A novel strategy towards the atorvastatin lactone

Article abstract of DOI:10.1016/j.tet.2010.10.028

We describe a novel strategy to the atorvastatin lactone based on a Paal-Knorr synthesis of pyrrole 24 by condensing diketone 23 with primary amine 22. The latter contains the syn-1,3-diol subunit and a benzyl ether function at the other end of the chain. This allowed for manipulations on the pyrrole ring via iodination at C2, metalation with t-BuLi and carboxylation. The obtained acid 26 could be converted via amide formation, debenzylation, oxidation and lactonization to atorvastatin lactone 6. The key building block, 2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethanamine (22) was obtained by two sequential asymmetric transfer hydrogenative carbonyl allylations according to Krische.

Full text of DOI:10.1016/j.tet.2010.10.028

Tetrahedron 66 (2010) 9738e9744
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A novel strategy towards the atorvastatin lactone
*
Pramod Sawant, Martin E. Maier
€
€
€
€
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a novel strategy to the atorvastatin lactone based on a PaaleKnorr synthesis of pyrrole 24 by
condensing diketone 23 with primary amine 22. The latter contains the syn-1,3-diol subunit and a benzyl
ether function at the other end of the chain. This allowed for manipulations on the pyrrole ring via iodination
at C2, metalation with t-BuLi and carboxylation. The obtained acid 26 could be converted via amide for-
mation, debenzylation, oxidation and lactonization to atorvastatin lactone 6. The key building block,
2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethanamine (22) was obtained by two
sequential asymmetric transfer hydrogenative carbonyl allylations according to Krische.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 September 2010
Received in revised form 11 October 2010
Accepted 12 October 2010
Available online 15 October 2010
Keywords:
Atorvastatin
Allylation
Pyrrole
1,3-Diol
Metalation
1. Introduction
F
HO
O
Statins, like compounds 1e4 represent a well established class of
drugs for reducing plasma cholesterol levels (Fig. 1).1 They are
commonly prescribed to lower the risk of cardiovascular disease.
Over the years the broad use of statins revealed a range of addi-
tional, mostly positive effects of these compounds.2 These include
increased nitric oxide bioavailability, antioxidant effects, and in
particular anti-inflammatory effects.3 For lovastatin (1) and some
derivatives thereof it could be shown that they suppress the in-
flammatory response in an animal model of peritonitis by binding to
CO2H
OH
O
OH
O
N
O
H
HN
O
lovastatin (1)
atorvastatin (2)
the b
2 integrin leukocyte function antigen-1 (LFA-1).4 However, it
seems that other statins like atorvastatin do not bind to this heter-
odimeric glycoprotein.5 In order to detect other cellular targets than
3-hydroxy-3-methylglutaryl coenzyme-A reductase,6 an atorvas-
tatin affinity probe might be useful.7,8 Since we wanted to keep the
F
F
CO2H
OH
CO2H
OH
OH
OH
side chain d-valerolactone part intact, the carboxyl function in the
N
O
O
pyrrole part appeared as a promising handle. In this paper we de-
scribe the synthesis of atorvastatin carboxylic acid 26 and its con-
version to atorvastatin lactone (6).
N
S
Me
N
N
Me
fluvastatin (3)
rosuvastatin (4)
2. Results and discussion
Fig. 1. Structures of some important statins.
In the original synthesis of atorvastatin the fully functionalized
pyrrole ring 5 with a 3-oxopropyl substitutent on the nitrogen was
obtained via [3þ2] cycloaddition of a mesoionic heterocycle with
a propynamide.9 This aldehyde was then extended by a sequence of
an acetate aldol reaction, a Claisen condensation to a -hydroxy-b-
ketoester, and a hydroxyl-directed reduction leading to chiral lac-
tone 6 (Fig. 2).
d
In a later report atorvastatin (1) was prepared by PaaleKnorr
condensation of diketoamide 7 with primary amine 8 leading to
* Corresponding author. E-mail address: martin.e.maier@uni-tuebingen.de
(M.E. Maier).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.028

P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
9739
allow for facile manipulations at the carboxylic function of the cor-
responding pyrrole. We tried this condensation with allylamine, 3,3-
diethoxypropan-1-amine and amine 8. These reactions were carried
out in a toluene/heptane/THF (6:10:5) mixture in presence of pivalic
acid under reflux and checked by TLC. These conditions20 led to a se-
ries of spots on TLC, however, the desired pyrroles were not formed.
This required a redesign of the synthetic route. The plan called
for pyrrole formation without the carboxylic function followed by
halogenation, metalation and carboxylation of the pyrrole ring.
Accordingly, an ester function at the amine terminus seemed not
compatible with these conditions. As an ideal building block we
identified amine 22. While in principle this amine could be pre-
pared from known tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxan-4-yl)acetate (10) this was considered lengthy
and redox-inefficient.21
The synthesis of amine 22 is described in Scheme 1. The syn-1,3-
diol subunit was fashioned from benzyloxy-propanol22 (13) by two
iterative asymmetric transfer hydrogenative carbonyl allylations as
described by Krische et al.23 Thus, using a catalyst generated from
[Ir(cod)Cl2], (R)-Cl, Meo-BIPHEP and 4-chloro-3-nitro-benzoic acid,
alcohol 13 was coupled with allyl acetate (2 equiv) to give homo-
allylic alcohol 14 in 90% yield (92% ee). Alcohol protection to 15
followed by ozonolysis and in situ reduction furnished alcohol 16.
Applying similar conditions to alcohol 16 syn-diol derivative 17 was
obtained. Protection of the diol as acetal to building block 18 and
oxidative degradation of the double bond led to alcohol 19. Via the
corresponding tosylate 20, azide 21 was prepared by the reaction of
20 with sodium azide in DMF. Reduction of the azide 21 with tri-
phenylphosphine24 in a THF/H2O mixture gave rise to amine 22.
