Facile and highly enantioselective synthesis of (+)- and (-)-fluvastatin and their analogues

Article abstract of DOI:10.1021/jo101542y

A highly enantioselective synthesis of (+)- and (-)-fluvastatin and their analogues has been facilitated by the reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)₄ and a chiral Schiff base ligand. Either enantiomer of the Schiff base could be employed to obtain (+)- or (-)-fluvastatin. Diastereoselective reductions of the resultant keto moiety of β-hydroxy ketoesters provided the syn-1,3-diol esters (91% ee), which were subsequently recrystallized and saponified to afford (+)- and (-)-fluvastatin in >99.9% ee.

Full text of DOI:10.1021/jo101542y

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Facile and Highly Enantioselective Synthesis of (þ)- and (-)-Fluvastatin
and Their Analogues
James T. Zacharia, Takanori Tanaka, and Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501, Japan
mhayashi@kobe-u.ac.jp
Received August 10, 2010
A highly enantioselective synthesis of (þ)- and (-)-fluvastatin and their analogues has been
facilitated by the reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)4 and a chiral
Schiff base ligand. Either enantiomer of the Schiff base could be employed to obtain (þ)- or (-)-
fluvastatin. Diastereoselective reductions of the resultant keto moiety of β-hydroxy ketoesters
provided the syn-1,3-diol esters (91% ee), which were subsequently recrystallized and saponified to
afford (þ)- and (-)-fluvastatin in >99.9% ee.
1. Introduction
Novartis’ group reported the method using Wadworth-
Horner-Emmons reaction.3 Thus, we developed an interest
in the respective biological activity of each of the four
fluvastatin stereoisomers. There are two sets of enantiomers,
which are diastereomeric relative to one another. For exam-
ple, 4-syn and 4-anti are not enantiomers. Toward this end, a
concise and efficient approach providing individual access to
all four of the fluvastatin stereoisomers has been implemented.
Gratifyingly, the reaction of the aldehyde 2 with diketene
provided the β-hydroxy ketone in 91% ee. The diastereo-
selectivereductionof the resultant β-hydroxyketoneprovided
a syn- 1,3-diol, of which the optical purity could be increased
to >99.9% ee by a single recrystallization without resorting
to the use of optical resolution reagents.
Statins represent a class of drugs that are capable of
regulating the biosynthesis of cholesterol by inhibiting the
enzyme that reduces 3-hydroxy-3-methylglutaric acid to
mevalonic acid, namely, the HMG-CoA reductase inhibi-
tors. Since the introduction of pravastatin by Sankyo and
lovastatin by Merck to the pharmaceutical market, this class
of drugs has been in eminent demand. Due to the importance
of these drugs, various synthetic strategies aimed at the con-
struction of statins have been reported. Many of these studies
have focused on the introduction of the statin side chain.1
During the course of our efforts to develop a facile synthesis
of HMG-CoA reductase inhibitors, a three-step linear syn-
thesis of fluvastatin 5 has been identified and successfully
implemented. Most of the statins, such as atorvastatin calcium
hydrate, simvastatin, and pravastatin sodium, are adminis-
tered in the optically pure form. However, to our knowledge,
fluvastatin has been approved as a racemic form. Actually,
Novartis’ group reported manufacturing process for fluvas-
tatin in racemic form.2 As for chiral version, Prasad and his
2. Results and Discussion
2.1. Synthesis of Chiral Schiff Base Ligands. The ligands
(S)-1 and (R)-1 were prepared as depicted Scheme 1.4
(3) Tempkin, O.; Abel, S.; Chen, C.-P.; Underwood, R.; Prasad, K.;
Cheng, K.-M.; Repic, O.; Blacklock, T. J. Tetrahedron 1997, 53, 10659–
10670.
(4) (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Chem. Soc.,
Chem. Commun. 1991, 1752–1753. (b) Hayashi, M.; Miyamoto, Y.; Inoue, T.;
Oguni, N. J. Org. Chem. 1993, 58, 1515–1522.
