An efficient organocatalytic route to the atorvastatin side-chain

Article abstract of DOI:10.1016/j.tetlet.2007.09.133

An organocatalytic route to the synthesis of the atorvastatin side-chain, a building block present in the statin family, is described using l-proline-catalyzed α-aminooxylation of an aldehyde. The method also employs an iodine-induced intramolecular electrophilic cyclization of a carbonate to produce the iodocarbonate in a highly diastereoselective manner.

Full text of DOI:10.1016/j.tetlet.2007.09.133

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Tetrahedron Letters 48 (2007) 8544–8546
An efficient organocatalytic route to the atorvastatin side-chain
Shyla George and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 25 July 2007; revised 11 September 2007; accepted 19 September 2007
Available online 25 September 2007
Abstract—An organocatalytic route to the synthesis of the atorvastatin side-chain, a building block present in the statin family, is
described using L-proline-catalyzed a-aminooxylation of an aldehyde. The method also employs an iodine-induced intramolecular
electrophilic cyclization of a carbonate to produce the iodocarbonate in a highly diastereoselective manner.
Ó 2007 Elsevier Ltd. All rights reserved.
Statins act by inhibiting HMG-CoA reductase
(HMG = 3-hydroxy-3-methylglutaryl), the rate-limiting
enzyme in cholesterol biosynthesis.1 They not only lower
the low-density lipoprotein (LDL) cholesterol as well as
triglyceride levels but also increase the levels of high-
density lipoprotein (HDL). Statin drugs such as atorva-
statin, fluvastatin or rosuvastatin are composed of large
lipophilic residues and a C-7 carboxylic acid side-chain
bearing a syn-1,3-diol. Due to their biological impor-
tance, a number of different routes to these statin side-
chains have been reported.2 These include chiral pool
synthesis,2a–c classical resolution of racemates,2k use of
intact cells, which secrete the final building block into
the culture broth2l and enzymatic desymmetrization.2n
However, all the reported methods for the preparation
of the statin side-chain involve several drawbacks such
as loss of 50% of starting material in the case of resolu-
tion methods, low yields and lengthy and tedious pro-
cessing steps.
A retrosynthetic analysis of atorvastatin shows that 1,3-
diol 1 is the key intermediate, which could be obtained
from iodocarbonate 2. Iodocarbonate 2 was to be pre-
pared by an intramolecular diastereoselective iodolact-
onization of olefin 3, which in turn could be prepared
by the proline catalyzed a-aminooxylation of readily
available n-butyraldehyde 4 (Scheme 1).
The complete synthetic sequences for statin side-chain 1,
commencing from the precursor aldehyde 4, obtained
from the corresponding monoprotected 1,4-butane diol
by oxidation with IBX in DMSO, are shown in Scheme
2. The proline catalyzed a-aminooxylation of aldehyde 4
involves a two-step reaction sequence: (i) reaction of
aldehyde 4 with nitrosobenzene as the oxygen source
in the presence of 25 mol % of L-proline in CH3CN at
ꢀ20 °C4a followed by treatment with NaBH4 in MeOH
gave the crude aminooxy alcohol, and (ii) subsequent
reduction of the crude aminooxy product with 30%
CuSO4 to yield chiral diol 57 in 87% yield and 97% ee
6
1
Proline, an abundant, inexpensive amino acid available
in both enantiomeric forms, has emerged recently as a
practical and versatile organocatalyst in organic synthe-
sis.3 It is equally efficient for the a-functionalization4 of
aldehydes and ketones. As part of our research efforts
aimed at developing stereocontrolled syntheses of bio-
active molecules,5 we report herein an alternative route
to atorvastatin side-chain building block 1, using two
key reactions: proline catalyzed a-aminooxylation of
n-butyraldehyde and iodine-induced intramolecular
electrophilic cyclization.
(determined by H NMR analysis of the corresponding
25
Mosher’s ester); ½aꢁD ꢀ 5:02 (c 1, CHCl3). Selective pro-
tection8 of the primary alcohol in 5 with mesyl chloride
gave mesylate 6, which on treatment with K2CO3 in
25
MeOH yielded the terminal epoxide 7; ½aꢁD þ 16:4 (c 3,
25
CHCl3) {lit.9 ½aꢁ þ 16:9 (c 2.51, CHCl3)}. Regioselec-
tive ring openingDof epoxide 7 with vinylmagnesium bro-
mide in the presence of CuI10 in THF at ꢀ40 °C gave
homoallylic alcohol 8, which was protected as its tert-
butyl carbonate 3 in high yield (di-tert-butyldicarbonate,
DMAP10 and CH3CN). Debenzylation of 3 was
achieved with DDQ in a 2:1 mixture of CH2Cl2 and
H2O11 to afford alcohol 9 in 85% yield. Mesylation of
primary alcohol 9 gave mesylate 10, which on treatment
*
Corresponding author. Tel.: +91 20 25902174; fax: +91 20
25902676; e-mail: a.sudalai@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.133