F
F
O
O
O
steps
H
N
N
OH
HN
5
6
HN
O
O
F
H+
(75%)
NH2
O
O
O
O
+
CO2tBu
O
NH
F
8
7
O
O
steps
CO2tBu
2
N
HN
9
O
(R)-(+)-BIPHEP, [Ir(COD)Cl]2
allyl acetate, ArCO2H
a) O3, MeOH
–80 °C
OBn OH
OBn OR
O
O
8
HO
CO2tBu
b) NaBH4
(97%)
Cs2CO3, THF, 120 °C
13
20 h (90%)
10
14 R = H
TBSCl, ImH
F
DMF, 50 °C
(91%)
F
15 R = TBS
(R)-(+)-BIPHEP, [Ir(COD)Cl]2
allyl acetate, ArCO2H
OBn OR OH
OBn OR OH
R2
O
O
H2N R2
N
+
Cs2CO3, THF, 120 °C
20 h (90%)
R1O2C
R1O2C
16 (R = TBS)
17 (R = TBS)
11
12
R2 = CH2CH=CH2
R2 = CH2CH2CH(OEt)2
a) O3, –80 °C
MeOH/CH2Cl2
a) pTsOH, MeOH
OBn O
O
Fig. 2. Approaches to atorvastatin with regard to the side chain.
b) NaBH4
(97%)
b) Me2C(OMe)2
(80%)
18
advanced intermediate 9.10,11 The key amine 8 is generally prepared
from tert-butyl-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-di-
oxan-4-yl] acetate (10) via chain extension.12 Several preparations
of this or related compounds have been described in the litera-
ture.13 In several cases biocatalytic methods have been used to
reduce prochiral precursors like 4-chloro-/4-bromo-3-oxobutyrate
or 3,5-dioxo-6-benzyloxy-hexanoate.14 In addition, enzymatic
symmetry breaking of 3-hydroxyglutaronitrile15 or 3-alkoxy-
glutaric acid ester11 have been employed to create building blocks
with one stereocenter. Another paper describes the lipase-medi-
ated resolution of 1-chloro-3-arylmethoxy-2-propanols and their
conversion into hydroxy ester 10.16 Furthermore, organocatalytic
aldol reactions to compounds like 10 have been reported.17 A highly
practical route to compound 10 involves the Noyori-type hydro-
genation of ethyl 4-benzyloxy acetoacetate followed by Claisen
condensation and syn-reduction of the hydroxy ketone function.18
OBn O
O
OR
OBn O
O
N3
NaN3, DMF
(97%)
19 R = H
20 R = Ts
21
TsCl, Et3N
CH2Cl2
(86%)
PPh3, THF/H2O
(94%)
OBn O
O
NH2
22
Scheme 1. Synthesis of primary amine 22; ArCO2H]4-Cl-3-NO2-C6H3CO2H.
Continuing with the synthesis, diketone9 23 was condensed
with amine 22 in xylene in presence of pTsOH$H2O (0.2 equiv)
(Scheme 2). The reaction was rather slow and required heating for 7
days to give pyrrole 24 in 68% yield. The acetal remained stable
under these conditions. Treatment of pyrrole 24 with N-
Finally,
-malic acid has served as a precursor to hydroxy ester 10.19
L
The initial idea was to perform a PaaleKnorr synthesis between
diketoester 11 and a primary amine like 8 (Fig. 2) since this would

9740
P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
iodosuccinimide (NIS) in DMF delivered iodopyrrole 25 in excellent
yield.25 Due to its somewhat sensitive nature it was subjected
without prolonged storage to halogenemetal exchange with t-BuLi.
Trapping of the lithiated intermediate with gaseous carbon dioxide
furnished carboxylic acid 26 in good yield. In order to reach ator-
vastatin, acid 26 was then condensed with aniline in presence of
PyBroP26,27 to afford amide 27. Now we could refocus on the ali-
phatic part and the oxidation of its terminus. Accordingly, the
benzyl ether group was cleaved by hydrogenation in the presence
of Pd(OH)2 and cyclohexene as hydrogen source28 to produce al-
cohol 28. Oxidation29 of the alcohol to acid 29 and treatment with
acid furnished the known atorvastatin lactone9 6.
3. Conclusion
In summary, we could illustrate a new strategy to atorvastatin.
One element includes a double Krische allylation to fashion the syn-
1,3-diol subunit of the aliphatic side chain. While this reaction re-
quires rather drastic conditions (heating to 120 ꢀC) it is practical for
simple substrates. Amine 22 derived from building block 19 was
subjected to a PaaleKnorr condensation with diketone 23 to give
pyrrole 24. Via iodination and metalation, the carboxylic group
could be introduced in the 2-position of the pyrrole. Conversion of
the acid 26 to amide 27 and oxidation of the side chain terminus led
to atorvastatin lactone 6. The developed strategy should open the
way to new amide derivatives of atorvastatin and should allow for
attachment of a linker to the pyrrole carboxylic group.
O
NH2
O
O
OBn
pTsOH, xylene
O
+
reflux, 7 d
(68%)
22
23
F
F
O
O
OBn
a) tBuLi, THF, –80 °C
N
b) CO2(g), 15 min (81%)
4. Experimental section
X
24 X = H
25 X = I
4.1. (3R)-1-(Benzyloxy)hex-5-en-3-ol (14)
NIS, DMF
(91%)
In a oven dried screw cap glass bottle (250 mL size) a mixture of
alcohol 13 (4.0 g, 24.07 mmol), allyl acetate (5.24 mL, 48.13 mmol),
[Ir(cod)Cl]2, (404 mg, 2.5 mol%), (R)-(þ)-Cl, MeO-BIPHEP, (784 mg,
5 mol%), 4-chloro-3-nitro-benzoic acid (485 mg, 2.41 mmol),
Cs2CO3 (1.57 g, 4.81 mmol) in THF (130 mL) was heated at 120 ꢀC
under nitrogen for 20 h. The reaction mixture was adsorbed on
silica gel and purified by flash chromatography (ethyl acetate/pe-
troleum ether, 2:8) to furnish alcohol 14 (4.50 g, 90%,) as colourless
oil. Enantiomeric ratio as determined by Mosher analysis 96:4. Rf
F
O
O
OBn
aniline, iPr2NEt, PyBroP
N
CH2Cl2, rt, 4 h (82%)
26
HO2C
F
(ethyl acetate/petroleum ether, 2:8) 0.34; [
a
]
20 þ2.7 (c 1.0, CHCl3);
D
dH (400 MHz,CDCl3) 1.71e1.81 (m, 2H, BnOCH2CH2), 2.22e2.26 (m,
2H, CH2CH]CH2), 3.61e3.74 (m, 2H, BnOCH2), 3.84e3.90 (m, 1H,
CHOH), 4.52 (s, 2H, PhCH2O), 5.07e5.13 (m, 2H, CH]CH2),
5.78e5.88 (m, 1H, CH]CH2), 7.26e7.36 (m, 5H, Ar-H); dC (100 MHz,
CDCl3) 35.8 (CH2), 41.9 (CH2), 68.9 (CH2), 70.3 (CH), 73.3 (CH2), 117.5
(CH]CH2), 127.6 (CH, phenyl), 127.7 (CH, phenyl), 128.4 (CH, phe-
nyl), 134.8 (CH]CH2), 137.9 (C, phenyl).
a) Dess-Martin oxidat.