€
(1) Christmann, M.; Brase, M. Asymmetric Synthesis—The Esentials, 2nd
ed.; Wiley-VCH: Weinheim, Germany, 2008; pp 342__347.
(2) Fuenfschiling, P. C.; Hoehn, P.; Mutz, J.-P. Org. Process Res. Dev.
2007, 11, 13–18.
7514 J. Org. Chem. 2010, 75, 7514–7518
Published on Web 10/12/2010
DOI: 10.1021/jo101542y
r
2010 American Chemical Society

Zacharia et al.
JOCFeatured Article
SCHEME 1. Preparation of Chiral Schiff Bases (S)-1 and (R)-1
SCHEME 2. Preparation of Aldehyde 2
SCHEME 3. Enantioselective Addition of Diketene to Aldehyde 2
Condensation of 3-tert-butylsalicylaldehyde with (S)-valinol
or (R)-valinol afforded ligands (S)-1 and (R)-1, respectively.3
2.2. Synthesis of 3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-
indol-2-yl]-(2E)-propenal (2)5. The preparation of 2 (Scheme 2)
was effected by the reaction of 3-(N-methyl-N-phenyl amino)-
acrolein (MPAA)3 with 3-(4-fluorophenyl)-1-(1-methylethyl)-
1H-indole conducted in refluxing acetonitrile. Following the
workup steps, the resultant aldehyde 2 was isolated as yellowish
crystals in 89% yield.
2.3. Enantioselective Addition of Diketene to Aldehyde 2.
The titanium-promoted asymmetric addition of diketene to 2
was carried out in the presence of the Ti(O-i-Pr)4-Schiff base
complex at -40 °C for 48 h (Scheme 3).6 Each of the chiral
Schiff base ligands [(S)-1 or (R)-1] were used to synthesize
each enantiomer of the β-hydroxy ketones in 91% ee, as
depicted in Table 1. These results are in agreement with the
fact that the ligands (S)-1 and (R)-1 are enantiomers and
should produce the same magnitude of stereoinduction,
differing only in the absolute configuration of the products
(91% 5S and 91% 5R, respectively).
2.3.1. Effect of Ligand Stoichiometry on the Enantioselec-
tive Addition of Diketene to Aldehyde 2. Various stoichiome-
tries of the Schiff base were examined ranging from 1 equiv to
catalytic amounts. Although a molarequivalent of Ti(O-i-Pr)4
was necessary to obtain sufficient conversion, the amount of
Schiff base could be reduced, which resulted in only a small
decrease in enantioselectivity (Table 1). This phenomenon can
be explained by invoking the concept of ligand-accelerated
catalysis.8 In other words, the Ti(O-i-Pr)4-Schiff base complex
TABLE 1. Enantioselective Addition of Diketene to Aldehyde 2
entry
ligand (mol %)
yielda (%)
eeb (%)
1
2
3
4
5
no ligand
(S)-1 (100)
(S)-1 (50)
(S)-1 (10)
(R)-1 (100)
61
78
73
70
84
91 (S)
83 (S)
74 (S)
91 (R)
aIsolated yield after silca gel column chromatography. bDetermined
by HPLCanalysis (CHIRALPAK AD-H).
accelerates the reaction relative to when Ti(O-i-Pr)4 is used
alone (Scheme 4). The identification of this phenomenon, in
the specific case, allowed for the use of a catalytic amount of
the Schiff base. In the absence of the Schiff base, the reaction
proceeds comparatively slower than when even small quan-
tities of the ligand were used. In this reaction, the ligand is
serving a dual purpose of inducing stereocontrol, as well as
accelerating the reaction rate.7
(7) Early attempts toward the enantioselective addition of diketene to 2 using
other types of Schiff bases were unsuccessful. Before arriving at the results shown in
Table 1, several attempts were made using the oxazoline Schiff bases such as 1and 2
(Scheme 4). The use of Schiff bases as in 1 resulted in the production of the R
enantiomer of the β-hydroxy ketone, while the Schiff bases as in 2 resulted in the
production of the Senantiomer. As summarized in the Supporting Information, the
best ee was 78% S when R1 = Et and 38% R when R1 = Me. These results
prompted us to try other types of Schiff bases. (b) Hentges, S. G.; Sharpless, K. B.
