A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; Application to an enantioselective synthesis of atorvastatin

Article abstract of DOI:10.1016/j.tet.2011.05.109

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH₃CN) ₄]PF₆/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Bronsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.

Full text of DOI:10.1016/j.tet.2011.05.109

Tetrahedron 67 (2011) 6539e6546
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simplified catalytic system for direct catalytic asymmetric aldol reaction of
thioamides; application to an enantioselective synthesis of atorvastatin
,
,
,
,
a,
Yuji Kawato a b, Mitsutaka Iwata a b, Ryo Yazaki a b, Naoya Kumagai a , Masakatsu Shibasaki
*
*
a Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2011
Received in revised form 25 May 2011
Accepted 26 May 2011
Available online 2 June 2011
A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides.
The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency
over the previously developed catalyst comprising [Cu(CH3CN)4]PF6/Ph-BPE/LiOAr (first-generation
catalyst), which required a tedious catalyst preparation process. In the reaction with the second-
generation catalyst, the intermediate Cu-aldolate functioned as a Brønsted base to generate thioamide
enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise
asymmetric synthesis of atorvastatin (LipitorÒ: atorvastatin calcium), a widely prescribed HMG-CoA
reductase inhibitor for lowering low-density lipoprotein cholesterol.
Keywords:
Asymmetric catalysis
Aldol reaction
Thioamide
Ó 2011 Elsevier Ltd. All rights reserved.
Atorvastatin
Mesitylcopper
1. Introduction
In this context, we recently developed a direct catalytic asym-
metric aldol reaction using thioamides 1 as the aldol donor pro-
The aldol reaction, one of the oldest reactions described in the
literature, is frequently used in both chemical and biochemical
processes.1 Historically, the focus of aldol chemistry gradually
shifted from the control of enolate geometries for diaster-
eoselection, a Lewis acid catalyzed aldol reaction using preformed
enolates, and enantioselection using auxiliaries, to catalytic asym-
metric aldol reactions using chiral Lewis acids.2 Most recently,
considerable advances have been made in direct catalytic asym-
metric aldol methodology, in which catalytic in situ generation of
enolates and the subsequent addition to aldehydes are promoted
by the actions of a specifically designed chiral catalyst.3 Because
catalytic in situ generation of enolates is central to triggering this
process, aldol donors, such as ketones and aldehydes that are tend
to form enolates through facile deprotonation are commonly used.4
Despite their prospective synthetic utility, however, the use of aldol
donors in the carboxylic acid oxidation state in a direct catalytic
asymmetric aldol reaction is limited due to reluctant enolate for-
moted by a soft Lewis acid/hard Brønsted base cooperative binary
catalyst.6,7 Thioamide 1 is expected to be chemoselectivelyactivated
by a soft Lewis acid in the presence of aldehyde 2 due to the soft
Lewis basic nature of thioamide functionality, allowing for the facile
generation of active thioamide enolate.8e11 The soft Lewis acid/hard
Brønsted base cooperative catalyst comprising [Cu(CH3CN)4]PF6/
(R,R)-Ph-BPE/LiOAr (first-generation catalyst, ArOH: 2,2,5,7,8-
pentamethylchromanol (4)) was identified as an optimal cata-
lyst,12 affording enantiomerically enriched
b-hydroxythioamides 3
under proton transfer conditions (Scheme 1a).6a,b Phosphine oxide
additive 5 as a hard Lewis basic catalyst component13,14 rendered
the reaction enantio- and syn-selective (Scheme 1b).6c These re-
actions are intriguing because the more acidic non-branched alde-
hydes, which notoriously undergo extensive self-condensation
under conventional basic conditions, afforded the desired aldol
products exclusively. However, the catalyst system was complicated
and freshly prepared Li-aryloxide solution was essential. Further-
more, particularly for the reaction with thioacetamide 1a, the cat-
alytic activity was eroded depending on the functional group of the
mation resulting from the intrinsic low acidity of the
a-proton in
this class of pronucleophiles.5
aldehyde, accompanied by undesired
b-elimination of the aldol
product. Herein, we report the second-generation catalyst com-
prising mesitylcopper and Ph-BPE, a simplified catalytic system
exhibiting identical or superior catalytic performance. The direct
catalytic asymmetric aldol reaction was successfully applied to
a concise enantioselective synthesis of atorvastatin (LipitorÒ:
* Corresponding authors. Tel.: þ81 3 3447 7779; fax: þ81 3 34417589 (M.S.); tel.:
þ81 3 3441 8133; fax: þ81 3 3441 7589 (N.K.); e-mail addresses: nkumagai@bi-
kaken.or.jp (N. Kumagai), mshibasa@bikaken.or.jp (M. Shibasaki).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.109

6540
Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
Table 1
(a)
Investigation of the catalyst
Entry
1
Catalyst (mol %)
Solvent
DMF
Yielda (%)
91
ee (%)
91
[Cu(CH3CN)4]PF6(3)
(R,R)-Ph-BPE
(b)
(3) Li salt of 4 (3)
Li salt of 4 (3)
2
3
DMF
DMF
0
0
d
d
[Cu(CH3CN)4]PF6(3)
(R,R)-Ph-BPE (3)
[Cu(CH3CN)4]PF6(3)
(R,R)-Ph-BPE (3)
Li salt of 4 (3)
[Cu(CH3CN)4]PF6(3)
(R,R)-Ph-BPE (3)þpyridine (30)
Li salt of 4 (3)
Mesitylcopper (3)
(R,R)-Ph-BPE (3)
4(3)
Mesitylcopper (3)
(R,R)-Ph-BPE (3)
4(3)
4
5
6
7
THF
THF
DMF
THF
DMF
0
d
8
90
93
89
94
97
98
83
8
Mesitylcopper (3)
(R,R)-Ph-BPE (3)
a
Determined by 1H NMR analysis with (CHCl2)2 as an internal standard.
mesitylcopper and (R,R)-Ph-BPE promoted the desired aldol re-
action with comparable enantioselectivity (entry 8). The likely
scenario for the catalytic cycle is as follows; first, mesitylcopper and
thioamide 1a generate thioamide enolate 6 decorated with a (R,R)-
Ph-BPE ligand, and subsequent addition to aldehyde 2 gives Cu-
aldolate 7, which functions as a soft Lewis acid/hard Brønsted
base cooperative catalyst to generate thioamide enolate from 1a,
promoting the following catalytic cycles (Fig. 1b). This catalytic
system is quite intriguing because the intermediate, Cu-aldolate 7,
plays a critical role as a catalyst to drive the catalytic cycles,
achieving efficient enantioselective CeC bond formation with
proton transfer between substrates. This simplified catalytic system
was applicable to other non-branched aldehydes 2b,c without self-
condensation, and a similar catalytic performance was observed
with [Cu(CH3CN)4]PF6/(R,R)-Ph-BPE/LiOAr, with which tedious and
careful preparation of LiOAr and the use of DMF as the solvent was
essential (Table 2).