b) 2-methyl-2-butene
NaH2PO4·2 H2O
O
O
OR
N
NaClO2, tBuOH, H2O
(96%, 2 steps)
HN
O
4.2. ({(1R)-1-[2-(Benzyloxy)ethyl]but-3-enyl}oxy)(tert-butyl)
dimethylsilane (15)
27 R = Bn
28 R = H
Pd(OH)2, cyclohexene
EtOH, reflux (86%)
F
A mixture of alcohol 14 (877 mg, 4.3 mmol), imidazole (723 mg,
10.6 mmol) and TBSCl (1.28 g, 8.5 mmol) in DMF (5 mL) was stirred at
50 ꢀC overnight. Thereafter, water (10 mL) was added and the mix-
ture extracted with diethyl ether (3ꢁ30 mL). The combined organic
extracts were dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography (diethyl ether/
O
O
CSA, CH3CN
rt (90%)
CO2H
F
N
29
petroleum ether, 2:98) togivesilyl ether 15 (1.27 g, 91%) as colourless
20
HN
oil. Rf (petroleum ether/diethyl ether, 98:2) 0.34; [
a
]
ꢂ17.3 (c 1,
D
O
O
CHCl3); dH (400 MHz, CDCl3) 0.30 (s, 3H, Si(CH3)2), 0.50 (s, 3H, Si
(CH3)2), 0.87 (s, 9H, C(CH3)3), 1.66e1.83 (m, 2H, BnOCH2CH2),
2.16e2.28 (m, 2H, CH2CH]CH2), 3.52e3.55 (m, 2H, BnOCH2),
3.87e3.92 (m, 1H, CHOH), 4.43 (d, J¼11.9 Hz, 1H, PhOCH2), 4.49 (d,
J¼11.9 Hz, 1H, PhOCH2), 5.02 (m, 2H, CH]CH2), 5.75e6.86 (m, 1H,
CH]CH2), 7.26e7.36 (m, 5H, phenyl); dC (100 MHz, CDCl3) ꢂ4.4 (Si
(CH3)2), 18.1 (C(CH3)3), 25.8 (C(CH3)3), 36.7 (CH2), 42.3 (CH2), 67.0
(BnOCH2), 68.9 (CHOH), 72.9 (PhCH2), 116.9 (CH]CH2), 127.6 (CH,
phenyl), 128.3 (CH, phenyl), 134.9 (CH]CH2), 138.5 (C, phenyl);
HRMS (ESI) calcd for C19H32O2Si [MþNa]þ 343.20638, found
343.206354.
O
N
OH
6
HN
O
Scheme 2. Condensation of amine 22 with diketone 23 to pyrrole 24 and conversion of
24 to atorvastatin lactone 6.

P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
9741
4.3. (3R)-5-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}
pentan-1-ol (16)
stirred for further 30 min at room temperature. The reaction mix-
ture was concentrated in vacuo, the residue diluted with CH2Cl2
(500 mL), then washed with saturated NaHCO3 solution (150 mL)
and saturated NaCl solution (150 mL). The organic layer was dried
over Na2SO4, filtered and concentrated on a rotary evaporator. The
residue was purified by flash chromatography (petroleum ether/
ethyl acetate, 19:1) to yield acetal 18 (3.51 g, 80%) as colourless oil.
To a solution of 15 (5.61 g, 17.5 mmol) in methanol (74 mL,
0.15 M), 2e3 drops of Sudan III (1% in methanol) were added as an
indicator resulting in a pink colour solution. The mixture was
cooled to ꢂ80 ꢀC and ozone gas was bubbled through the solution
until it turned pink to colourless (about 50 min). Residual O3 was
removed by passing nitrogen through the reaction (about 5 min).
Thereafter, NaBH4 (6.62 g, 175 mmol) was added and the reaction
mixture was slowly allowed to reach room temperature, with the
flask kept in the cooling bath. Water (30 mL) was added and the
mixture was concentrated to w50 mL on a rotary evaporator before
it was extracted with ethyl acetate (3ꢁ120 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash chromatography (petro-
Rf (petrol ether/ethyl acetate, 17:3) 0.48; [
a
]
20 ꢂ9.0 (c 1, CHCl3); dH
D
(400 MHz, CDCl3) 1.15 (dd, J¼11.6, 12.9 Hz, 1H, dioxane CH2), 1.37 (s,
3H, C(CH3)2), 1.42 (s, 3H, C(CH3)2), 1.50 (dt, J¼2.5, 12.9 Hz, 1H, di-
oxane CH2), 1.70e1.81 (m, 2H, BnOCH2CH2), 2.10e2.17 (m, 1H,
CH2CH]CH2), 2.26e2.33 (m, 1H, CH2CH]CH2), 3.50e3.61 (m, 2H,
BnOCH2), 3.83e3.90 (m, 1H, dioxane CH), 3.99e4.05 (m, 1H, di-
oxane CH), 4.48 (d, J¼12.1 Hz, 1H, PhCH2O), 4.52 (d, J¼12.1 Hz, 1H,
PhCH2O), 5.03e5.10 (m, 2H, CH]CH2), 5.74e5.84 (m,1H, CH]CH2),
7.27e7.36 (m, 5H, phenyl); dC (100 MHz, CDCl3) 19.8 (C(CH3)2), 30.2
(C(CH3)2), 36.5 (CH2), 36.6 (CH2), 40.8 (CH2), 66.0 (dioxane CH), 66.2
(BnOCH2), 68.6 (dioxane CH), 73.0 (PhCH2O), 98.5 (C(CH3)2), 117.2
(CH]CH2), 127.5 (CH, phenyl), 127.6 (CH, phenyl), 128.3 (CH, phe-
nyl), 134.2 (CH]CH2), 138.5 (C, phenyl); HRMS (ESI) calcd for
C18H26O3 [MþNa]þ 313.17742, found 313.177541.
leum ether/ethyl acetate, 5:1) to provide alcohol 16 (5.52 g, 97%) as
colourless oil. Rf (petroleum ether/ethyl acetate, 5:1) 0.24; [a]
20
D
þ3.2 (c 1, CHCl3); dH (400 MHz, CDCl3) 0.07 (s, 3H, Si(CH3)2), 0.09 (s,
3H, Si(CH3)2), 0.88 (s, 9H, C(CH3)3), 1.62e1.69 (m, 1H, BnOCH2CH2),
1.79e1.90 (m, 3H, BnOCH2CH2, CH2CH2OH), 2.18 (br s, 1H, OH), 3.52
(t, J¼6.3 Hz, 2H, BnOCH2), 3.67e3.73 (m, 1H, CH2OH), 3.78e3.84 (m,
1H, CHOH), 4.07e4.13 (m, 1H, CH2OH), 4.43 (d, J¼11.9 Hz, 1H,
PhOCH2), 4.49 (d, J¼11.9 Hz, 1H, PhOCH2); 7.26e7.36 (m, 5H, phe-
nyl); dC (100 MHz, CDCl3) ꢂ4.7 (2Si(CH3)2), 17.9 (C, silyl), 25.8 (C
(CH3)3), 36.7 (CH2), 38.3 (CH2), 60.0 (CH2OH), 66.8 (BnOCH2), 69.0
(CHOH), 73.0 (PhCH2O), 127.6 (CH, phenyl), 127.7 (CH, phenyl),
128.4 (CH, phenyl), 138.3 (C, phenyl); HRMS (ESI) calcd for
C18H32O3Si [MþNa]þ 347.20129, found 347.201340.