J. Am. Chem. Soc. 1980, 102, 4263–4265.
(5) Lee, G. T.; Amedio, J. C.; Underwood Jr.; Prasad, K.; Repic, O.
J. Org. Chem. 1992, 57, 3250–3252.
(6) The first report of enantioselective addition of diketene to aldehydes:
(a) Hayashi, M.; Inoue, T.; Oguni, N. J. Chem. Soc., Chem. Commun. 1994,
341–342. (b) Hayashi, M.; Kaneda, H.; Oguni, N. Tetrahedron: Asymmetry
1995, 6, 2511–2516.
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SCHEME 4. Proposed Reaction Mechanism of the Ti(O-i-Pr)4-
Schiff Base Catalyzed Addition of Diketene to Aldehyde 2 (Ligand
Acceleration Effect8)
TABLE 2. Effect of Temperature on the Enantioselectivity in Addition of
Diketene to Aldehyde
entry
temp (°C)
yielda (%)
eeb (%)
1
2
3
4
25
-20
-40
-60
84
81
78
38
12 (S)
70 (S)
91 (S)
93 (S)
aIsolated yield after silica gel column chromatography. bDetermined
by HPLC analysis (CHIRALPAK AD-H).
TABLE 3. Diastereoselective Reductions of β-Hydroxy Ketones To
Provide 1,3-Diols
diolester
entry
β-ketoester/ee (%)
yielda (%)
syn/antib (eec (%))
1
2
3
4
91 (5S)
91 (5R)
91 (5S)
91 (5R)
78
79
44
46
99/1 (99.8(3R,5S))
99/1 (99.9(3S,5R))
9/91 (92(3S,5S))
9/91 (92(3R,5R))
aIsolated yield after silica gel column chromatography followed by
recrystallization. bDetermined by HPLC analysis (CHIRALCEL OD-H).
cEnantiomeric excess of major isomer determined by HPLC analysis
(CHIRALCEL OD-H) after recrystallization.
The increased diastereoselectivity of the syn-reduction rela-
tive to that of the anti-reduction is a remarkable break-
through, which provides the means of obtaining the biologically
potent syn-isomers in excellent enantiopurity and yield:
99.8% ee (3R,5S) and 99.9% ee (3S,5R) after recrystallization
(Table 3).
2.5. Saponification To Provide Fluvastatin 5. The isopropyl
ester was saponified (aq NaOH) and lyophilized to provide
fluvastatin sodium in good yield (78%).
2.3.2. Effect of Temperature on the Enantioselective Addi-
tion of Diketene to Aldehyde 2. Table 2 illustrates a general
trend in which a decrease in the temperature resulted in an
increased enantioselectivity with a concomitant decreased
chemical yield. An optimum temperature for this reaction
was found to be -40 °C, which provided the product in 91%
ee and 78% yield.
2.4. Diastereoselective Reductions of β-Hydroxy Ketones to
Provide syn-1,3-Diols. A diastereoselective syn-reduction of
either the (S)-3 or (R)-3 β-hydroxy ketone was achieved by
using NaBH4 as the reducing agent in the presence of diethyl
methoxy borane as a chelating agent (Narasaka’s method)8
The reaction provided high syn-selectivity (99:1, syn/anti) and
afforded the syn-1,3-diol 4 [(3R,5S) or (3S,5R)] in 78-79%
yield. The preferential formation of the syn-product can be
rationalized by the preorganization of the substrate with the
chelating agent (Et2BOMe) prior to the intermolecular axial
hydride attack (NaBH4) occurring at the ketone.
Alternatively, we performed an anti-reduction on either
the (S)-3 or (R)-3 β-hydroxy ketone using the Evans method
[Me4NHB(OAc)3].9 This protocol provided the anti-1,3-diol
4 with 91:9 anti/syn selectivity [(3R,5R) or (3S,5S)]. In this
case, the reducing agent [Me4NBH(OAc)3] effects an intra-
molecular hydride transfer, which results in the preferential
formation of the anti-isomer.10,11
(8) (a) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233–2238.
