An efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol reactions and synthesis of atorvastatin lactone

Article abstract of DOI:10.1016/j.tetlet.2015.08.011

An efficient strategy for the synthesis of syn 1,3-diol has been developed, employing an imidazolidinone based chiral auxiliary via stereoselective and sequential double acetate aldol reactions. The syn 1,3-diol subunit was modified to obtain the C-7 carboxylic acid side chain and further subjected to reaction with a suitable 1,4-diketone under Paal-Knorr conditions to obtain atorvastatin lactone.

Full text of DOI:10.1016/j.tetlet.2015.08.011

Accepted Manuscript
An efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol
reactions and synthesis of atorvastatin lactone
Sandeep Goyal, Bhautikkumar Patel, Ratnesh Sharma, Mangilal Chouhan,
Kapil Kumar, Mukesh Gangar, Vipin A. Nair
PII:
S0040-4039(15)01292-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.011
TETL 46595
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2015
4 August 2015
5 August 2015
Please cite this article as: Goyal, S., Patel, B., Sharma, R., Chouhan, M., Kumar, K., Gangar, M., Nair, V.A., An
efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol reactions and synthesis of atorvastatin
lactone, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.011
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Graphical Abstract
An efficient strategy for the synthesis of syn
1,3-diols via iterative acetate aldol reactions
and synthesis of atorvastatin lactone
Leave this area blank for abstract info.
Sandeep Goyal, Bhautikkumar Patel, Ratnesh Sharma, Mangilal Chouhan, Kapil Kumar, Mukesh
Gangar and Vipin A. Nair*

1
Tetrahedron Letters
An efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol
reactions and synthesis of atorvastatin lactone
Sandeep Goyal, Bhautikkumar Patel, Ratnesh Sharma, Mangilal Chouhan, Kapil Kumar, Mukesh Gangar
and Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160062, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient strategy for the synthesis of syn 1,3-diol has been developed, employing an
imidazolidinone based chiral auxiliary via stereoselective and sequential double acetate aldol
reactions. The syn 1,3-diol subunit was modified to obtain the C-7 carboxylic acid side chain
and further subjected to reaction with a suitable 1,4-diketone under Paal Knorr conditions to
obtain the atorvastatin lactone.
Available online
© 2013 Elsevier Ltd. All rights reserved.
Keywords:
Atorvastatin
Aldol
Chiral auxiliary
Syn 1,3-diol
Diastereoselectivity
The occurrence of syn/anti 1,3-diols in natural products and drug
molecules (Fig. 1) has drawn considerable attention over the years.
Its stereoselective construction is of great interest to medicinal
chemists,1 and has resulted in the development of several synthetic
strategies which includes diastereoselective reduction of β-hydroxy
ketones,2 sequential chain elongation,3 asymmetric hydrogenation,4
catalytic asymmetric Overman esterification,5 enzymatic resolution6,
and enzymatic and nonenzymatic desymmetrization.7 Based on our
interests and literature reports on asymmetric aldol reactions and
heterocycle synthesis,8 we devised an aldol based strategy for the
stereoselective synthesis of the 1,3-diol unit using a chiral auxiliary
followed by an efficient synthesis of the atorvastatin lactone from the
enantiomerically pure diol intermediate.
Atorvastatin (2, Lipitor®) is widely prescribed and well
acknowledged as the world’s leading cholesterol lowering drug in
treating hypercholesterolemia because of its efficacy, safety and long
term benefits.9 Different methods to synthesize the statin side chains
have been reported in the last two decades. This includes the chiral
pool synthesis,10 cycloaddition reaction,11 resolution of racemates,12
chemoenzymatic synthesis13 and organocatalytic approaches.14
However, low yields, expensive reagents, tedious workup procedures
and significant loss in the case of resolution methods sustain
considerable interests to develop newer protocols. The structure of
atorvastatin comprises of a substituted pyrrole nucleus and a C-7
carboxylic acid side chain fragment bearing a syn 1,3-diol unit.
Stereoselective synthesis of 1,3-diol unit requires the investment of
chirality and an imidazolidinone based chiral auxiliary was
envisaged to this objective.
Figure 1. Structures of a few molecules containing 1,3-diol subunit
Figure 2. Retrosynthetic strategy for atorvastatin
———
 Corresponding author. Tel.: +91-172-229-2045; fax: +91-172-221-4692; e-mail: vn74nr@yahoo.com