The newly developed second-generation catalyst was applied to
a concise enantioslective synthesis of atorvastatin (LipitorÒ; ator-
vastatin calcium), which is an HMG-CoA reductase inhibitor widely
marketed throughout the world for the treatment of hypercholes-
terolemia. Due to the importance of the drug, extensive synthetic
studies were conducted,15,16 in particular for the synthetic study for
optically active syn-3,5-dihydroxy carboxylic acid moiety.21 Our
synthesis commenced with the direct catalytic asymmetric aldol
reaction of functionalized aldehyde, 3-benzyloxypropanal (2d)
Scheme 1. Direct catalytic asymmetric aldol reaction of thioamides promoted by a soft
Lewis acid/hard Brønsted base cooperative catalyst comprising [Cu(CH3CN)4]PF6/(R,R)-
Ph-BPE/LiOAr (the first-generation catalyst).
atorvastatin calcium),
a
widely prescribed 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for
lowering low-density lipoprotein (LDL) cholesterol.15,16
2. Results and discussion
The design of the first-generation catalyst was based on a binary
catalyst endowed with soft Lewis acid and hard Brønsted base
functions for chemoselective activation of thioamides 1 in the
presence of aldehyde. [Cu(CH3CN)4]PF6/(R,R)-Ph-BPE and Li salt of
2,2,5,7,8-pentamethylchromanol (4) emerged as the best combi-
nation of soft Lewis acid and hard Brønsted base components,
respectively.6a,17 The Cu(I) cation was proved essential because the
aldol reaction of N,N-diallylthioacetamide (1a) and iso-
butyraldehyde (2a) did not proceed at all in the absence of Cu as
a soft Lewis acid component (Table 1, entries 1 and 2). In contrast,
the presence of a Li cation was not crucial; Li aryloxide was in-
dispensable for the aldol reaction (entry 3), but the Li cation itself
may be nothing more than a counter cation of aryloxide and may
thus have no specific role in the proposed catalytic cycle (Fig. 1a).
Furthermore, {CuPF6/(R,R)-Ph-BPEþLiOAr} is in equilibrium with
{[CuOAr/(R,R)-Ph-BPEþLiPF6],17c in which CuOAr might be able to
function as a soft Lewis acid/hard Brønsted base cooperative cata-
lyst. To clarify the function of the Li cation and catalytic activity of
CuOAr, we conducted a control experiment using the chiral CuOAr
catalyst in the absence of a Li source, which was prepared from
mesitylcopper,18,19 (R,R)-Ph-BPE, and 4. Surprisingly, the Li-free
catalyst exhibited higher catalytic efficiency (entry 6). In the pres-
ence of Li cation, a Lewis basic additive or solvent, such as DMF or
pyridine were essential for catalyst turnover (entries 4 and 5). In
contrast, in the absence of a Li cation, the reaction proceeded
without any Lewis basic species and the reaction outcome was
similar with DMF or THF solvent (entries 6 and 7).20 More in-
triguingly, the aldol reaction proceeded without 4; only
(Scheme 2). The
conversion of the thioamide functionality and the following syn-
selective reduction of -hydroxy ketone delivers 8. Installation of
b-ketoester moiety of 9 can be installed by direct
b
a pyrrole moiety and deprotection affords atorvastatin. Initially, we
conducted the aldol reaction using thioamide 1a with the first-
generation catalyst, comprising [Cu(CH3CN)4]PF6/(S,S)-Ph-BPE/
LiOAr or KOAr, but, the catalytic performance was not satisfactory in
a series of trials (Table 3, left column). Even in the presence of
phosphine oxides, which are anticipated to enhance the Brønsted
basicity of LiOAr, no improvement of yield was observed (entries
1e3). The reaction at the higher temperature (ꢀ40 ꢁC) partly im-
proved the yield (entry 4). Changing the counter cation of the

Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
6541
Fig. 1. Proposed catalytic cycle of a direct aldol reaction with (a) the first-generation catalyst and (b) the second-generation catalyst.
Table 2
aryloxide base from lithium to potassium led to a higher yield, but
there was also a greater tendency to produce the undesired cor-
Application of the second-generation catalysta
responding unsaturated thioamide 10ad via b-elimination (entry
5). Our next focus was the use of the second-generation catalyst,
which is anticipated to offer higher catalytic efficiency with
a lower tendency for triggering b-elimination (Table 3, right col-
umn).With 10 mol % of mesitylcopper/(S,S)-Ph-BPE, the desired
reaction proceeded at ꢀ60 ꢁC in DMF to afford 3ad in 49% with 84%
ee (Table 3, entry 8). The use of dried MS 5A was beneficial to
improve the enantioselectivity to 94% ee (entry 9). The yield in-
creased by changing the reaction solvent from DMF to THF with
compensation for the enantioselectivity (entry 10). Binary solvent
system of DMF/THF¼1/1 marginally compromised the yield and
enantioselectivity (entry 11). The use of MS 5A and binary solvent
system were also effective for the first-generation catalyst with
KOAr base (entries 5e7). The addition of 1 equiv of 2,2,5,7,8-
pentamethylchromanol (4) to the second-generation catalyst en-
hanced the catalytic efficiency without affecting enantiose-
lectivity, presumably because proton transfer was mediated by
phenolic proton of 4, and MS 5A was equally effective (entries 12
and 13). The thus identified optimal reaction conditions can be run
with 5 mol % of catalyst loading and scaled to 1 g reaction (entries
14 and 15).
Entry
1
Aldehyde
Product
Yieldb (%)
81
ee (%)
94
2
79
66
89
89
3
a
Compound la: 0.24 mmol, 2: 0.2 mmol.
Isolated yield.
b
We set out to the enantioseletive synthesis of atorvastatin
(Scheme 3). After protecting the secondary alcohol of 3ad as TBS
ether with TBSOTf/2,6-lutidine in 96% yield, the thioamide func-
tionality was chemoselectively activated by treatment with methyl
triflate at room temperature to give methylthioiminium in-
termediate 11, which was subjected to the lithium enolate derived
from tert-butyl acetate to afford b-ketoester 12 in 72% in two steps.
Removal of TBS by TBAF, followed by syn-selective reduction of the
ketone with Et2B(OMe)/NaBH4, furnished syn-diol in a highly dia-
stereoselective manner,22 which was isolated after converting to
the corresponding acetonide 13 in 88% yield in three steps.16a,21a,21g
Hydrogenolysis of benzyl ether was performed over Pd(OH)2 cat-
alyst under 1 atm of hydrogen atmosphere at 60 ꢁC and subsequent
tosylation of the primary alcohol gave 14 in 91% yield in two
steps.21a,21g,21h Introduction of pyrrole moiety was conducted by
transformation into a primary amine followed by a PaaleKnorr
reaction with diketone 16.16b 14 was treated with NaN3 in DMF to
give the corresponding azide in 82% yield, which was reduced to
primary amine 15 with PPh3 in wet THF in 87%.21h,21i The
Scheme 2. Retrosynthetic analysis of atorvastatin.

