Streamlined catalytic asymmetric synthesis of atorvastatin

Article abstract of DOI:10.1002/chem.201204609

An efficient enantioselective synthetic route to atorvastatin was developed based on a direct catalytic asymmetric aldol reaction. The expensive chiral ligand used in the initial aldol reaction was readily recovered (91 %) and reused. Implementation of an oxy-Michael reaction for the construction of the syn-1,3-diol unit eliminated several redundant steps, allowing for rapid access to the common intermediate in six steps (see scheme). Copyright

Full text of DOI:10.1002/chem.201204609

DOI: 10.1002/chem.201204609
Streamlined Catalytic Asymmetric Synthesis of Atorvastatin
Yuji Kawato,[a, b] Sandeep Chaudhary,[a] Naoya Kumagai,*[a] and
Masakatsu Shibasaki*[a, c]
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Chem. Eur. J. 2013, 19, 3802 – 3806

COMMUNICATION
lengthy reaction sequence associated with unproductive pro-
tection/deprotection steps and the introduction of an amino
group. It is clear that a cost-effective and scalable methodol-
ogy that allows rapid access to 2 is desirable. Herein, we
report a significantly improved synthetic route to 2 in which
the issues mentioned above were resolved by the following
key implementations: 1) efficient recovery of expensive Ph-
BPE and the coupling of this procedure with the requisite
desulfurization step to give amine 8; 2) the amino function-
ality in 2 is retained, eliminating the redundant “nitrogen-in-
troduction step”; 3) the construction and protection of syn-
1,3-diol is performed in a single step by an intramolecular
oxy-Michael reaction of unsaturated ester 9 (Scheme 1b).
This second-generation synthetic route allows us to access
2b in six steps, five steps shorter than the first-generation
route.
Initially, we set out to identify a suitable oxygen-function-
alized aldehyde for the direct catalytic, asymmetric aldol re-
action (Table 1). N,N-Diallylthioacetamide (3) was utilized
as the aldol donor in light of its facile removal of allyl
groups after desulfurization. The catalyst components (R,R)-
Ph-BPE, mesitylcopper, and 2,2,5,7,8-pentamethylchroman-
6-ol (10) are commercially available materials and work as a
precatalyst.[9,12b] Initially, the (R,R)-Ph-BPE/mesitylcopper
Figure 1. Structure of atorvastatin (1) and its common intermediate 2.
Atorvastatin (1), an effective HMG-CoA reductase inhib-
itor,[1,2] and the active ingredient in Lipitor, is in widespread
clinical use for the treatment of hypercholesterolemia
(Figure 1; HMG-CoA=3-hydroxy-3-methylglutaryl coen-
zyme A).[3] Given its reliable efficacy for lowering LDL
(low-density lipoprotein) cholesterol and its established
safety profile, continuous demand is expected and the devel-
opment of an efficient and scalable synthetic route to 1 is of
sustained interest.[4] In this context, extensive efforts have
been devoted to the synthesis of enantioenriched primary
amine 2 and its related compounds, which are common in-
termediates for 1. Indeed, a wide variety of synthetic strat-
egies have been applied to the synthesis of the relatively
simple compound 2, including syntheses through optical res-
olution and chiral auxiliary,[2b,c,5] chiral pool methodology,[6]
enzymatic reactions,[7] and asymmetric catalysis.[8]
Table 1. Direct catalytic asymmetric aldol reaction of oxygen-functional-
ized aldehydes 4.[a]
Recently, we documented a concise enantioselective syn-
thesis of 1, in which a direct catalytic asymmetric aldol reac-
À
tion of thioamide 3 was implemented as the key C C bond-
forming reaction with the introduction of chirality.[9] In this
direct aldol methodology,[10] chemoselective activation of
thioamide by a soft–soft interaction of the Cu+ and a sulfur
atom allowed for the exclusive generation of the thioamide
enolate even in the presence of enolizable aldehydes 4
(Scheme 1a).[11–13] Direct transformation of the thioamide