4.6. 2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethanol (19)
A solution of alkene 18 (2.69 g, 9.3 mmol) in methanol/CH2Cl2
(7:3, 100 mL), containing 4-5 drops of Sudan III (1% in methanol)
was cooled to ꢂ80 ꢀC followed by bubbling ozone through the
solution for 1 h until it become colourless. Residual O3 was removed
by bubbling nitrogen through the solution. Thereafter, NaBH4
(3.50 g, 92.6 mmol) was added and the reaction mixture allowed to
reach room temperature with the flask kept in the cooling bath.
Now, H2O (40 mL) was added and the mixture concentrated to
w50 mL before it was extracted with ethyl acetate (3ꢁ60 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography (petroleum ether/ethyl acetate, 5:5) to furnish primary
alcohol 19 (2.60 g, 96%) as colourless oil. Rf (petroleum ether/ethyl
4.4. (4R,6S)-8-(Benzyloxy)-6-{[tert-butyl(dimethyl)silyl]oxy}
oct-1-en-4-ol (17)
An oven dried screw cap bottle (200 mL) was charged under
nitrogen with alcohol 16 (5.90 g, 18.2 mmol), [Ir(cod)Cl]2 (305 mg,
0.46 mmol), (R)-(þ)-Cl, MeO-BIPHEP (592 mg, 0.91 mmol), Cs2CO3
(1.18 g, 1.2 mmol) and 4-chloro-3-nitro-benzoic acid (366 mg,
1.82 mmol) in THF (100 mL) to which allyl acetate (3.64 g,
36.4 mmol) was added. The mixture was heated at 100 ꢀC for 40 h.
The mixture was cooled and then absorbed on silica gel (about 40 g)
loaded on a column and purified by flash chromatography (petro-
leum ether/ethyl acetate, 6:1) to afford homoallyl alcohol 17 (5.26 g,
93%) as colourless oil. Rf (petroleum ether/ethyl acetate, 6:1) 0.38;
acetate, 5:5) 0.2; [
a]
20 ꢂ10.0 (c 1, CHCl3); dH (400 MHz, CDCl3) 1.28
D
(dd, J¼11.6, 12.6 Hz, 1H, dioxane CH2), 1.36 (s, 3H, C(CH3)2), 1.44 (s,
3H, C(CH3)2), 1.45 (dt, J¼2.5, 12.6 Hz, 1H, dioxane CH2), 1.64e1.80
(m, 4H, BnOCH2CH2, CH2CH2OH), 2.16 (s,1H, OH), 3.49e3.67 (m, 2H,
CH2OH), 3.71e3.84 (m, 2H, BnOCH2), 4.02e4.18 (m, 2H, dioxane
CH), 4.48 (d, J¼12.1 Hz, 1H, PhCH2O), 4.52 (d, J¼12.1 Hz, 1H,
PhCH2O), 7.27e736 (m, 5H, phenyl); dC (100 MHz, CDCl3) 19.9 (C
(CH3)2), 30.2 (C(CH3)2), 36.5 (CH2), 36.8 (CH2), 38.0 (dioxane CH2),
61.1 (BnOCH2), 66.0 (dioxane CH), 66.1 (CH2OH), 69.6 (dioxane CH),
73.0 (PhCH2O), 98.7 (C(CH3)3), 127.6 (CH, phenyl), 127.7 (CH, phe-
nyl), 128.4 (CH, phenyl), 138.5 (C, phenyl); HRMS (ESI) calcd for
C17H26O4 [MþNa]þ 317.17233, found 317.172357.
[
a]
20þ14.2 (c 1, CHCl3); dH (400 MHz, CDCl3) 0.08 (s, 3H, SiC(CH3)2),
D
0.10 (s, 3H, SiC(CH3)2), 0.88 (s, 9H, SiC(CH3)3), 1.52e1.59 (m, 1H,
CH2CHOH), 1.63e1.68 (m, 1H, CH2CHOH), 1.76e1.90 (m, 2H,
BnOCH2CH2), 2.18e2.22 (m, 2H, CH2CH]CH2), 3.51 (t, J¼6.3 Hz, 2H,
BnOCH2), 3.77e3.83 (m, 1H, CHOH), 4.04e4.10 (m, 1H, CHOTBS),
4.44 (d, J¼11.9 Hz, 1H, PhCH2O), 4.48 (d, J¼11.9 Hz, 1H, PhCH2O),
5.07e5.11 (m, 2H, CH]CH2), 5.75e5.86 (m,1H, CH]CH2), 7.26e7.35
(m, 5H, phenyl); dC (100 MHz, CDCl3) ꢂ4.6 (Si(CH3)2), ꢂ4.3 (Si
(CH3)2), 17.9 (C(CH3)3), 25.8 (SiC(CH3)3), 37.7 (CH2), 42.2 (CH2), 42.8
(CH2), 66.6 (CHOH), 69.7 (BnOCH2), 70.2 (CHOTBS), 73.0 (PhCH2O),
117.5 (CH]CH2), 127.6 (CH, phenyl), 127.6 (CH, phenyl), 128.4 (CH,
phenyl), 134.8 (CH]CH2), 138.3 (C, phenyl); HRMS (ESI) calcd for
C21H37O3Si [MþNa]þ 387.23259, found 387.232566.