6542
Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
Table 3
Direct catalytic asymmetric aldol reaction of functionalized aldehyde 2da
aCompound la: 0.24 mmol, 2d: 0.2 mmol.
bDetermined by 1H NMR analysis with (CHCl2)2 as an internal standard.
cCompound 2d (1.0 g) was used.
dDMF/THF¼1/1.
PaaleKnorr reaction of the amine 15 and diketone 16 was per-
formed at 110 ꢁC to construct a pyrrole ring,16b,23 which was sub-
jected to the acidic hydrolysis to afford atorvastatin in 67% yield in
three steps.
PheBPE ligand and mesitylcopper,19 which are both commercially
available, allowing us to skip the tedious preparation of LiOAr,
which should be prepared just before use with extensive care for
moisture. It is intriguing that the intermediate Cu-aldolate works as
a soft Lewis acid/hard Brønsted base cooperative catalyst to pro-
mote deprotonation and enolate generation in the catalytic cycle.
The direct catalytic asymmetric aldol reaction was successfully
applied to a concise enantioselective synthesis of atorvastatin, in
which transformation of the thioamide functionality to b-ketoester
was a secondary key step. Further improvement of catalytic
efficiency and enantioselectivity in the catalytic asymmetric aldol
reaction for the practical synthesis of atorvastatin is currently
underway.
4. Experimental
4.1. General
Direct catalytic asymmetric aldol reaction was performed in
a flame-dried 20 mL test tube with a Teflon-coated magnetic stir-
ring bar except for the reaction described as entry 15 in Table 3. The
test tubes were fitted with a 3-way glass stopcock and reactions
were run under Ar atmosphere. Dry THF, DMF, and nBuLi in
n-hexane were purchased from commercial sources. THF was fur-
ther purified through a Glass Contour system. Flash chromatogra-
phy was performed using silica gel 60 (230e400 mesh) purchased
from Merck. All work-up and purification procedures were carried
out with reagent-grade solvents under an ambient atmosphere.
Infrared (IR) spectra were recorded on a Horiba FT210 Fourier
transform infrared spectrophotometer. NMR spectra were recorded
on JEOL ECS-400 or ECA-600 spectrometers. Optical rotation was
measured using a 2 mL cell with a 1.0 dm path length on a JASCO
polarimeter P-1030. ESI mass spectra were measured on JEOL
AccuTOF JMS-T100LC. High-resolution mass spectra (ESI TOF (þ))
were measured on ThermoFisher Scientific LTQ Orbitrap XL. HPLC
analysis was conducted on a JASCO HPLC system equipped with
Scheme 3. Enantioselective synthesis of atorvastatin.
DAICEL chiral stationary phase columns (0.46 cm
fꢂ25 cm).
3. Summary
4.2. General procedure for direct catalytic asymmetric aldol
reaction
We developed
a simplified catalytic system, the second-
generation catalyst, for the direct catalytic asymmetric aldol re-
action of thioamide. The second-generation catalyst comprises of
4.2.1. Aldol reaction with the first-generation catalyst (Table 3,
entry 1). To a flame-dried 5 mL pear-shaped flask equipped with

Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
6543
a magnetic stirring bar and a 3-way glass stopcock was charged
with 2,2,5,7,8-pentamethylchromanol (4) (88.1 mg, 0.40 mmol) and
dried under vacuum for 60 min. Ar was back-filled to the flask and
dry THF (2.0 mL) was added via a stainless steel needle and a sy-
1H), 4.14e4.08 (m, 1H), 3.90 (ddd, J¼9.8, 5.5, 1.9 Hz, 1H), 3.70 (br s,
1H), 2.80 (dd, J¼15.6, 1.9 Hz, 1H), 2.65 (dd, J¼15.6, 9.8 Hz, 1H),
1.79e1.70 (m, 1H), 0.95 (d, J¼7.0 Hz, 3H), 0.93 (d, J¼7.3 Hz, 3H); 13C
NMR (CDCl3)
d 203.5, 130.6, 130.5, 118.6, 117.9, 74.6, 55.8, 52.9, 45.2,
ringe. To the solution was added nBuLi (247
mL, 0.40 mmol,1.62 M in
33.3,18.5,17.8; [
a
]
23 þ92.1 (c 1.0, CHCl3, 91% ee sample); ESI-MS m/z
D
n-hexane) at ꢀ78 ꢁC and stirred at the same temperature for 60 min
to give 0.2 M lithium 2,2,5,7,8-pentamethylchromanolate solution
in THF, which was stored at room temperature and used within
15 min.
250 [MþNa]þ; HRMS (ESI-TOF) Anal. Calcd for C12H21NNaOS m/z
250.1232 [MþNa]þ, found 250.1246; HPLC: DAICEL CHIRALCEL
OD-H (
f
0.46 cmꢂ25 cm), 2-propanol/n-hexane¼1/99, flow rate
0.5 mL/min, detection at 254 nm, tR¼17.0 min (minor), 22.1 min
To a flame-dried 5 mL pear-shaped flask equipped with a mag-
netic stirring bar and a 3-way glass stopcock were charged with
(S,S)-Ph-BPE (202.5 mg, 0.40 mmol) and [Cu(CH3CN)4]PF6 (149.0 mg,
0.40 mmol) in a dry box. To the mixture was added THF (4.0 mL) via
syringe to give 0.1 M THF solution of (S,S)-Ph-BPE/Cu solution, which
was stored at room temperature and used within 3 h.
(major).