functionality of aldol adduct (R)-5 into b-ketoester 6 and
the subsequent diastereoselective reduction of the ketone
produced the requisite syn-1,3-diol 7.[9] The major draw-
backs of this first-generation synthetic route are 1) the use
of costly chiral bisphosphine ligand, Ph-BPE; and 2) the
R
4
Catalyst
loading [mol%]
Product
T
T
Yield[b]
[8C] [h] [%]
ee[c]
[%]
1
2
3
4
5
TBS 4a 10
PMB 4b 10
Tr
Tr
Tr
5a
5b
5c
5c
5c
À60 48
À60 48
58 (15) 83
56 (28) 86
4c 10
4c 10
4c
À60 48 76 (trace) 84
À40 24
À40 24
1
73[d] (18) 94
70[d] (8) 91
6
[a] 3: 0.24 mmol, 4: 0.2 mmol. [b] Determined by H NMR analysis of the
crude mixture with 1,1,2,2-tetrachloroethane as an internal standard. The
yield of bisthioamide 12 is shown in parentheses. [c] Determined by
HPLC analysis. [d] Isolated yield.
[a] Y. Kawato, Dr. S. Chaudhary, Dr. N. Kumagai,
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo (BIKAKEN)
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax: (+81)3-3441-8133
E-mail: nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
[b] Y. Kawato
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[c] Prof. Dr. M. Shibasaki
JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku
Tokyo 141-0021 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204609.
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N. Kumagai, M. Shibasaki et al.
Scheme 1. Outline of the first- and second-generation synthetic routes based on the direct catalytic asymmetric aldol reaction.
complex chemoselectively deprotonated thioamide 3 to gen-
erate (R,R)-Ph-BPE/Cu–enolate with the liberation of mesi-
tylene. Subsequently, the aldol addition proceeded with al-
dehyde 4 to generate (R,R)-Ph-BPE/Cu–aldolate 11, which
functioned as a soft Lewis acid/hard Brønsted base coopera-
tive catalyst in the following catalytic cycles.[12b,14] Among
the aldehydes screened (Table 1, entries 1–3) with 10 mol%
of the catalyst at À608C, 3-trityloxypropanal (4c) gave the
aldol product 5c in high yield and enantioselectivity with
minimal contamination from 1,5-bisthioamide 12, which was
likely produced by undesirable dehydration followed by
conjugate addition of thioamide 3 (entry 3). The highly crys-
talline nature of 4c also make it suitable for large-scale syn-
thesis. In contrast to our previous studies, further optimiza-
tion of the reaction conditions using 4c revealed that a
higher reaction temperature (À408C) gave an improved
enantioselectivity, although the amount of byproduct 12 in-
creased (entry 4). Reducing the catalyst loading to 6 mol%
suppressed the formation of 12, albeit with a marginal loss
in enantioselectivity (entry 5).
With the optimized conditions of the aldol reaction in
hand, we turned our attention to the practical enantioselec-
tive synthesis of atorvastatin (1; Scheme 2). The direct cata-
lytic asymmetric aldol reaction was scaled up using 30.6 g of
aldehyde 4c, and no detrimental effects on catalytic efficien-
cy were observed. The reaction was quenched with AcOH/
THF after 24 h of stirring at À408C, and the resulting mix-
ture was extracted with EtOAc. (R,R)-Ph-BPE formed a
tight complex with Cu+ and the complex was partitioned
into the organic extracts together with the aldol product. A
small aliquot of the extract was purified and analyzed by
chiral stationary-phase HPLC to determine the enantiomer-
ic excess of the aldol product (91% ee). The concentrated
organic extracts were dissolved in dry THF for the subse-
quent LiAlH4 reduction, reducing both Cu+ and the thio-
tallization from 2-propanol) and crude tertiary amine 13,
which was subjected to acidic removal of the trityl group to
give aminodiol 8 in 52% yield over three steps from the
aldol reaction. The recovered (R,R)-Ph-BPE was analytical-
ly pure and verified in the direct catalytic asymmetric aldol
reaction, producing comparable catalytic efficiency and
enantioselectivity [Eq. (1)]. For the expeditious preparation