4.7. 2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethyl 4-methylbenzenesulfonate (20)
To a mixture of alcohol 19 (2.60 g, 8.83 mmol), Et3N (3.69 mL,
26.5 mmol), DMAP (323 mg, 2.65 mmol) in CH2Cl2 (50 mL), p-tol-
uene sulphonyl chloride (3.37 g, 17.66 mmol) was added in one
portion at 0 ꢀC. The reaction mixture was allowed to stir at room
temperature overnight before it was diluted with CH2Cl2 (70 mL),
washed with saturated NaHCO3 solution (50 mL) and saturated
NaCl solution (50 mL), dried over Na2SO4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography (pe-
4.5. (4R,6S)-4-Allyl-6-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxane (18)
A mixture of p-toluenesulphonic acid monohydrate (268 mg,
1.51 mmol) and alcohol 17 (5.49 g, 15.06 mmol) in methanol
(150 mL) was stirred at room temperature for 1 h to complete the
deprotection (confirmed by TLC). The reaction mixture was con-
centrated on the rotary evaporator to about 50 mL before it was
diluted with 2,2-dimethoxypropane (150 mL, 602 mmol) and
troleum ether/ethyl acetate, 8:2) to afford tosylate 20 (3.42 g, 86%)
20
as colourless oil. Rf (petroleum ether/ethyl acetate, 8:2) 0.28; [a]
D
ꢂ2.6 (c 1, CHCl3); dH (400 MHz, CDCl3) 1.09 (dd, J¼11.6, 12.6 Hz, 1H,
dioxane CH2), 1.27 (s, 3H, C(CH3)2), 1.31 (s, 3H, C(CH3)2), 1.39 (dt,

9742
P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
J¼2.5, 12.6 Hz, 1H, dioxane CH2), 1.63e1.81 (m, 4H, BnOCH2CH2,
CH2CH2OTs), 2.43 (s, 3H, CH3, tosyl), 3.47e3.58 (m, 2H, BnOCH2),
3.87e4.01(m, 2H, CH2OTs), 4.05e4.10 (m, 1H, dioxane CH),
4.12e4.19 (m,1H, dioxane CH), 4.44 (d, J¼12.1 Hz,1H, PhCH2O), 4.47
(d, J¼12.1 Hz, 1H, PhCH2O), 7.26e7.36 (m, 5H, phenyl), 7.33 (d,
J¼8.3 Hz, 2H, tosyl), 7.78 (d, J¼8.3 Hz, 2H, tosyl); dC (100 MHz,
CDCl3) 19.7 (C(CH3)2), 21.6 (CH3, tosyl), 30.0 (C(CH3)2), 35.5 (CH2),
36.5 (CH2), 36.8 (CH2), 64.9 (dioxane CH), 65.9 (dioxane CH), 66.1
(BnOCH2), 66.8 (CH2OTs), 73.0 (CH2, benzyl), 98.6 (C(CH3)2), 127.6
(CH, benzyl),127.6 (CH, benzyl),127.9 (CH, tosyl),128.4 (CH, benzyl),
129.8 (CH, tosyl), 133.1 (C, tosyl), 138.5 (C, benzyl), 144.7 (C, tosyl);
HRMS (ESI) calcd for C24H32O6S [MþNa]þ 471.18118, found
471.181152.
4.10. 1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethyl)-2-(4-fluorophenyl)-5-isopropyl-3-phenyl-
1H-pyrrole (24)
A mixture of 1,4-diketone 23 (500 mg, 1.68 mmol), amine 22
(516 mg, 1.76 mmol) and p-toluenesulphonic acid monohydrate
(64 mg, 0.335 mmol, 0.2 equiv) in xylene (20 mL) was refluxed for 7
days using a DeaneStark trap to remove water as azeotrope. The
completion of the reaction was checked by TLC. The reaction mix-
ture was diluted with diethyl ether (30 mL), washed with saturated
NaHCO3 (30 mL) and saturated NaCl solution (30 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The crude residue was purified by flash chromatography
(petroleum ether/diethyl ether, 9:1) to afford pyrrole 24 (520 mg,
68%) as colourless sticky solid. Rf (petroleum ether/diethyl ether,
20
4.8. (4R,6S)-4-(2-Azidoethyl)-6-[2-(benzyloxy)ethyl]-2,2-
dimethyl-1,3-dioxane (21)
9:1) 0.25; [
a
]
D
þ4.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.95 (dd,
J¼11.6, 12.6 Hz, 1H, dioxane CH2), 1.15 (dt, J¼2.3, 12.6 Hz, 1H, di-
oxane CH2), 1.31e1.35 (m, 12H, C(CH3)2, CH(CH3)2), 1.44e1.75 (m,
4H, NCH2CH2, CH2CH2OBn), 2.96e3.06 (septet, J¼6.8 Hz, 1H, CH
(CH3)2), 3.44e3.59 (m, 3H, dioxane CH, CH2OBn), 3.76e3.84 (m, 1H,
NCH2), 3.88e3.99 (m, 2H, dioxane CH, NCH2), 4.44 (d, J¼12.1 Hz,1H,
PhCH2O), 4.47 (d, J¼12.1 Hz, 1H, PhCH2O), 6.18 (s, 1H, pyrrole CH),
7.02e7.07 (m, 3H, aryl), 7.10e7.16 (m, 4H, aryl), 7.26e7.35 (m, 7H,
aryl); dC (100 MHz, CDCl3) 19.8 (C(CH3)2), 23.3 (CH(CH3)2), 23.7 (CH
(CH3)2), 25.5 (CH(CH3)2), 30.1 (C(CH3)2), 36.4 (CH2), 36.5 (CH2), 37.9
(dioxane CH2,), 39.8 (NCH2), 65.7 (dioxane CH), 66.0 (OCH2Ph), 66.3
(dioxane CH), 72.9 (OCH2Ph), 98.4 (C(CH3)2), 103.4 (pyrrole C-3),
115.6 (C-3, JC,F¼21.2 Hz, 4-FeC6H4), 122.0 (C, aryl), 124.8 (CH, aryl),
127.5 (CH, aryl), 127.5 (CH, aryl), 127.6 (CH, aryl), 127.8 (C, aryl),
128.0 (CH, aryl), 128.3 (CH, aryl), 129.8 (C-2, JC,F¼3.7 Hz, 4-FeC6H4),
132.9 (C-1, JC,F¼8.1 Hz, 4-FeC6H4), 136.5 (C, aryl), 138.5 (C, aryl),
140.4 (C, aryl), 162.2 (C-4, JC,F¼246.6 Hz, 4-FeC6H4); HRMS (ESI)
calcd for C36H42FNO3 [MþNa]þ 578.30409, found 578.304437.
A mixture of tosylate 20 (3.41 g, 7.60 mmol) and sodium azide
(1.05 g, 15.20 mmol) in DMF (40 mL) was stirred for 12 h at room
temperature. The reaction mixture was diluted with water (20 mL)
and extracted with ethyl acetate (3ꢁ100 mL). The combined or-
ganic layers were dried over MgSO4, filtered and concentrated in
vacuo. The crude azide was purified by a simple filtration column
(flash silica gel, petroleum ether/ethyl acetate, 8:2) yielding pure
azide 21 (2.35 g, 97%) as colourless oil. Rf (petroleum ether/ethyl
acetate, 8:2) 0.53; [
a
]
20 ꢂ3.0 (c 1, CHCl3); dH (400 MHz, CDCl3) 1.17
D
(dd, J¼11.6, 12.6 Hz, 1H, dioxane CH2), 1.36 (s, 3H, C(CH3)2), 1.42 (s,
3H, C(CH3)2), 1.46 (dt, J¼2.5, 12.9 Hz, 1H, dioxane CH2), 1.65e1.81
(m, 4H, BnOCH2CH2, CH2CH2N3), 3.31e3.44 (m, 2H, CH2N3),
3.49e3.61 (m, 2H, BnOCH2), 3.92e3.99 (m, 1H, dioxane CH),
4.01e4.08 (m, 1H, dioxane CH), 4.46 (d, J¼12.1 Hz, 1H, PhCH2O),
4.49 (d, J¼12.1 Hz, 1H, PhCH2O), 7.26e7.36 (m, 5H, phenyl); dC
(100 MHz, CDCl3) 17.8 (C(CH3)2), 28.1 (C(CH3)2), 33.6 (CH2), 34.5
(CH2), 35.0 (CH2), 45.5 (CH2N3), 63.9 (dioxane CH), 64.0 (dioxane
CH), 64.1 (BnOCH2), 73.0 (PhCH2O), 98.7 (C(CH3)2), 127.6 (CH,
phenyl), 127.6 (CH, phenyl), 128.3 (CH, phenyl), 138.5 (C, phenyl);
HRMS(ESI) calcd for C17H25N3O3 [MþNa]þ 342.17881, found
342.178839.