4.2.4. (S)-N,N-Diallyl-3-hydroxydecanethioamide (3ab). Pale yellow
oil; IR (neat) n
3408, 3084, 2925, 2854, 1642 cmꢀ1; 1H NMR (CDCl3)
d
5.87 (dddd, J¼17.1, 10.5, 5.9, 5.9 Hz, 1H), 5.77 (dddd, J¼17.1, 10.4,
4.9, 4.9 Hz,1H), 5.30e5.13 (m, 4H), 4.69 (dd, J¼14.9, 5.9 Hz,1H), 4.58
(dd, J¼14.9, 5.9 Hz, 1H), 4.27e4.20 (m, 1H), 4.19e4.10 (m, 3H), 2.76
(dd, J¼15.9, 1.9 Hz, 1H), 2.63 (dd, J¼15.9, 9.6 Hz, 1H), 1.60e1.26 (m,
To a flame-dried 20 mL test tube equipped with a magnetic
stirring bar and a 3-way glass stopcock were added (S,S)-Ph-BPE/Cu
solution (0.1 M/THF, 200
mL, 0.02 mmol), dry DMF (2 mL), N,N-
12H), 0.88e0.86 (m, 3H); 13C NMR (CDCl3)
d 203.0, 130.6, 130.4,
diallylthioacetamide (1a) (38.5
m
L, 0.24 mmol) and 3-
118.7, 117.9, 69.9, 55.6, 52.8, 47.9, 36.6, 31.8, 29.6, 29.2, 25.6, 22.6,
23
benzyloxypropanal (2d) (32.5
m
L, 0.2 mmol) under Ar at room
14.1; [
a
]
þ74.0 (c 1.3, CHCl3, 89% ee sample); ESI-MS m/z 306
D
temperature. The test tube was cooled to ꢀ60 ꢁC and lithium
[MþNa]þ; HRMS (ESI-TOF) Anal. Calcd for C16H29NNaOS m/z
2,2,5,7,8-pentamethylchromanolate (0.2 M/THF,100 mL, 0.02 mmol)
306.1862 [MþH]þ, found 306.1859; HPLC: DAICEL CHIRALCEL OD-H
was added slowly. After 60 h of stirring at ꢀ60 ꢁC, acetic acid in THF
(0.1 M/THF, 0.2 mL, 0.02 mmol), satd NH4Cl aq and bipyridine
(3.1 mg, 0.02 mmol, essential to make sure the dissociation of the
product from Cu complex) were added to the reaction mixture. The
aqueous layer was extracted with ethyl acetate and the combined
organic layers were washed with brine, dried over Na2SO4. Filtrate
was concentrated under reduced pressure. The chemical yield of
3ad was determined by 1H NMR analysis of the crude sample with
(CHCl2)2 as an internal standard (43%). Enantiomeric excess was
determined by HPLC analysis (90% ee).
(
f
0.46 cmꢂ25 cm), 2-propanol/n-hexane¼1/19, flow rate 0.5 mL/
min, detection at 254 nm, tR¼10.4 min (minor), 12.5 min (major).
4.2.5. (S)-10-(Diallylamino)-8-hydroxy-10-thioxodecyl benzoate
(3ac). Colorless oil; IR (neat)
3414, 2929, 2856, 1717, 1276 cmꢀ1
1H NMR (CDCl3)
8.03 (d, J¼7.3 Hz, 2H), 7.54 (t, J¼7.9 Hz, 1H), 7.43
n
;
d
(dd, J¼7.9, 7.3 Hz, 2H), 5.88 (dddd, J¼16.8, 10.7, 6.0, 6.0 Hz, 1H), 5.77
(dddd, J¼17.1,10.9, 4.5, 4.5 Hz,1H), 5.81e5.73 (m,1H), 5.29e5.13 (m,
4H), 4.69 (dd, J¼14.9, 6.0 Hz, 1H), 4.59 (dd, J¼14.9, 6.0 Hz, 1H), 4.31
(t, J¼6.6 Hz, 2H), 4.25e4.09 (m, 3H), 3.50 (br s, 1H), 2.75 (dd, J¼15.9,
1.5 Hz, 1H), 2.63 (dd, J¼15.9, 9.5 Hz, 1H), 1.79e1.73 (m, 2H),
4.2.2. Aldol reaction with the second-generation catalyst (Table 3,
entry 15). To a flame-dried 5 mL pear-shaped flask equipped with
a magnetic stirring bar and a 3-way glass stopcock were charged
with (S,S)-Ph-BPE (151.8 mg, 0.31 mmol) and mesitylcopper
(56.7 mg, 0.31 mmol) in a dry box. To the mixture was added THF
(1.0 mL) via syringe at 0 ꢁC. After 10 min of stirring at room tem-
perature, pale yellow 0.1 M THF solution of (S,S)-Ph-BPE/mesi-
tylcopper solution was obtained, which was used within 15 min.
A 200 mL flask charged with MS 5A (6.10 g, 1.0 g/mmol alde-
hyde) equipped with a magnetic stirring bar and a 3-way glass
stopcock was flame-dried under reduced pressure. After cooling to
room temperature, dry DMF (30 mL), THF (27 mL), N,N-diallylth-
ioacetamide (1a) (1.15 g, 7.31 mmol), and 3-benzyloxypropanal (2d)
(1.0 g, 6.10 mmol) were added via syringe. The flask was cooled to
ꢀ60 ꢁC. To the resulting cooled solution was added (S,S)-Ph-BPE/
mesitylcopper solution (0.1 M/THF, 3.05 mL, 0.305 mmol) dropwise
to run the reaction. After 72 h of stirring at ꢀ60 ꢁC, acetic acid
solution in THF (0.1 M/THF, 3.1 mL, 0.31 mmol), satd NH4Cl aq and
bipyridine (47.6 mg, 0.305 mmol, essential to make sure the dis-
sociation of the product from Cu complex) were added to the re-
action mixture and aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine and dried
over Na2SO4. Filtrate was concentrated under reduced pressure and
the resulting residue was purified by silica gel column chroma-
tography (eluent: n-hexane/EtOAc¼5/1 to 2/1) to give 3ad as a pale
yellow oil (1.20 g, 62%). Enantiomeric excess was determined by
HPLC analysis (83% ee).
1.61e1.34 (m, 10H); 13C NMR (CDCl3)
d 202.9, 166.6, 132.7, 130.6,
130.5, 130.5, 129.5, 128.3, 118.7, 117.9, 69.8, 65.0, 55.6, 52.8, 47.9,
23
36.5, 29.4, 29.2, 28.7, 25.9, 25.5; [
a
]
þ55.6 (c 1.2, CHCl3, 90% ee
D
sample); ESI-MS m/z 264 [MþNa]þ; HRMS (ESI-TOF) Anal. Calcd for
C23H33NNaOS m/z 426.2062 [MþNa]þ, found 426.2081; HPLC:
DAICEL CHIRALCEL OD-H (
hexane¼1/19, flow rate 1.0 mL/min, detection at 254 nm,
tR¼13.6 min (minor), 17.0 min (major).
f
0.46 cmꢂ25 cm), 2-propanol/n-
4.2.6. (R)-N,N-Diallyl-5-(benzyloxy)-3-hydroxypentanethioamide
(3ad). Pale yellow oil; IR (neat)
n
3413, 3085, 2919, 2861, 1643,
7.34e7.29 (m, 5H), 5.86 (dddd,
1496, 1411 cmꢀ1; 1H NMR (CDCl3)
d
J¼5.7, 5.7, 10.3, 17.2 Hz, 1H), 5.73 (dddd, J¼5.0, 5.0, 10.3, 17.2 Hz, 1H),
5.26e5.09 (m, 4H), 4.75 (dd, J¼5.7, 14.7 Hz, 1H), 4.54e4.50 (m, 1H),
4.51 (s, 2H), 4.41e4.35 (m, 1H), 4.32e4.25 (m, 1H), 4.10e4.04 (m,
1H), 3.71e3.68 (m, 2H), 2.84 (dd, J¼2.8, 15.4 Hz, 1H), 2.76 (dd, J¼8.7,
15.4 Hz, 1H), 1.91e1.79 (m, 2H); 13C NMR (CDCl3)
d 202.5, 138.1,
130.5, 130.5, 130.5, 128.3, 127.6, 127.5, 118.4, 117.7, 73.1, 69.0, 67.9,
22
55.5, 52.8, 48.3, 36.3; [
a
]
ꢀ33.9 (c 0.33, CHCl3, 92% ee sample);
D
ESI-MS m/z 342.2 [MþNa]þ; HRMS (ESI) Anal. Calcd for
C18H25NNaO2S m/z 342.1498 [MþNa]þ, found; 342.1500.