of oxy-Michael reaction precursor 9, we examined a tandem
oxidation/Wittig olefination process. Treatment of aminodiol
8 with manganese dioxide (MnO2) in the presence of stabi-
lized ylide 14a in refluxing toluene afforded the a,b-unsatu-
rated ester 9 in 49% yield through chemoselective oxidation
of a primary alcohol. Detailed analysis of the associated by-
products indicated that the unstable b-hydroxyaldehyde in-
termediate readily underwent dehydration and subsequent
undesired reactions. Therefore, we attempted to use an ylide
with enhanced nucleophilicity to increase the reaction rate
of the Wittig olefination of the intermediary aldehyde. With
ylide 14b bearing an electron-rich para-anisyl group at phos-
phorus,[16] the yield of the tandem reaction was improved to
deliver 9 in 81%. syn-1,3-Diol protected as a benzylidene
acetal 15 was then constructed by intramolecular oxy-Mi-
chael reaction of the transient hemiacetal by the treatment
with benzaldehyde and tBuOK.[17] This reaction could be
run without purification of 9 after the previous tandem reac-
tion, affording 15 in 53% yield from aminodiol 8. Removal
of the N-allyl groups of 15 with a palladium catalyst pro-
ceeded smoothly to furnish the common intermediate 2b.
Without tedious purification of 2b, Paal–Knorr pyrrole syn-
thesis with known 1,4-diketone 16 was applied according to
ACHTUNGTRENNUNGamide functionality of the product to achieve liberation of
free (R,R)-Ph-BPE as well as desulfurization to afford terti-
ary amine 13.[13d,15] Short-pad silica-gel column chromatogra-
phy (650 g silica gel, not optimized) allowed for facile sepa-
ration of low-polarity (R,R)-Ph-BPE in 91% (after recrys-
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Synthesis of Atorvastatin
COMMUNICATION
Scheme 2. Enantioselective synthesis of atorvastatin (1). Reagents and conditions: a) mesitylcopper (6 mol%), (R,R)-Ph-BPE (6 mol%), 2,2,5,7,8-pen-
tamethylchroman-6-ol (10; 6 mol%), 3 (1.2 equiv), THF/DMF=1:1, À408C, 24 h; b) LiAlH4 (4 equiv), THF, À788C to room temperature, 3.5 h; c) 2n
HCl/EtOH, CH2Cl2, 08C to room temperature, 1 h, 52% (three steps); d) MnO2 (12 equiv), Ar3PCHCO2tBu (14b; 1.4 equiv), toluene, reflux, 12 h;
e) PhCHO (3.5 equiv), tBuOK (1.2 equiv), THF, 08C, 1.5 h, 53% (two steps) with 14b; f) [PdACTHNUGTRENUNG(dba)2] (6 mol%), dppb (6 mol%), thiosalicyclic acid
(2.2 equiv), THF, 608C, 12 h; g) tBuCO2H (0.67 equiv), 16 (0.73 equiv), heptane/toluene/THF, 1108C, 26 h, 67% (two steps); h) recrystallization from di-
ethyl ether/hexane, 78%, >99% ee; i) 2n HCl/EtOH, 08C to room temperature, 12 h; j) 2n NaOH (4.2 equiv), THF/H2O, 0 8C to room temperature,
6 h, then 1n HCl, 71% (two steps). dba=dibenzylideneacetone, dppb=1,4-bis(diphenylphosphino)butane.
a reported procedure.[6e,18] The resulting fully-substituted
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sis afforded atorvastatin (1) in 71% yield over two steps.
In summary, we have developed a second-generation syn-
thetic route to atorvastatin (1) based on the direct catalytic
asymmetric aldol reaction of a thioamide. The major draw-
back of the previous route, single use of an expensive chiral
ligand, was eliminated by an efficient recovery process that
was coupled with thioamide reduction. Retention of the
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Acknowledgements
This work was financially supported by JSPS KAKENHI Grant Numbers
20229001 and 23590038, and JST, ACT-C. Y.K. thanks JSPS for a predoc-
toral fellowship. S.C. thanks JSPS for a postdoctoral fellowship. N.K.
thanks Suzuken Memorial Foundation for financial support.
Keywords: aldol reaction
·
asymmetric catalysis
·
atorvastin · thioamides · total synthesis
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Received: December 27, 2012
Published online: February 21, 2013
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