Scheme 2. Iterative acetate aldol reaction of -silyloxy aldehyde
We envisioned that the side chain of atorvastatin constructed from 3-
(benzyloxy)propanal via iterative double acetate aldol reactions can
be condensed with the appropriate 1,4-diketone as shown in scheme
3. Hydrolytic cleavage of the chiral auxiliary from the intermediate
(14) using aq. NaOH under reflux conditions followed by
esterification by diazomethane,16 freshly prepared from
nitrosomethyl urea,17 and a tert-butyldimethylsilyl protection of the
free hydroxy group using 2,6-lutidine and tert-butyldimethyl
silyltrifluoromethanesulfonate gave (3R,5R)-methyl-7-(benzyloxy)-
3,5-bis((tert-butyldimethylsilyl)oxy)heptanoate
(15).
This
Scheme 1. Synthesis of chiral β-alkoxy aldehyde
intermediate was subjected to debenzylation using catalytic amount
of palladium hydroxide in methanol followed by mesylation using
mesyl chloride and Et3N at 0 oC, and then treated with sodium azide
to give (3R,5R)-methyl-7-azido-3,5-bis((tert-butyldimethylsilyl)
oxy)heptanoate (16). It was reacted with the 1,4-diketone (17)18
under Paal-Knorr conditions by in situ generation of the
corresponding amine using triphenyl phosphine, followed by a
cyclization to afford (3R,5R)-methyl-3,5-bis((tert-butyldimethyl
silyl)oxy)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcar-
bamoyl)-1-H-pyrrol-1-yl)heptanoate (18). Finally deprotection of the
silyl groups using 5N HCl afforded the atorvastatin lactone (19) in
good yield and high steroeselectivity. The optical rotation of the
atorvastatin lactone (19) was found to be in good agreement with the
literature reported value for the (R,R) enantiomer (reported [α]D
+26.05 (c 1, CHCl3); found [α]D20 +21.7 (c 1, CHCl3)14d, reiterating
the high anti selectivity observed for the lithium enolate in acetate
aldol reactions of the imidazolidinone auxiliary (6).
A retrosynthetic analysis of the syn 1,3-diol unit containing
carboxylic acid side chain of atorvastatin is illustrated in Figure 2.
The synthesis and applications of (S)-4-isopropyl-1-[(R)-1-
phenylethyl]imidazolidin-2-one as a chiral auxiliary in acetate aldol
reactions employing LiHMDS with various aldehydes had been
examined by us in detail recently.8d The reactions were found to
afford the acetate aldol adducts stereoselectivily, bearing an anti
relation between the newly generated hydroxy group and the resident
isopropyl group of the auxiliary. The excellent selectivity imparted
by the chiral auxiliary gave sufficient encouragement to carry out
double acetate aldol reactions to gain access to the desired
stereoisomer of the 1,3-diol subunit. The synthesis commenced with
the acetylation of the chiral auxiliary (6) followed by treatment with
LiHMDS to generate the corresponding lithium enolate (Scheme 1).
It was reacted with 3-(benzyloxy)propanal (8) to give (S)-3-[(R)-5
(benzyloxy)-3-hydroxypentanoyl]-4-isopropyl-1-[(R)-1-phenylethyl]
imidazolidin-2-one (9) in good yield, and a high diastereoselectivity
1
of 98:02 as determined from the H NMR spectra of the reaction
mixture. The aldol adduct was subjected to hydrolysis using aq.
NaOH under reflux condition to obtain the β-hydroxy acid (10).
Using catalytic amount of sulfuric acid and methanol as a solvent
under reflux condition gave the corresponding β-hydroxy ester (11).
The free hydroxy group was protected thereafter using tert-
butyldimethylsilyltriflate and 2,6-lutidine to give (R)-methyl-5-
(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)pentanoate
(12).
Reduction of the protected hydroxy ester was carried out using
diisobutylaluminium hydride to afford (R)-5-(benzyloxy)-3-((tert-
butyldimethylsilyl)oxy)pentanal (13). The optical rotation of the
compound (13) was compared with literature15 (reported [α]D25 +9.8
20
(c 1.36, CH2Cl2), found [α]D +8.7 (c 1.36, CH2Cl2), and an (R)
configuration was unambiguously assigned to the newly generated
stereocentre, confirming an anti relation between the hydroxy group
and the isopropyl group for the major isomer of the acetate aldol
adduct (9). The β-silyloxy aldehyde (13) was further subjected to a
second acetate aldol reaction (Scheme 2) to obtain the 1,3-diol
subunit. The reaction afforded good yield, and
a
high
diastereoselectivity of 95:05 was observed in the 1H NMR spectra of
the reaction mixture. As before, an anti selectivity of the newly
generated hydroxy group with respect to the isopropyl group of the
auxiliary was expected again in the second acetate aldol reaction.
More interestingly the newly formed hydroxy group would share a
syn relation with the incumbent protected hydroxy group of the
substrate, giving rise to a syn 1,3-diol subunit after desilylation.
Scheme 3. Synthesis of atorvastatin lactone

3
Appl. Organometal. Chem. 2011, 25, 305; (d) Khatik, G. L.;
In conclusion, a convenient synthetic strategy to prepare syn 1,3-diol
unit stereoselectively was explored by an imidazolidinone based
auxiliary mediated sequential double acetate aldol reactions. The
strategy afforded the syn 1,3-diol of the C-7 carboxylic acid side
chain fragment of atorvastatin. Subsequent reaction with the
appropriate 1,4-diketone under Paal-Knorr conditions provided
access to atorvastatin lactone in good yield and selectivity.
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Acknowledgments
Research funding from the Department of Science and Technology,
Government of India, and a research fellowship to S.G. from the
University Grants Commission (UGC-RGNF) are gratefully
acknowledged.
Supplementary Material
Supplementary material which includes experimental procedures and
compound data can be found in the online version.
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