(b) Chen, K.-M.; Hardmann, G. E.; Prasada, K.; REpic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155–158.
(9) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
(10) Tempkin, O.; Abel, S.; Chen, C. P.; Underwood, R.; Prasad, K.; Cheng,
K. M.; Repic, O.; Blacklock, T. J. Tetrahedron 1997, 53, 10659–10670.
7516 J. Org. Chem. Vol. 75, No. 22, 2010

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3. Conclusion
layer was concentrated to give thick stirrable oil (7.6 g, 94%).
Purification of crude MPAA was done by dissolving the crude
MPAAin 2-propanol (IPA) (5 mL) at45-50 °C, andthenhexane
(8.5 mL) was added with continuous stirring. The mixture was
cooled to 0 °C over 30 min under vigorous agitation. A few seed
crystals of MPAA were added, and the slurry was further chilled
to -15 °C for 1 h. The solid was collected by rapid suction filtra-
tion at -10 °C. The product was washed with a cold (-10 °C)
solution of IPA/hexane (35/65, 25 mL ꢀ 2) and then dried to
a constantweight:yield9.6 g (94%);mp 44-45 °C; 1H NMR (400
MHz, CDCl3) δ 3.37 (s, 3H), 3.51, (s, 1H), 5.4-5.5 (m, 1H),
7.1-7.6 (m, 5H), 9.27 (d, J = 7.6 Hz, 1H); 13C NMR (100.6
MHz, CDCl3) δ 24.7, 62.9, 77.0, 104.8, 119.8, 124.7, 129.0, 189.5.
Synthesis of 3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-in-
dol-2-yl]-(2E)-propenal 25. A solution of POCl3 (908 mg, 5.92
mmol, 3.0 equiv) in 2 mL of acetonitrile was cooled to -5 °C,
then a solution of MPAA (947 mg, 5 mmol, 2.5 equiv) in 1 mL
of acetonitrile was added slowly over 45 min under argon
atmosphere and stirred at 5-7 °C for 10 min. A solution
of 3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indole (508 mg,
2 mmol) in 5 mL of acetonitrile was injected rapidly into the
mixture, and the reaction content was heated to reflux for 3 h. The
mixture was allowed to cool to room temperature and quenched
with 5 mL of water. The solution was then warmed to 55 °C for 2 h
and then cooled to 15 °C and diluted with 20 mL of toluene. The
organic layer was separated and washed with 50 mL ꢀ 2 of water,
dried over anhydrous Na2SO4, and concentrated to a residue. The
oily residue was purified by silica gel column chromatography (5:1,
hexane/ethyl acetate). The fractions of interest were combined,
and evaporated and the residue was recrystallized from isopropyl
alcohol to give 551 mg (89%) of pale yellow crystals: Rf 0.27
(5:1, hexane/ethyl acetate); mp 129-130 °C (lit.5 129-130 °C);
1H NMR (400 MHz, CDCl3) δ 1.72 (d, J = 6.8 Hz, 6H), 2.84 (s,
1H).4.9-5.0 (m, 1H), 6.2-6.3 (m, 1H), 7.1-7.6 (m, 8H), 9.56 (d,
J = 8.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ21.8, 25.4, 48.3,
76.7, 77.3, 112.5, 115.8, 120.6, 124.6, 131.9, 137.5, 141.1, 193.3.