4.3. Synthesis of atorvastatin
4.3.1. (R)-N,N-Diallyl-5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)
pentanethioamide. To a stirred solution of 3ad (800 mg, 2.5 mmol,
92% ee sample) in CH2Cl2 (30 mL) were added 2,6-lutidine (575
mL,
5.0 mmol) and TBSOTf (860
m
L, 3.75 mmol) at 0 ꢁC. After stirring the
4.2.3. (R)-N,N-Diallyl-3-hydroxy-4-methylpentanethioamide
resulting solution at room temperature for 3 h, satd NH4Cl aq was
added and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine and dried over
Na2SO4. The filtrate was concentrated under reduced pressure to
give the title compound as a pale yellow oil (1.04 g, 96%). Pale
(3aa). Colorless oil; IR (neat)
n 3405, 2956, 2929, 2856, 1521, 1073,
5.86 (dddd, J¼17.7, 10.4, 5.8, 5.8 Hz,
835 cmꢀ1 1H NMR (CDCl3)
;
d
1H), 5.77 (dddd, J¼17.1,10.7, 4.6, 4.6 Hz,1H), 5.29e5.12 (m, 4H), 4.69
(dd, J¼14.7, 5.8 Hz, 1H), 4.57 (dd, J¼14.7, 5.8 Hz, 1H), 4.29e4.22 (m,

6544
Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
yellow oil; IR (neat)
n
2954, 2858, 1643, 1493, 1257, 1115 cmꢀ1
;
1H
(93% of the crude material was used) was dissolved in acetone
NMR (CDCl3);
d
7.33e7.29 (m, 5H), 5.92 (dddd, J¼5.8, 5.8, 10.8,
(2.6 mL). After the addition of p-toluenesulfonic acid monohydrate
(16.0 mg, 0.084 mmol) and 2,2-dimethoxypropane (205 mL,
16.7 Hz, 1H), 5.75 (dddd, J¼4.8, 4.8, 10.3, 17.2 Hz, 1H), 5.25e5.08 (m,
4H), 4.83 (dd, J¼5.7, 14.2 Hz, 1H), 4.61e4.53 (m, 2H), 4.48 (dd, J¼3.0,
15.1 Hz, 1H), 4.34 (dd, J¼6.9, 14.2 Hz, 1H), 4.00e3.95 (m, 1H),
3.64e3.51 (m, 2H), 3.10 (dd, J¼8.2, 13.8 Hz, 1H), 2.83 (dd, J¼4.1,
13.8 Hz, 1H), 1.90e1.86 (m, 2H), 0.84 (s, 9H), 0.06 (s, 3H), 0.02 (s,
1.68 mmol), the resulting solution was stirred for 4 h at room
temperature. After the reaction was completed, satd NaHCO3 aq
was added to neutrality. The resulting mixture was extracted with
ether, and the combined organic phase was washed with brine,
then dried over Na2SO4. Filtrate was concentrated under reduced
pressure to give 13 as a colorless oil (294 mg, 88% over three steps).
3H); 13C NMR (CDCl3)
d
203.0, 138.6, 131.5, 131.3, 128.3, 127.6, 127.5,
119.3, 117.6, 73.0, 72.1, 66.5, 56.4, 53.1, 50.2, 37.4, 25.9, 25.7, 25.6,
22
17.9, ꢀ4.3, ꢀ4.8; [
a
]
þ6.8 (c 1.0, CHCl3); ESI-MS m/z 456.3
Colorless oil; IR (neat)
n
2954, 2931, 2858, 1739, 1716, 1647, 1458,
D
[MþNa]þ; HRMS (ESI) Anal. Calcd for C24H39NNaO2SSi m/z
456.2363 m/z [MþNa]þ, found; 456.2358.
1369, 1254, 1146, 1115 cmꢀ1
;
1H NMR (CDCl3)
d
7.38e7.27 (m, 5H),
4.50 (dd, J¼4.8, 12.1 Hz, 2H), 4.28e4.21 (m, 1H), 4.09e4.03 (m, 1H),
3.62e3.50 (m, 2H), 2.42 (dd, J¼7.1, 15.1 Hz, 1H), 2.29 (dd, J¼6.2,
15.1 Hz, 1H), 1.81e1.68 (m, 2H), 1.56 (dt, J¼2.3, 12.6 Hz, 1H), 1.44 (s,
9H), 1.44 (s, 3H), 1.35 (s, 3H), 1.21e1.15 (m, 1H); 13C NMR (CDCl3)
4.3.2. (R)-tert-Butyl 7-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-
3-oxoheptanoate (12). To a solution of TBS protected 3ad (920 mg,
2.12 mmol) in dry ether (23 mL) was added MeOTf (467
m
L,
d 170.3, 138.5, 128.4, 127.6, 127.5, 98.7, 80.5, 73.0, 66.3, 66.2, 66.0,
4.24 mmol) at 0 ꢁC. After stirring the resulting solution at room
42.8, 36.6, 36.5, 30.1, 28.1, 19.6; [
a
]
D
22 þ21.9 (c 0.26, CHCl3); ESI-MS
temperature for 4.5 h, the reaction mixture was cooled to ꢀ78 ꢁC.
m/z 387.2 [MþNa]þ; HRMS (ESI) Anal. Calcd for C21H32NaO5 m/z
To the mixture was added CH2]C(OLi)OtBu (640
mL, 1.0 M in THF,
387.2142 [MþNa]þ, found; 387.2140.
6.40 mmol) and resulting solution was stirred for 3 h. The reaction
was quenched with silica gel (5 g) at ꢀ78 ꢁC and diluted with
CH2Cl2 (7 mL). The resulting mixture was stirred at room temper-
ature for 1.5 h, then filtered through a short pad of silica gel with
CH2Cl2 as eluent. The filtrate was concentrated under reduced
pressure. The resulting residue was dissolved in THF (20 mL). To the
solution was added 1 N HCl aq (2 mL) at room temperature and the
resulting solution was stirred for 30 min at the same temperature.
