are pre-
sented in Table 2. The physical data of both of the
compounds matched with those reported in the litera-
ture [13,14].
ing a Rudolph Autopol III polarimeter with that re-
ported in the literature. The 1H, 11B and 13C-NMR
spectra were plotted on a Varian Gemini-300 spectrom-
eter with a Nalorac-Quad probe.
4.2. Materials.
Anhydrous ethyl ether and dichloromethane were
purchased from Mallinckrodt, Inc. and was used as
received. THF was distilled from sodium benzophenone
ketyl. DIP-ChlorideTM, allylmagnesium bromide, acry-
loyl chloride, sodium borohydride, diphenyl diselenide,
benzyloxyacetaldehyde and cinnamaldehyde, were all
obtained from the Aldrich Chemical Co. 3-phenyl-1-
propanal was prepared by Swern oxidation of the cor-
responding alcohol (Aldrich). Grubbs’ ruthenium
catalyst was purchased from Strem Chemicals.
3. Conclusion
In conclusion, we have described a general asymmet-
ric synthesis of b-hydroxy-d-lactones via an asymmetric
allylboration-ring-closing metathesis–diastereoselective
epoxidation–regioselective 1,3-reduction strategy. All
of these sequences can be carried out within a short
time on a large scale. The ready availability of both
isomers of a-pinene for the preparation of either enan-
tiomer of the allylborating agent makes this procedure
especially attractive. With the availability of several
types of ‘allylborating’ agents that have been developed
using a-pinene as chiral auxiliary [22], several different
analogs of 2a–c can be readily accessed. Moreover,
such a general synthesis can be readily adopted for the
preparation of a library of statin drug analogs via
combinatorial synthesis.
4.3. Methods
4.3.1. Allylboration of aldehydes
General procedure. The synthesis of 5a is representa-
tive. To a stirred solution of (−)-B-allyldiisopinocam-
pheylborane (prepared from DIP-Chloride™) was
added, at −100°C, 3-phenylpropionaldehyde (4a)
(1.34 g, 10 mmol) in 5 ml of Et2O. The mixture was
stirred at this temperature for 1 h, 1 ml of methanol
was added, warmed to room temperature (r.t.), and
worked up as usual with NaOH and H2O2. The product
was extracted with Et2O, washed with brine, and dried
over anhydrous MgSO4. Removal of the solvent and
partial purification by silica gel column chromatogra-
phy provided 2.6 g of a liquid mixture, which contained
1.34 g (76%) of (S)-(+)-1-phenyl-hex-5-en-3-ol (5a)
along with isopinocampheol [18].
4. Experimental
4.1. General methods
All operations were carried out under a nitrogen
atmosphere. Techniques for handling air-sensitive com-
pounds have been previously described [23]. Enan-
tiomeric excesses were determined by analysis of the
products on a Chiralcel® OD–H™ column using a
Rainin HPLC. Optical purities were determined by
comparing the rotations of the products measured us-
4.3.2. Preparation of acryloyl ester
General procedure. The synthesis of 6a is representa-
tive. The above mixture was dissolved in 10 ml of
CH2Cl2, cooled to 0°C, and 1.92 ml (23.7 mmol) of
acryloyl chloride and 6.6 ml (47.4 mmol) of Et3N were
Table 2
Synthesis of b-hydroxy-d-lactonesa
Alcohol no.
Acryloyl ester
Lactenone
Epoxy lactone
Hydroxy lactone
No.
Yield (%)
No. Yield (%)
[h]D
No.
Yield (%)
[h]D
No.
Yield (%)
87
[h]D
5a
5b
5c
6a
80
75
76
8a
8b
8c
84
78
82
−46.09
(c 0.64)
9a
86
70
78
115.08
(c 1.53)
2a
69.21
(c 1.45)
6b
6c
−170.12
(c 1.2)
9b
9c
53.15
(c 0.5)
2b
2c
89
81
9.89
(c 0.99)
−110.22
(c 0.45)
6.85
(0.7)
a All of the rotations were measured in CHCl3.