S. George, A. Sudalai / Tetrahedron Letters 48 (2007) 8544–8546
8545
F
OH OH
OH OH
CO2H
CN
N
N3
1
O
NH
Atorvastatin
O
O
O
O
O
O
I
N3
BnO
CHO
BnO
4
3
2
Scheme 1. Retrosynthetic analysis of the atorvastatin side-chain.
OH
O
b
a
OR
BnO
CHO
BnO
BnO
7
4
5 R = H
6 R = Ms
OBoc
OR
e
c
d
X
BnO
8 R = H
9 X = OH
10 X = OMs
11 X = N3
3 R = Boc
O
OH
O
O
O
g
1
f
I
N3
N3
12
2
Scheme 2. Reagents and conditions: (a) (i) PhNO, L-proline (25 mol %), CH3CN, ꢀ20 °C, 24 h then MeOH, NaBH4; (ii) CuSO4 (30 mol %), MeOH,
0 °C, 10 h, 87% (over two steps); (b) (i) MsCl, Et3N, CH2Cl2, 0 °C, 15 min, 92%; (ii) K2CO3, MeOH, rt, 1 h, 95%; (c) vinylmagnesium bromide, THF,
CuI, ꢀ40 °C, 1 h, 92%; (d) (i) (Boc)2O, DMAP, CH3CN, rt, 5 h, 95%; (ii) DDQ, CH2Cl2:H2O (2:1), rt, 20 h, 85%; (e) (i) MsCl, Et3N, CH2Cl2, 0 °C,
30 min, 94%; (ii) NaN3, DMF, 60 °C, 2 h, 83%; (iii) NIS, CH3CN, ꢀ40 to 0 °C, 20 h, 87%; (f) K2CO3, MeOH, 0 °C to rt, 2 h, 96%; (g) NaCN,
Ti(OiPr)4, n-Bu4NI, DMSO, 70 °C, 6 h, 80%.
with NaN3 in DMF at 60 °C yielded the corresponding
azide 11 in 83% yield.
In conclusion, an enantioselective synthesis of the statin
side-chain, 1 is described by employing an organocata-
lytic a-aminooxylation methodology. The synthesis
made use of cheaply available, naturally occurring L-
proline in catalytic amounts for the induction of chiral-
ity, while the syn-1,3-diol moiety was introduced in a
highly diastereoselective manner using an iodine-
induced electrophilic cyclization. The synthetic strategy
described here has significant potential for the synthesis
of a variety of other biologically important substituted
1,3-polyol/5,6-dihydropyran-2-one-containing natural
products.
In order to construct the syn-1,3-diol moiety from azide
11, with high diastereoselectivity, the iodine-induced
carbonate cyclization methodology, originally published
by Bartlett et al.12a and later improved by Smith and
Duan12b was employed. Accordingly, homoallylic tert-
butyl carbonate 11 was subjected to the diastereoselec-
tive iodolactonization using N-iodosuccinimide13 in
CH3CN at low temperature (ꢀ40 to 0 °C) to furnish
the iodocarbonate derivative 214 in 87% yield as a single
1
diastereomer (determined by H NMR analysis). Iodo-
carbonate 2, upon exposure to a basic methanolic solu-
tion,12 gave the desired syn-epoxy alcohol 12 in 96%
yield. Finally, nucleophilic ring opening of epoxide 12
using NaCN15 in the presence of titanium tetraisoprop-
Acknowledgements
oxide and tetrabutylammonium iodide in DMSO gave
25
the corresponding nitrile 1,15 ½aꢁD ¼ þ40:0 (c 0.2,
S.G. thanks CSIR, New Delhi for the award of research
fellowship. The authors are thankful to Dr. B. D. Kulk-
arni, Head, CEPD, for his constant support and
encouragement.
CHCl3) in 80% yield. The synthesis of atorvastatin has
already been reported from 1,2g hence this report consti-
tutes a formal synthesis.

8546
S. George, A. Sudalai / Tetrahedron Letters 48 (2007) 8544–8546
Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem.,
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