Synthesis of 3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-in-
dol-2-yl]-5-hydroxy-3-oxo-(6E)-heptenoic acid-1-isopropyl ester
3. In an ampular tube were placed Schiff base (S)-1 ligand (144.9
mg, 0.55 mmol) and CH2Cl2 (5 mL). To this solution was added
Ti(O-i-Pr)4 (142.1 mg, 0.5 mmol) at room temperature and
stirred for 1 h, then the mixture was cooled to -40 °C. Aldehyde
(153.7 mg, 0.5 mmol) was added followed by diketene (210.2 mg,
2.5 mmol). The mixture was stirred at -40 °C for 48 h. Then
after, isopropyl alcohol (2 mL) was added to the mixture, and
the mixture was further stirred for 3 h. The reaction mixture was
poured into a mixture of 1 M HCl (10 mL) and diethyl ether
(10 mL) and stirred vigorously for 1 h at room temperature. The
mixture was extracted with ethyl acetate (30 mL ꢀ 3), and the com-
bined extract was washed with saturated NaHCO3 (30 mL ꢀ 3)
and brine (30 mL x 3) and dried over anhydrous Na2SO4 and
then evaporated to a residue. The residue was purified by
column chromatography on silica gel using hexane/ethyl acetate
(5:1) to give the S enantiomer of the β-hydroxy ketoester 3. The
R enantiomers of the β-hydroxy ketoester were obtained follow-
ing the same procedure by only substituting the (S)-1 ligand with
(R)-1 ligand: Rf 0.15, hexane/ethyl acetate (5:1). Enantiomeric
excess of the β-hydroxy-ketoester (91% ee) was determined by
HPLC using CHIRALPAK AD-H column (250 mm ꢀ 4.6 mm ꢀ
5 μm), run time 30 min, flow rate 1.0 mL/min, injection volume
10 μL, mobile phase hexane/isopropyl alcohol 90:10 (v/v) con-
taining 0.01% of trichloroacetic acid, retention time 17.38 min
(5R) and 25.31 min (5S): 1H NMR (400 MHz, CDCl3) δ 1.2-1.3
(m, 6H), 1.42 (s, 1H), 1.5-1.7 (m, 6H), 2.17 (s, 1H), 2.6-2.7
(m, 1H), 3.42 (s, 2H), 4.1-4.2 (d, J = 7.2 Hz, 2H), 4.84 (s, 1H),
5.0-5.1 (m, 1H), 5.68 (d, J = 5.2 Hz, 1H), 6.75 (d, J = 14.4 Hz,
1H), 7.1-7.6 (m, 8H); 13C NMR (100.6 MHz, CDCl3) δ14.2, 21.7,
47.8, 48.9, 50.2, 60.4, 68.1, 69.4, 77.1, 96.1, 111.7, 136.9, 166.4.
In summary, a concise and efficient synthesis of each of the
four stereoisomers of fluvastatin has been established. This
was realized by employing a stereodivergent approach from
β-hydroxy ketone precursor: syn-reduction (Et2BOMe,
NaBH4) or anti-reduction [Me4NHB(OAc)3]. Recrystalliza-
tion of the resultant 1,3-diol upgraded the enantiopurity
to >99.9% ee for the syn-isomers and >92% ee of the anti-
isomers. The increased diastereoselectivity observed in the
syn-reduction enabled the formation of the biologically potent
syn-isomers (3R,5S) and (3S,5R) in excellent enantiopurity.
4. Experimental Section
General Procedures. All starting materials were obtained
from commercial sources and used without further purification,
except for diketene, which was distilled under reduced pressure
prior to its use. Reactions that required anhydrous conditions
were carried out using dehydrated solvents under an argon
atmosphere. 1H and 13C NMR spectra (400 and 100.6 MHz, re-
spectively) were recorded using Me4Si as an internal standard
(0 ppm). HPLC analyses were carried out equipped with diode
array detector using chiral columns CHIRALPAC AD-H or
CHIRALCEL OD-H (250 mm ꢀ 4.6 mm ꢀ 5 μm).