The mixture was diluted with ethyl acetate, and resulting biphasic
mixture was washed with satd NaHCO3 aq and brine, then dried
over Na2SO4. The filtrate was concentrated under reduced pressure
and the resulting residue was purified by silica gel column chro-
matography (eluent n-hexane/ethyl acetate¼20/1) to give 12 as
4.3.4. tert-Butyl 2-((4R,6R)-2,2-dimethyl-6-(2-(tosyloxy)ethyl)-1,3-
dioxan-4-yl)acetate (14). A solution of 13 (153 mg, 0.419 mmol)
containing 20% Pd(OH)2 on carbon (25 mg), ethyl acetate (1.5 mL)
was stirred under H2 atmosphere for 24 h at 60 ꢁC. After cooling, the
catalyst was filtrated, and the filtrate was concentrated in vacuo. The
crude was dissolved in CH2Cl2 (2.5 mL). After the addition of Et3N
(175 mL, 1.25 mmol), DMAP (15.3 mg, 0.417 mmol), and p-toluene-
sulfonyl chloride (159.3 mg, 0.834 mmol) in one portion at 0 ꢁC, the
reaction mixture was stirred at room temperature for 4 h. The
resulting mixture was diluted with CH2Cl2 (10 mL) and water
(10 mL), and the organic layer was washed with satd NaHCO3 aq and
dried over Na2SO4. Volatiles were removed under reduced pressure
and the resulting residue was purified by flash chromatography (n-
hexane/ethyl acetate¼10/1e5/1) to afford tosylate 14 (165.1 mg, 91%
a colorless oil (821 mg, 72% over two steps). Colorless oil; IR (neat)
2954, 2931, 2858, 1739, 1716, 1647, 1458, 1369, 1254, 1146,
1115 cmꢀ1; 1H NMR (CDCl3) keto form;
7.36e7.28 (m, 5H), 4.50 (s,
n
d
over two steps). Colorless oil; IR (neat)
1H NMR (CDCl3)
n ;
2981,1728,1365,1176 cmꢀ1
7.91 (d, J¼8.2 Hz, 2H), 7.79 (d, 4H), 7.34 (d, J¼8.2 Hz,
2H), 4.50e4.43 (m, 1H), 3.56e3.48 (m, 2H), 3.34 (s, 2H), 2.69 (d,
J¼6.4 Hz, 2H), 1.81e1.77 (m, 2H), 1.45 (s, 9H), 0.85 (s, 9H), 0.05 (s,
d
2H), 4.26e4.13 (m, 2H), 4.11e4.06 (m,1H), 3.97e3.91 (m,1H), 2.45 (s,
3H), 2.39 (dd, J¼7.1, 15.1 Hz, 1H), 2.26 (dd, J¼6.2, 15.1 Hz, 1H),
1.84e1.67 (m, 2H),1.51e1.45 (m, 2H),1.44 (s, 9H),1.34 (s, 3H),1.27 (s,
3H), 0.03 (s, 3H); enol form;
d 12.15 (br s, 1H), 7.36e7.28 (m, 5H),
4.90 (s, 1H), 4.33 (s, 2H), 4.35e4.31 (m, 1H), 3.56e3.48 (m, 2H), 2.29
(d, J¼6.6 Hz, 2H), 1.77e1.73 (m, 2H), 1.47 (s, 9H), 0.87 (s, 9H), 0.05 (s,
3H); 13C NMR (CDCl3)
d 170.1, 144.7, 133.0, 129.8, 127.9, 98.8, 80.6,
3H), 0.02 (s, 3H); 13C NMR (CDCl3) keto-enol mixture;
d
202.1, 166.3,
66.7, 66.0, 64.7, 42.6, 36.2, 35.4, 29.9, 28.1, 21.6, 19.5; [
a
]
22 þ12.9 (c
D
138.4, 128.3, 127.6, 127.5, 113.9, 92.8, 81.8, 80.6, 73.0, 73.0, 72.9, 67.2,
0.9, CHCl3); ESI-MS m/z 451.2 [MþNa]þ; HRMS (ESI) Anal. Calcd for
66.6, 66.4, 52.0, 50.3, 43.8, 37.3, 37.2, 28.6, 28.3, 28.0, 25.8, 17.9,
C21H32NaO7S m/z 451.1761 [MþNa]þ, found; 451.1756.
22
ꢀ4.7, ꢀ4.8, ꢀ4.9; [
a]
ꢀ7.6 (c 0.5, CHCl3); ESI-MS m/z 459.3
D
[MþNa]þ; HRMS (ESI) Anal. Calcd for C24H40NaO5Si m/z 459.2537
[MþNa]þ, found; 459.2534.
4.3.5. tert-Butyl 2-((4R,6R)-6-(2-azidoethyl)-2,2-dimethyl-1,3-
dioxan-4-yl)acetate. A mixture of tosylate 14 (120.0 mg,
0.277 mmol) and sodium azide (36.0 mg, 0.555 mmol) in DMF
(1.5 mL) was stirred for 6 h at room temperature. The reaction
mixture was diluted with water (1 mL) and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4. Re-
moval of the volatiles under reduced pressure gave crude azide,
which was purified by a short pad of silica gel (n-hexane/ethyl
acetate¼2/1) to afford azide as colorless oil (67.8 mg, 82%). Colorless
4.3.3. tert-Butyl 2-((4R,6R)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-
dioxan-4-yl)acetate (13). A solution of 12 (400 mg, 0.916 mmol)
and dry THF (2.5 mL) was cooled to 0 ꢁC, then TBAF (1.30 mL, 1.0 M
in THF, 1.30 mmol) was added dropwise. After 30 min of stirring at
the same temperature, the resulting mixture was stirred at room
temperature for 3 h, then water (2 mL) was added and aqueous
layer was extracted with ethyl acetate. The combined organic layers
were washed with brine, then dried over Na2SO4. Filtrate was
concentrated under reduced pressure and the resulting pale yellow
residue (98% of the crude residue was used) was dissolved in THF
(8.5 mL) and MeOH (2.4 mL). The solution was cooled to ꢀ80 ꢁC and
diethylmethoxyborane (1.0 mL, 1.0 M in THF, 1.0 mmol) was slowly
added at the same temperature. After 10 min of stirring, sodium
borohydride (37.8 mg, 1.0 mmol) was added and the resulting
mixture was stirred for 10 h at the same temperature. The reaction
was quenched with acetic acid (2 mL) and the resulting mixture
was diluted with ethyl acetate, which was washed with satd
NaHCO3 aq and brine, then dried over Na2SO4. Filtrate was con-
centrated under reduced pressure to give crude syn-diol, which
oil; IR (neat)
4.37e4.30 (m, 1H), 4.12e4.06 (m, 1H), 3.48e3.41 (m, 2H), 2.37 (dd,
n
2978, 2939, 2877, 2098, 1732 cmꢀ1; 1H NMR (CDCl3)
d
J¼5.5, 14.9 Hz, 1H), 2.33 (dd, J¼7.6, 14.9 Hz, 1H), 1.80e1.65 (m, 2H),
1.66 (dt, 2.5, 12.6 Hz, 1H), 1.48 (s, 3H), 1.46 (s, 9H), 1.32 (s, 3H),
1.22e1.13 (m, 1H); 13C NMR (CDCl3)
d
170.1, 98.8, 80.6, 66.1, 65.8,
47.5, 42.6, 36.4, 35.6, 30.0, 28.1, 19.6; [
a
]
22 þ17.9 (c 0.21, CHCl3); ESI-
D
MS m/z 322.2 [MþNa]þ; HRMS (ESI) Anal. Calcd for C14H25N3NaO4
m/z 322.1737 [MþNa]þ, found; 322.1737.