242
M.V. Ram Reddy et al. / Journal of Organometallic Chemistry 624 (2001) 239–243
added, warmed to r.t. and stirred for 4 h. The resulting
mixture was filtered through a short pad of Celite to
remove solid Et3N·HCl, poured into water and the
product was extracted with CH2Cl2. The crude product
was partially purified by silica gel column chromatogra-
phy (hexane:ethyl acetate: 99:1) and concentrated to
obtain 2.2 g of a mixture, which contained 1.4 g (80%)
of 6a along with isopinocampheyl acrylate [18].
Compound 8b: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 2.54 (2H, m), 5.10 (1H, m), 6.09 (1H, dt, J=9.8,
1.8 Hz), 6.28 (1H, dd, J=15.99, 6.33 Hz), 6.73 (1H, d,
J=15.93 Hz), 6.93 (1H, dt, J=9.8, 4.2 Hz), 7.34 (5H,
m); 13C-NMR (CDCl3) l (ppm) 29.93, 78.00, 121.68,
125.70, 126.75, 128.41, 128.74, 133.16, 135.80, 144.74,
163.94; MS EI m/z 200 (M+), 172, 104, 68 (100%); CI
m/z 201 (M+H)+ (100%).
Compound 8c: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 2.43 (2H, m), 3.66 (2H, d, J=4.68 Hz), 4.56
(3H, m), 5.97 (1H, ddd, J=9.72, 2.64, 1.02 Hz), 6.86
(1H, ddd, J=9.72, 5.91, 2.58 Hz), 7.32 (5H, m); 13C-
NMR (CDCl3) l (ppm) 26.14, 70.86, 73.59, 76.70,
121.04, 127.75, 127.87, 128.50, 137.75, 145.31, 163.82;
MS EI m/z 218 (M+), 127, 112, 97 (100%); CI m/z 219
(M+H)+ (100%).
4.3.3. Ring-closing metathesis reaction
General procedure. The synthesis of 8a is representa-
tive. Grubbs’ catalyst (0.5 g, 0.6 mmol, 10 mol%) was
dissolved in 25 ml of CH2Cl2 and was added dropwise
to a refluxing solution of the above mixture of 6a and
isopinocampheyl acrylate in 1 l of CH2Cl2. Refluxing
was continued for 12 h, by which time all of 6a was
consumed (TLC). The solvent was removed under as-
pirator vacuum and the crude product was purified by
silica gel column chromatography (hexane:ethylacetate:
75:25) to obtain 1.02 g (84%) of pure 8a.
Compound 9a: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 1.92 (3H, m), 2.35 (1H, dt, J=9.93, 3.00 Hz),
2.71 (1H, m), 2.86 (1H, m), 3.59 (1H, d, J=3.84 Hz),
3.66 (1H, m), 4.53 (1H, m), 7.25 (5H, m); 13C-NMR
(CDCl3) l (ppm) 29.49, 31.13, 36.46, 49.14, 52.11,
72.97, 126.24, 128.47, 128.61, 140.78, 167.73; MS EI
m/z 218 (M+), 155, 143, 91 (100%); CI m/z 219 (M+
H)+ (100%).
4.3.4. Preparation of epoxylactone
General procedure. The synthesis of 9a is representa-
tive. Lactenone 8a (0.79 g, 3.9 mmol) in methanol was
treated with 1.33 ml (13.2 mmol) of H2O2 and 0.39 ml
of 6 N NaOH at 0°C. The reaction mixture was stirred
for 1 h, diluted with Et2O and water, acidified with
concentrated HCl, and extracted with Et2O (3×50 ml).
The solvents were removed under aspirator and the
crude product was cyclized with PPTS in refluxing
toluene using a Dean–Stark apparatus and purified by
column chromatography (EtOAc:hexane: 1:4) to obtain
0.73 g (86%) of the epoxy lactone 9a.
Compound 9b: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 2.16 (1H, dd, J=15.12, 11.8 Hz), 2.37 (1H, dt,
J=15.12, 3.03 Hz), 3.65 (1H, d, J=4.05 Hz), 3.74 (1H,
m), 5.17 (1H, m), 6.13 (1H, dd, J=15.87, 6.84 Hz),
6.69 (1H, d, J=15.93 Hz), 7.34 (5H, m); 13C-NMR
(CDCl3) l (ppm) 30.17, 49.16, 52.09, 74.17, 125.00,
126.78, 128.51, 128.75, 133.42, 135.62, 167.33; MS EI
m/z 216 (M+), 171, 131 (100%), 104; CI m/z 217
(M+H)+ (100%), 199, 173.