Synthesis of 3-tert-Butylsalicylaldehyde. To a solution of
2-tert-butylphenol (3 g, 20 mmol) in toluene (50 mL) were added
paraformaldehyde (1.8 g, 60 mmol), anhydrous tin(II) chloride
(0.38 g, 2 mmol), and 4-picoline (0.75 g, 8 mmol). The mixture
was allowed to stir at 95 °C for 6 h. The mixture was subse-
quently cooled to room temperature, and the resultant suspen-
sion was filtered and concentrated to provide a residue. The
residue was extracted with diethyl ether (30 mL ꢀ 2), and the
combined organic layer was washed with brine (30 mL), dried
over anhydrous Na2SO4, and evaporated to provide the crude
material. The crude material was purified by distillation at
reduced pressure to afford the desired product as thick yellow
oil: yield 1.87 g (52%); bp 120-122 °C/17 mmHg; 1H NMR (400
MHz, CDCl3) δ 1.41 (s, 9H), 4.86 (s, 1H), 6.6-7.8 (m, 3H), 9.86
(s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 29.2, 34.7, 65.5, 77.0,
116.5, 138.2, 161.2, 197.2.
Synthesis of (S)-2-(N-3-tert-Butylsalicylidene)amino-3-meth-
yl-1-butanol (Ligand (S)-1). A mixture of 3-tert-butylsalicylal-
dehyde (892 mg, 5 mmol), (S)-valinol (515.8 mg, 5 mmol, 1 equiv),
and methanol (30 mL) was refluxed for 9 h in the presence of
anhydrous Na2SO4 (5 g). The mixture was filtered through a pad
of Celite, and the filtrate was concentrated to provide the crude
residue. The crude material was purified by recrystallization
from petroleum ether to afford 2a as yellow needles: yield 1.28 g
(97%); mp 56.9-57.5 °C (lit.4b 57-58 °C); [R]24D -39.8; 1H NMR
(400 MHz, CDCl3) δ 0.92 (d, J = 8.8 Hz, 6H), 1.41 (s, 9H), 1.9-2.0
(m, 1H), 2.17 (s, 1H), 3.0-3.1 (m, 1H), 3.7-3.9 (m, 2H), 4.87 (s,
1H), 6.8-7.4 (m, 3H), 8.37 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
δ 18.8, 29.3, 34.8, 64.6, 77.3, 117.9, 129.5, 160.4, 166.7.
Synthesis of 3-(N-Methyl-N-phenylamino)acrolein (MPAA).
To a precooled (-10 °C) solution of oxalyl chloride (COCl)2
(7.0 g, 55.1 mmol, 1.1 equiv) and acetonitrile (10 mL) was slowly
added a mixture of N-methylformanilide (6.8 g, 50.1 mmol) and
butyl vinyl ether (5.4 g, 53.6 mmol) in acetonitrile over 30 min
while maintaining the internal temperature at -5 to -10 °C. The
reaction mixture was to 20 °C over 30 min, and stirring was
continued for 1 h. The reaction contents were cooled to 0 °C, and
a solution of Na2CO3 (6.4 g, 60.12 mmol) in water (30 mL) was
added over 45 min while maintaining the internal temperature at
8-10 °C. Then toluene (25 mL) was added, and the solution was
stirred at 20-22 °C for 15 min. The solution was allowed to
settle for 15 min. The layers were separated, and the toluene
layer was washed with water (25 mL ꢀ 2). The combined toluene
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Synthesis of 3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-
2-yl]-3,5-dihydroxy-(6E)-heptenoic acid-1-isopropyl ester 4. So-
dium borohydride (50 mg, 1.32 mmol) was added to a mixture of
THF (8 mL) and MeOH (2 mL) at -78 °C in a three-necked
flask under argon atmosphere. Diethylmethoxyborane (1 M
solution in THF) (0.52 mL, 0.52 mmol) was added dropwise and
stirred for 15 min. β-Hydroxy ketoester 3 (200 mg, 0.44 mmol)
was added dropwise over 1 h as a solution in 4:1 THF/MeOH
(15 mL). Stirring was continued at -78 °C for 2 h after addition.
The reaction mixture was diluted with saturated NaHCO3 (20 mL),
heptane (40 mL), and ethyl acetate (20 mL). The upper organic
layer was washed with brine and saturated NaHCO3 solution,
then dried with anhydrous Na2SO4 and evaporated to a residue.