4.11. 1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethyl)-2-(4-fluorophenyl)-4-iodo-5-isopropyl-3-
phenyl-1H-pyrrole (25)
To a solution of pyrrole 24 (206 mg, 0.37 mmol) in DMF (5 mL) N-
iodosuccinimide (100 mg, 0.45 mmol) was added in one portion and
the reaction mixture was stirred for 30 min at room temperature.
The reaction mixturewas diluted with diethyl ether (15 mL), washed
with 10% Na2S2O3 solution (5 mL), saturated NaHCO3 solution
(10 mL) and saturated NaCl solution (10 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated. The crude
product was purified by flash chromatography (petroleum ether/
4.9. 2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethylamine (22)
To a solution of azide 21 (2.55 g, 7.98 mmol) in a mixture (10:1)
of THF (50 mL) and H2O (5 mL), triphenylphosphine (4.19 g,
15.97 mmol) was added and the mixture was stirred at room
temperature for 10e12 h. The reaction mixture was concentrated
to remove most of the THF. Benzene (100 mL) was added and the
reaction mixture was concentrated to remove water as azeotrope.
This manipulation was repeated once. The crude residue was
ethyl acetate, 9:1) to give iodopyrrole 25 (230 mg, 91%) as colourless
20
oil. Rf (petroleum ether/ethyl acetate, 9:1) 0.3; [
a
]
ꢂ2.0 (c 1,
D
CHCl3); dH (400 MHz, CDCl3) 0.98 (dd, J¼11.6, 12.9 Hz, 1H, dioxane
CH2), 1.20 (dt, J¼2.3, 12.9 Hz, 1H, dioxane CH2), 1.29 (s, 3H, C(CH3)2),
1.32 (s, 3H, C(CH3)2), 1.49 (d, J¼7.1 Hz, 3H, CH(CH3)2), 1.51 (d,
J¼7.1 Hz, 3H, CH(CH3)2), 1.56e1.75 (m, 4H, NCH2CH2, CH2CH2OBn),
3.26e3.37 (septet, J¼7.1 Hz, 1H, CH(CH3)2), 3.45e3.65 (m, 3H, dio-
xane CH, CH2OBn), 3.76e3.84 (m, 1H, NCH2), 3.89e3.96 (m, 1H, di-
oxane CH), 4.00e4.07 (m, 1H, NCH2), 4.44 (d, J¼12.1 Hz, 1H,
PhCH2O), 4.48 (d, J¼12.1 Hz, 1H, PhCH2O), 6.92e6.97 (m, 2H, aryl),
7.09e7.22 (m, 7H, aryl), 7.26e7.35 (m, 5H, aryl); dC (100 MHz, CDCl3)
19.8 (C(CH3)2), 21.4 (CH(CH3)2), 21.5 (CH(CH3)2), 27.2 (CH(CH3)2),
30.0 (C(CH3)2), 36.4 (CH2), 36.5 (CH2), 38.3 (dioxane CH2), 41.2
(NCH2), 65.7 (dioxane CH), 66.0 (CH2OBn), 66.5 (dioxane CH), 72.9
(OCH2Ph), 98.5 (C(CH3)2), 117.2 (C-3, JC,F¼21.2 Hz, 4-FeC6H4,), 126.0
(CH, aryl), 126.5 (C, aryl), 127.4 (CH, aryl), 127.5 (CH, aryl), 127.6 (CH,
aryl), 128.3 (CH, aryl), 129.8 (C-2, JC,F¼3.7 Hz, 4-FeC6H4), 128.7 (C,
aryl), 129.7 (C, aryl), 130.9 (2 CH, aryl), 132.9 (C-1, JC,F¼8.1 Hz, 4-
FeC6H4), 135.9 (C, aryl), 137.1 (C, aryl), 138.5 (C, aryl), 162.1 (C-4,
purified
by
flash
chromatography
(CH2Cl2/MeOH/Et3N,
9.5:0.4:0.1) to furnish amine 22 (2.2 g, 94%) as colourless oil. Rf
20
(CH2Cl2/MeOH/Et3N, 9.5:0.4:0.1) 0.29; [
a
]
ꢂ10.0 (c 1, CHCl3); dH
D
(400 MHz, CDCl3) 1.19 (dd, J¼11.6, 12.6 Hz, 1H, dioxane CH2), 1.35
(s, 3H, C(CH3)2), 1.41 (s, 3H, C(CH3)2), 1.44 (dt, J¼2.3, 12.6 Hz, 1H,
dioxane CH2), 1.53e1.80 (m, 4H, CH2CH2NH2, BnOCH2CH2), 1.97 (s,
2H, NH2), 2.79e2.82 (m, 2H, CH2NH2), 3.49e3.60 (m, 2H, BnOCH2),
3.91e3.97 (m, 1H, dioxane CH), 3.99e4.06 (m, 1H, dioxane CH),
4.45 (d, J¼11.9 Hz, 1H, benzyl CH2), 4.49 (d, J¼11.9 Hz, 1H, benzyl
CH2), 7.26e7.35 (m, 5H, phenyl); dC (100 MHz, CDCl3) 19.9 (C
(CH3)2), 30.2 (C(CH3)2), 36.5 (CH2), 37.1 (CH2), 38.4 (CH2), 38.5
(CH2), 39.4 (CH2), 66.0 (dioxane CH), 66.1 (OCH2), 67.7 (dioxane
CH), 73.0 (CH2, benzyl), 127.5 (CH, phenyl), 127.6 (CH, phenyl),
128.34 (CH, phenyl), 138.49 (C, phenyl); HRMS (ESI) calcd for
C17H27NO3 [MþNa]þ 294.20637, found 294.206401.

P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
9743
JC,F¼247.4 Hz, 4-FeC6H4); HRMS (ESI) calcd for C36H41FINO3
[MþNa]þ 704.20074, found 704.200369.