Compound 9c: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 2.21 (1H, m), 2.36 (1H, m), 3.62 (4H, m), 4.61
(3H, m), 7.32 (5H, m); 13C-NMR (CDCl3) l (ppm)
26.01, 49.10, 52.14, 70.68, 73.04, 73.61, 127.76, 127.92,
128.52, 137.63, 167.29.
4.3.5. Preparation of hydroxylactone
General procedure. The synthesis of 2a is representa-
tive. Sodium borohydride (0.057 g, 1.5 mmol) was
added, in small portions, to a stirred solution of
diphenyldiselenide (0.234 g, 0.75 mmol) in ethanol at
r.t. and cooled to 0°C. Acetic acid (120 ml) was then
added, followed by the addition 0.109 g (0.5 mmol) of
9a dissolved in 2 ml of THF–ethanol (1:1) and stirred
for 20 min. The product was extracted with ethyl ace-
tate, washed with brine, and dried over MgSO4. Evapo-
ration of the solvents, followed by column
chromatography over silica (ethyl acetate:hexane: 3:2 as
eluent) provided 0.096 g (87%) of the hydroxylactone
2a.
Compound 2a: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 1.91 (4H, m), 2.22 (1H, s, br), 2.76 (4H, m), 4.38
(1H, quintet, J=4.00 Hz), 4.72 (1H, m), 7.25 (5H, m);
13C-NMR (CDCl3) l (ppm) 31.17, 35.97, 37.35, 38.66,
62.63, 75.24, 126.16, 128.50, 128.58, 141.10, 170.92; MS
EI m/z 220 (M+), 202, 142, 91 (100%); CI m/z 221
(M+H)+ (100%), 203.
Compound 2b: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 1.96 (1H, m), 2.14 (1H, m), 2.32 (1H, s, br), 2.73
(2H, m), 4.45 (1H, quintet, J=3.98 Hz), 5.38 (1H, m),
6.21 (1H, dd, J=15.93, 6.48 Hz), 6.71 (1H, d, J=
15.93 Hz), 7.33 (5H, m); 13C-NMR (CDCl3) l (ppm)
36.30, 38.71, 62.56, 76.43, 126.56, 126.73, 128.30,
128.73, 132.58, 135.89, 170.56; MS EI m/z 218 (M+),
200, 104 (100%), 91; CI m/z 219 (M+H)+, 201 (100%).
Compound 2c: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 1.92 (2H, m), 2.61 (2H, m), 3.58 (1H, dd, J=
10.71, 4.32 Hz), 3.67 (1H, dd, J=10.7, 3.81 Hz), 4.35
Compound 8a: 1H-NMR (300 MHz) l (CDCl3)
(ppm) 1.94 (1H, m), 2.15 (1H, m), 2.35 (2H, m), 2.84
(2H, m), 4.42 (1H, m), 6.03 (1H, dt, J=9.78, 1.8 Hz),
6.87(1H, m), 7.26(5H, m); 13C-NMR (CDCl3) l (ppm)
29.49, 30.99, 36.55, 76.96, 121.43, 126.20, 128.53,
128.59, 140.93, 145.15, 164.51; MS EI m/z 202 (M+),
184, 117 (100%), 91; CI m/z 203 (M+H)+ (100%).

M.V. Ram Reddy et al. / Journal of Organometallic Chemistry 624 (2001) 239–243
243
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(1H, m), 4.56 (2H, d, J=1.98 Hz), 4.84 (1H, m), 7.31
(5H, m); 13C-NMR (CDCl3) l (ppm) 31.98, 38.58,
62.34, 71.68, 73.57, 75.28, 127.78, 127.89, 128.51,
137.75, 170.87; MS EI m/z 189, 107 (100%), 91; CI m/z
237 (M+H)+ (100%), 219.
Acknowledgements
Financial assistance from the Purdue Borane Re-
search Fund is gratefully acknowledged.
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