The residue was coevaporated with MeOH three times to
hydrolyze the excess borane. Column chromatography on silica
gel using hexane/ethyl acetate (5:1) as eluting solvent gave the
pure syn-product of the 3,5-dihydroxyester 4 with syn/anti
diastereoselectivity of >99:1. Alternatively the anti-product of
the 3,5-dihydroxyester was achieved following the Evans meth-
od [(Me4NBH(OAc)3] with anti/syn diastereoselectivity of 91:9.
The diastereoselectivity ratios were measured by HPLC using
CHIRALCEL OD-H (250 mm ꢀ 4.6 mm ꢀ 5 μm) column, run
time 30 min, flow rate 1.0 mL/min, injection volume 10 μL,
mobile phase hexane/isopropyl alcohol 95:5 (v/v) containing
0.01% of trichloroacetic acid, retention times 8.47 min (3S,5S),
9.43 min (3R,5R), 13.79 min (3R,5S), and 14.85 min (3S,5R).
The enantiomeric excess of the syn- and anti-stereoisomers was
improved by a single recrystallization from 91% to over 99.9%
for the syn-isomers and 94% for the anti-isomers using acetoni-
Synthesis of 3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-in-
dol-2-yl]-3,5-dihydroxy-(6E)-heptenoic acid Sodium Salt 5. The
3,5-dihydroxyester 4 (150 mg, 0.33 mmol) was added to a 50 mL
three-necked round-bottomed flask equipped with a magnetic
stirrer and a dropping funnel. To the flask was added methanol
(20 mL). A solution of NaOH (1.0 N NaOH) in water (0.32 mL)
was placed in the dropping funnel and was added slowly to the
flask over 5 min while maintaining the temperature at 25 °C. The
suspension was stirred for 2 h, and then the reaction mixture was
filtered and diluted with water (15 mL) and methyl-tert-butyl ether
(MTBE) (15 mL). The lower aqueous layer was washed with MTBE,
and the combined organic layer was concentrated to a volume of
about 20 mL. The heterogeneous mixture was then lyophilized for
72 h to obtain 5 as a pale yellow powder: Rf 0.45; mp 141-143 °C;
1H NMR (400 MHz, DMSO) δ 1.2-1.3 (m, 6H), 1.3-1.7 (m, 6H),
2.05 (s, 2H), 2.3-2.4 (m, 1H), 3.31 (s, 1H), 4.0-4.1 (m, 2H), 4.85 (s,
1H), 5.0-5.1 (m, 1H), 5.77 (d, J = 16 Hz, 1H), 6.76 (d, J = 16 Hz,
1H), 7.0-7.5 (m, 8H); 13C NMR (100.6 MHz, DMSO) δ 21.7, 25.2,
25.3, 38.9, 39.1, 39.3, 39.5, 39.7, 39.9, 40.1, 95.7, 176.2.
Acknowledgment. This work was supported by Grants-in-
Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” and No.
B17340020 from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: Details of experimental
procedures and characterization data (1H, 13C, HPLC chromato-
grams) for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
trile/water (9:1): H NMR (400 MHz, CDCl3) δ 1.2-1.3 (m,
6H), 1.42 (s, 1H), 1.5-1.7 (m, 6H), 2.17 (s, 1H), 2.6-2.7 (m, 1H),
3.42 (s, 2H), 4.1-4.2 (d, J = 7.2 Hz, 2H), 4.84 (s, 1H), 5.0-5.1
(m, 1H), 5.68 (d, J = 5.2 Hz, 1H), 6.75 (d, J = 14.4 Hz, 1H),
7.1-7.6 (m, 8H); 13C NMR (100.6 MHz, CDCl3) δ 21.7, 41.6,
42.2, 47.7, 68.5, 72.2, 76.7, 77.0, 77.3, 111.6, 115.1, 118.3, 119.4,
121.7, 128.4.131.9, 134.9, 138.8, 172.3.
Note Added after ASAP Publication. Table 4 was removed
from this paper because it appears in the Supporting Informa-
tion. It was reposted without Table 4 on October 21, 2010.
7518 J. Org. Chem. Vol. 75, No. 22, 2010