(dioxane CH2), 40.9 (NCH2), 65.7 (dioxane CH), 66.0 (CH2OBn), 66.5
(dioxane CH), 72.9 (PhCH2O), 98.5 (C(CH3)2), 115.24, 115.3 (4-
FeC6H4, C-3, JC,F¼21.2 Hz), 119.5 (CH, aryl), 121.7 (C, aryl), 123.5 (CH,
aryl), 126.5 (CH, aryl), 127.6 (CH, aryl), 127.6 (CH, aryl), 128.2 (C,
aryl), 128.3 (CH, aryl), 128.6 (CH, aryl), 128.7 (C, aryl), 130.5 (CH,
aryl), 133.2 (C-2, JC,F¼8.1 Hz, 4-FeC6H4,), 134.6 (C, aryl), 138.4 (C-1,
JC,F¼7.3 Hz, 4-FeC6H4,), 141.5 (C, aryl), 149.9 (C, aryl), 141.5 (C, aryl),
162.2 (C-4, JC,F¼248.1 Hz, 4-FeC6H4), 164.8 (CONH); HRMS (ESI)
calcd for C43H47FO4 [MþNa]þ 697.34121, found 697.341636.
4.12. 1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-
1H-pyrrole-3-carboxylic acid (26)
A solution of iodopyrrole 25 (201 mg, 0.29 mmol) in THF
(10 mL) was cooled to ꢂ80 ꢀC, then t-BuLi (0.387 mL, 0.62 mmol,
2.5 M in hexane) was added dropwise. After 10 min, excess of CO2
was bubbled through the reaction mixture with stirring for
15 min. Thereafter, the mixture was allowed to reach room tem-
perature within 1 h. The progress of the reaction was checked by
TLC. The reaction mixture was treated with saturated NH4Cl so-
lution and extracted with ethyl acetate (3ꢁ30 mL). The combined
organic layers were washed with saturated NaCl solution, dried
over Na2SO4, filtered and concentrated. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate, 8:2) to
furnish acid 26 (144 mg, 81%) as white solid, mp 73e78 ꢀC. Rf
4.14. 5-(4-Fluorophenyl)-1-{2-[(4R,6S)-6-(2-hydroxyethyl)-
2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-2-isopropyl-N,4-
diphenyl-1H-pyrrole-3-carboxamide (28)
A solution of benzyl ether 27 (20 mg, 0.03 mmol) containing 20%
Pd(OH)2 (5 mg, 25% by weight of substrate), cyclohexene (1 mL) and
ethanol (2 mL) were stirred for 4 h at 80 ꢀC. After cooling, the
catalyst was filtered off, and the filtrate concentrated in vacuo. The
crude product was purified by flash chromatography (petroleum
ether/ethyl acetate, 6:4) to afford alcohol 28 (15 mg, 86%) as white
(petroleum ether/ethyl acetate, 7:3) 0.3; [
a
]
20 ꢂ1.7 (c 1, CHCl3); dH
D
(400 MHz, CDCl3) 0.98 (dd, J¼11.6, 13.1 Hz, 1H, dioxane CH2), 1.19
(dt, J¼2.5, 13.1 Hz, 1H, dioxane CH2), 1.28 (s, 3H, C(CH3)2), 1.31 (s,
3H, C(CH3)2), 1.45 (d, J¼7.1 Hz, 3H, CH(CH3)2), 1.46 (d, J¼7.1 Hz, 3H,
CH(CH3)2), 1.55e1.74 (m, 4H, NCH2CH2, CH2CH2OBn), 3.44e3.65
(m, 4H, dioxane CH, CH2OBn, CH(CH3)2), 3.74e3.81(m, 1H, NCH2),
3.89e3.95 (m, 1H, dioxane CH), 4.00e4.07 (m, 1H, NCH2), 4.43 (d,
J¼12.1 Hz, 1H, PhCH2O), 4.47 (d, J¼12.1 Hz, 1H, PhCH2O), 6.91e6.95
(m, 2H, aryl), 7.03e7.14 (m, 7H, aryl), 7.27e7.35 (m, 5H, aryl); dC
(100 MHz, CDCl3) 19.8 (C(CH3)2), 20.8 (CH(CH3)2), 20.8 (CH(CH3)2),
26.0 (CH(CH3)2), 30.0 (C(CH3)2), 36.4 (CH2), 36.4 (CH2), 37.9 (di-
oxane CH2), 41.1 (NCH2CH2), 65.7 (dioxane CH), 66.0 (CH2OBn),
66.5 (dioxane CH), 72.9 (PhCH2O), 98.5 (C(CH3)2), 109.4 (C, aryl),
115.2 (C-3, JC,F¼21.2 Hz, 4-FeC6H4,), 125.8 (CH, aryl), 127.2 (CH,
aryl), 127.6 (CH, aryl), 127.6 (CH, aryl), 128.1 (C-2, JC,F¼2.9 Hz, 4-
FeC6H4), 128.3 (CH, aryl), 130.0 (C, aryl), 130.5 (2 CH, aryl), 133.2
(C-1, JC,F¼8.1 Hz, 4-FeC6H4), 135.4 (C, aryl), 138.4 (C, aryl), 144.9 (C,
aryl), 162.2 (C-4, JC,F¼248.1 Hz, 4-FeC6H4), 170.7 (C, aryl), 177.3
(COOH); HRMS (ESI) calcd for C37H42FNO5 [MþNa]þ 622.29392,
found 622.293491.
solid, mp 75e85 ꢀC. Rf (petroleum ether/ethyl acetate, 6:4) 0.11;
20
[a
]
ꢂ6.0 (c 1, in CHCl3); dH (400 MHz, CD3OD) 0.95 (dd, J¼11.4,
D
12.6 Hz, 1H, dioxane CH2), 1.26e1.30 (m, 4H, dioxane CH2, C(CH3)2),
1.36 (s, 3H, C(CH3)2), 1.46 (d, J¼7.1 Hz, 3H, CH(CH3)2), 1.47 (d,
J¼6.8 Hz, 3H, CH(CH3)2), 1.52e1.65 (m, 4H, NCH2CH2, CH2CH2OH),
3.34e3.39 (m, 1H, CH(CH3)2), 3.53e3.62 (m, 2H, CH2OH), 3.68e3.78
(m, 1H, dioxane CH), 3.84e3.99 (m, 2H, NCH2, dioxane CH),
4.03e4.12 (m, 1H, NCH2), 7.00e7.33 (m, 14H, aryl); dC (100 MHz,
CD3OD) 20.1 (C(CH3)2), 22.6 (CH(CH3)2), 22.8 (CH(CH3)2), 27.6 (CH
(CH3)2), 30.4 (C(CH3)2), 37.7 (dioxane CH2), 39.4 (CH2), 40.1 (CH2),
41.4 (NCH2), 59.0 (CH2OH), 67.3 (dioxane CH), 67.8 (dioxane CH),
99.8 (C(CH3)2), 116.2 (C-3, J¼22.0 Hz, 4-FeC6H4), 118.1 (C, aryl),
121.5 (CH, aryl), 123.3 (C, aryl), 125.1 (CH, aryl), 126.80, 126.9, 128.8,
128.9 (CH, aryl), 129.4, 129.6 (2 CH, aryl), 130.2 (C-1, J¼3.7 Hz, 4-
FeC6H4), 130.9 (CH, aryl), 132.8 (CH, aryl), 134.8 (C-2, J¼8.1 Hz, 4-
FeC6H4), 136.3 (C, aryl), 138.9 (C, aryl), 139.0 (C, aryl), 139.8 (C, aryl),
163.8 (C-4, J¼246.6 Hz, 4-FeC6H4), 169.5 (CONH); HRMS (ESI) calcd
for C36H41FN2O4 [MþNa]þ 607.29426, found 607.294097.