4.3.6. tert-Butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-
dioxan-4-yl)acetate (15). To
a solution of azide (52.1 mg,
0.174 mmol) in a mixture of THF (1.0 mL) and water (0.1 mL), tri-
phenylphosphine (91.3 mg, 0.348 mmol) was added and the

Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
6545
resulting mixture was stirred at 50 ꢁC for 2 h. The reaction mixture
was concentrated to remove THF, followed by coevaporation with
toluene two times. The crude residue was purified by flash chro-
matography (CH2Cl2/MeOH/Et3N, 95:4:1) to give amine 15 as col-
3. Reviews of direct catalytic asymmetric aldol reactions, see: (a) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187; (b) Alcaide, B.; Almendros, P. Eur. J.
Org. Chem. 2002, 1595; (c) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580; (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471; (e) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600 See
also Ref. 1.
orless oil (41.2 mg, 87%). Colorless oil; IR (neat)
n 3374, 2981, 2938,
4. There are numerous examples of direct aldol reactions using aldol donors
2873, 1731, 1176 cmꢀ1 1H NMR (CDCl3)
;
d
4.25e4.19 (m, 1H),
bearing electron-withdrawing
mild basic conditions
a-substituents that are readily enolized under
3.98e3.92 (m, 1H), 2.80e2.77 (m, 2H), 2.39 (dd, J¼6.9, 15.1 Hz, 1H),
2.26 (dd, J¼6.2, 15.1 Hz, 1H), 1.95 (br s, 2H), 1.64e1.50 (m, 3H), 1.42
(s, 9H), 1.42 (s, 3H), 1.33 (s, 3H), 1.30e1.15 (m, 1H); 13C NMR (CDCl3)
5. For direct catalytic asymmetric aldol (-type) reactions using aldol donors at the
carboxylic acid oxidation state without electron-withdrawing -substituents:
a
(a) Alkylnitriles: Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7,
3757; (b) Activated amides: Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128,
8704; (c) b,g-Unsaturated ester: Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2009, 131, 10842; (d) 5H-Oxazol-4-ones: Misaki, T.; Takimoto, G.;
Sugimura, T. J. Am. Chem. Soc. 2010, 132, 6286; (e) Direct catalytic asymmetric
aldol reaction of thiazolidinethiones where the use of stoichiometric amount of
silylating reagent was essential: Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am.
Chem. Soc. 2003, 125, 8706.
6. (a) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 18244; (b) Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Tetrahe-
dron: Asymmetry 2010, 21, 1688; (c) Iwata, M.; Yazaki, R.; Chen, I.-H.; Sure-
shkumar, D.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5554.
7. Recent reviews on cooperative catalysis, see: (a) Lewis acid/Brønsted base Ref. 3a.
(b) Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc. Jpn. 2008, 81, 60; (c) Lewis acid/
Lewis base: Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491; (d)
Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem.
Res. 2008, 41, 655; (e) Lewis acid/Brønsted acid and Lewis acid/Lewis acid: Ya-
mamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924; (f) Yamamoto, H.;
Futatsugi, K. In Acid Catalysis in Modern Organic Synthesis; Yamamoto, H., Ishihara,
K., Eds.; Wiley-VCH: Weinheim, 2008; (g) Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2011, 50, 4760; (h) Heterogeneous catalysis: Lee, J.-K.; Kung, M. C.;
Kung, H. H. Top. Catal. 2008, 49,136; (i) Metal-organic cooperative catalysis: Park,
Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222.
d
170.2, 98.6, 80.5, 67.4, 66.2, 42.6, 39.5, 38.4, 36.5, 30.1, 28.0, 19.7;
22
[a]
þ11.5 (c 0.28, CHCl3); ESI-MS m/z 274.2 [MþH]þ; HRMS (ESI)
D
Anal. Calcd forC14H28NO4 m/z 274.2013 [MþH]þ, found; 274.2015.
4.3.7. (3R,5R)-7-(2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phe-
nylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid (ator-
vastatin). A mixture of amine 15 (40.2 mg, 0.147 mmol), diketone 16
(55.8 mg, 0.133 mmol), pivalic acid (12.0 mg, 0.118 mmol) in n-
hexane/toluene/THF¼1:4:1 (0.48 mL) was heated at 110 ꢁC for 30 h
under Ar. After cooling to room temperature, the mixture was di-
luted with AcOEt and washed with satd NaHCO3 aq, then dried over
Na2SO4. The resulting residue afterevaporationwas dissolved inTHF
(0.5 mL). To the solution was added 2 N HCl in MeOH (1 mL) at 0 ꢁC
and the resulting solution was stirred at room temperature for
30 min. The mixture was diluted with CH2Cl2, and resulting biphasic
mixturewas separated. Organic layer was washed with satd NaHCO3
aq and brine, then dried over Na2SO4. The filtrate was concentrated
under reduced pressure and the resulting residue was dissolved in
wet THF (0.2 mL). 1 N NaOH aq (2 mL) was added at 0 ꢁC and the
resulting solution was stirred at room temperature for 6 h. The
mixture was diluted with CH2Cl2 and 1N HCl aq. The resulting bi-
phasic mixture was extracted with CH2Cl2. The combined organic
layers were washed with brine, then dried over Na2SO4. Volatiles
were removed under reduced pressure and the resulting solid res-
idue was purified by flash chromatography (CH2Cl2/MeOH 18/1) on
silica gel to give atorvastatin as a colorless solid. (54.8 mg, 67% over
8. Use of thioamide as pronucleophile in diastereoselective CeC bond-forming
reactions, see: (a) Tamaru, Y.; Harada, T.; Nishi, S.; Mizutani, M.; Hioki, T.;
Yoshida, Z. J. Am. Chem. Soc. 1980, 102, 7806; (b) Goasdoue, C.; Goasdoue, N.;
Gaudemar, M.; Mladenova, M. J. Organomet. Chem. 1981, 208, 279; (c) Goasdoue,
C.; Goasdoue, N.; Gaudemar, M. Tetrahedron Lett. 1983, 24, 4001; (d) Goasdoue,
C.; Goasdoue, N.; Gaudemar, M. J. Organomet. Chem. 1984, 263, 273.
9. Use of thioamide as pronucleophile in enantioselective CeC bond-forming
reactions, see: Iwasawa, N.; Yura, T.; Mukaiyama, T. Tetrahedron 1989, 45, 1197.
ꢀ
10. For the utility of thioamide functionality, see: Jagodzinski, T. S. Chem. Rev. 2003,
103, 197.
11. Use of thioamides in catalytic asymmetric reactions CeC bond-forming reactions,
see: (a) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed.
2009, 48, 5026; (b) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 10275; (c) Yazaki, R.; Kumagai, N.; Shibasaki, M. Org. Lett. 2011, 13, 952; (d)
Yazaki, R.; Kumagai, N.; Shibasaki, M. Chem.dAsian J., in press. See also Ref. 6.
12. For the use of 2,2,5,7,8-pentamethylchroman unit as electron-donating group,
see: Ramage, R.; Green, J.; Blake, A. J. Tetrahedron 1991, 47, 6353 and references
cited therein.
13. Enhanced Lewis basicity of LiOPh was observed by using a bidentate phosphine
oxide in the Mukaiyama aldol reactions. X-ray crystallographic analysis con-
firmed the coordination of the bidentate phosphine oxide to an Li cation in
a bidentate fashion Hatano, M.; Takagi, E.; Ishihara, K. Org. Lett. 2007, 9, 4527.
14. A comprehensive review of Lewis base catalysis: (a) Denmark, S. E.; Beutner,
G. L. Angew. Chem., Int. Ed. 2008, 47, 1560 and references cited therein. Se-
lected examples for Lewis base activation of Brønsted base, see: (b) McGrath,
M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378; (c) Saito, S.; Tsubogo, T.;
Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364; (d) Morimoto, H.; Yoshino, T.;
Yukawa, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47,
9125.
15. (a) Roth, B. D.; Mich, A. A. U.S. Patent 4,681,893, 1987; (b) Roth, B. D.; Blankley,
C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R.
S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem.
1991, 34, 357; (c) Roth, B. D.; Mich, A. A. U.S. Patent 5,273,995, 1993.
16. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.;
Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279; (b) Baumann, K. L.;
Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C.
W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2283; (c) Wade, R. A.; Zennie, T. M.;
Briggs, C. A.; Jennings, R. A.; Nanninga, T. N.; Palmer, C. W.; Ronald, J. C. Org.
Process Res. Dev. 1997, 1, 320; (d) Butler D. E.; Dejong, R. L.; Nelson, J. D.;
Pamment, M. G.; Stuk, T. L. W. O. Patent 02/055519, 2002. (e) Moody, D. J.;
Wiffen, J. W. W. O. Patent 05/012246, 2005. (f) Srinath, S.; Mathew, J.; Ujire, S.;
Sridharan, M.; Sambasivam, G. W. O. Patent 02/057274, 2002. (g) Sattigeri, J. A.;
Salman, M.; Rawat, S.; Sethi, S. W. O. Patent 05/118536, 2005. (h) Lee, H. W.;
Kim, Y. M.; Yoo, C. L.; Kang, S. K.; Ahn, S. K. Biomol. Ther. 2008, 16, 28.
17. Other examples in which the catalytic system [Cu(CH3CN)4]PF6/chiral phos-
phine ligand/LiOAr is effective for catalytic asymmetric CeC bond forming re-
actions, see: (a) Yazaki, R.; Nitabaru, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 14477; (b) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 3195; (c) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 5522 See also Refs. 6 and 11.
three steps). Colorless solid; IR (KBr)
1529, 1508, 1438, 1315, 1241, 1226 cmꢀ1
7.30e7.29 (m, 2H), 7.25e7.20 (m, 4H), 7.15e7.13 (m, 2H), 7.11e7.02
n
3410, 2964, 2929, 1731, 1652,
;
1H NMR (CD3OD)
d
(m, 6H), 4.08 (ddd, J¼5.3, 7.8, 16.0 Hz 1H), 4.02e3.98 (m, 1H), 3.91
(ddd, J¼5.3, 7.6, 16.0 Hz, 1H), 3.69e3.63 (m, 1H), 3.40e3.34 (m, 1H),
2.41 (dd, J¼5.2,15.5 Hz,1H), 2.35 (dd, J¼7.6,15.5 Hz,1H),1.75e1.6 (m,
2H), 1.56e1.51 (m, 1H), 1.49 (d, J¼7.1 Hz, 3H), 1.48 (d, J¼7.1 Hz, 3H),
1.47e1.43 (m, 1H); 13C NMR (CD3OD)
d 175.9, 169.5, 163.8
(1JCF¼245.5 Hz), 139.9, 139.1, 139.1, 136.4, 134.7 (3JCF¼7.2 Hz), 131.0,
130.3 (4JCF¼2.9 Hz),129.6,128.9,126.9,125.2,123.3,121.5,118.1,116.3
(2JCF¼21.6 Hz), 68.6, 67.9, 44.2, 43.3, 42.2, 40.1, 27.7, 22.9, 22.8; 19F
NMR (CDCl3)
d
ꢀ113.8; [
a
]
D
23 þ5 (c 0.94, CH3OH); ESI-MS m/z 581.2
[MþNa]þ; HRMS (ESI) Anal. Calcd for C33FH35N2NaO5 m/z 581.2422
[MþNa]þ, found; 581.2421.
Acknowledgements
This work was financially supported by a Grant-in-Aid for Sci-
entific Research (S). N.K. thanks the Sumitomo Foundation for fi-
nancial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.109.
References and notes
1. General review of aldol reactions, see:Modern Aldol Reactions; Mahrwald, R.,
Ed.; Wiley-VCH: Weinheim, 2004.
2. Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131.
18. Synthesis, characterization and application of mesitylcopper, see: (a) Tsuda, T.;
Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T. J. Org. Chem. 1981, 46, 192; (b)

6546
Y. Kawato et al. / Tetrahedron 67 (2011) 6539e6546
2275; (d) Liu, J.; Hsu, C.-C.; Wong, C.-H. Tetrahedron Lett. 2004, 45, 2439; (e)
Tsuda, T. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L., Ed.;
Wiley: New York, NY, 1995; p 3271; (c) Eriksson, H.; Hakansson, M. Organo-
metallics 1997, 16, 4243.
ꢁ
€
Muller, M. Angew. Chem., Int. Ed. 2005, 44, 362; (f) Tararov, V. I.; Andrushko, N.;
€
€
Andrushko, V.; Konig, G.; Spannenberg, A.; Borner, A. Eur. J. Org. Chem. 2006,
5543; (g) Sun, F.; Xu, G.; Wu, J.; Yang, L. Tetrahedron: Asymmetry 2007, 18, 2454;
(h) George, S.; Sudalai, A. Tetrahedron Lett. 2007, 48, 8544; (i) Sawant, P.; Maier,
M. E. Tetrahedron 2010, 66, 9738.
19. Freshly prepared mesitylcopper afforded better catalytic efficiency than the
commercial source.
20. Li cation might form a stable complex with Cu-aldolate to halt the catalytic
cycle in the absence of Lewis basic additive or solvent.
22. (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233; (b) Chen, K.-M.; Hardt-
mann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
23. (a) Knorr, L. Ber. 18, 299. (b) Paal, C. Ber. 1885, 18, 367.
€
21. (a) Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014; (b) Ohrlein, R.;
ꢀ
Baisch, G. Adv. Synth. Catal. 2003, 345, 713; (c) Radl, S. Synth. Commun. 2003, 33,