4.15. (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-
phenylcarbamoyl pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]
dioxan-4-yl)-acetic acid (29)
4.13. 1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-
diphenyl-1H-pyrrole-3-carboxamide (27)
To a cooled solution alcohol 28 (147 mg, 0.25 mmol) in CH2Cl2
(10 mL) at 0 ꢀC, DesseMartin reagent (145 mg, 0.50 mmol) was
added in one portion. The reaction mixture was stirred at room
temperature for 1 h before it was quenched with a mixture of
saturated NaHCO3 solution and 0.1 M Na2S2O3 (4 mL, 1:1). The
organic layer was dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude aldehyde was dissolved in
tert-butanol (10 mL) and 2-methyl-2-butene (1.2 mL) was added.
The mixture was cooled to 0 ꢀC, then a solution of NaH2PO4$2H2O
(224 mg, 1.44 mmol) and NaClO2 (43 mg, 0.480 mmol) in H2O
(10 mL) was added dropwise and the mixture allowed to stir at
room temperature for 6 h. The mixture was diluted with satu-
rated NaCl solution and extracted with ethyl acetate (3ꢁ20 mL).
The combined organic extracts were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude acid was purified by flash chromatography (CH2Cl2/meth-
anol/acetic acid, 25:1:0.1) to furnish acid 29 as white solid
(144 mg, 96%). Rf (CH2Cl2/methanol/acetic acid, 25:1:0.1) 0.33;
To a solution of acid 26 (73 mg, 0.12 mmol) and aniline (13
0.15 mmol) in CH2Cl2 (5 mL), N-ethyldiisopropyl amine (63
m
m
L,
L,
0.36 mmol) was added and the reaction mixture was cooled to 0 ꢀC.
PyBrOP (85 mg, 0.18 mmol) was then added and the mixture
allowed to stir at room temperature for 4 h. Completion of the re-
action was checked by TLC. The reaction mixture was diluted with
CH2Cl2 (5 mL), washed with water (3ꢁ5 mL) and saturated NaCl
solution. The organic layer was dried over Na2SO4, filtered and
concentrated in vacuo. The crude residue was purified by flash
chromatography (petroleum ether/ethyl acetate, 8:2) to afford
amide 27 (65 mg, 82%) as white solid, mp 75e82 ꢀC. Rf (petroleum
ether/ethyl acetate, 8:2) 0.29; [
a]
20 ꢂ1.5 (c 1, CHCl3); dH (400 MHz,
D
CDCl3) 0.94 (dd, J¼11.6, 12.4 Hz, 1H, dioxane CH2), 1.14e1.18 (m, 1H,
dioxane CH2), 1.23 (s, 3H, C(CH3)2), 1.26 (s, 3H, C(CH3)2), 1.46 (d,
J¼7.1 Hz, 6H, CH(CH3)2), 1.53e1.69 (m, 4H, NCH2CH2, BnOCH2CH2),
3.38e3.60 (m, 4H, NCH2, CH2OBn, CH(CH3)2), 3.70e3.78 (m, 1H,
NCH2), 3.85e3.91 (m, 1H, dioxane CH), 3.95e4.03 (m, 1H, dioxane
CH), 4.37 (d, J¼12.4 Hz, 1H, PhCH2O), 4.41 (d, J¼12.4 Hz, 1H,
PhCH2O), 6.78 (s, 1H, NH), 6.89e6.93 (m, 3H, aryl), 6.98e7.00 (m,
2H, aryl), 7.08e7.13 (m, 9H, aryl), 7.20e7.28 (m, 5H, aryl); dC
(100 MHz, CDCl3) 19.8 (C(CH3)2), 21.5 (CH(CH3)2), 21.7 (CH(CH3)2),
26.1 (CH(CH3)2), 30.0 (C(CH3)2), 36.4 (CH2), 36.4 (CH2), 38.1
[
a
]
20 þ5.0 (c 1, in CHCl3); dH (400 MHz, CD3OD) 0.93e1.02 (m, 1H,
D
dioxane CH2), 1.25 (s, 3H, C(CH3)2), 1.29e1.34 (m, 1H, dioxane
CH2), 1.34 (s, 3H, C(CH3)2), 1.46 (d, J¼7.1 Hz, 3H, CH(CH3)2), 1.47
(d, J¼6.8 Hz, 3H, CH(CH3)2), 1.60e1.65 (m, 2H, NCH2CH2),
2.25e2.38 (m, 2H, CH2CO2H), 3.32e3.41 (m, 1H, CH(CH3)2),

9744
P. Sawant, M.E. Maier / Tetrahedron 66 (2010) 9738e9744
3.70e3.82 (m, 1H, dioxane CH), 3.85e3.94 (m, 1H, NCH2),
4.03e4.12 (m, 1H, NCH2), 4.16e4.26 (m, 1H, dioxane CH),
7.00e7.36 (m, 14H, aryl); dC (100 MHz, CD3OD) 20.0 (C(CH3)2),
22.6 (CH(CH3)2), 22.8 (CH(CH3)2), 27.6 (CH(CH3)2), 30.3 (C(CH3)2),
37.1 (CH2), 39.4 (dioxane CH2), 41.4 (CH2CO2H), 42.2 (NCH2), 67.2
(dioxane CH), 67.7 (dioxane CH), 100.0 (C(CH3)2), 116.3 (C-3,
JC,F¼22.0 Hz, 4-FeC6H4), 118.1 (C, aryl), 121.5 (CH, aryl), 123.3 (C,
aryl), 125.1 (CH, aryl), 126.9, 128.8, 128.9 (CH, aryl), 129.0, 129.5,
129.6 (CH, aryl), 129.6 (C, aryl), 130.2 (C-1, JC,F¼3.7 Hz, 4-FeC6H4),
130.9 (2 CH, aryl), 131.8, 132.8 (CH, aryl), 134.8 (2 C-2,
JC,F¼8.05 Hz, 4-FeC6H4), 136.3 (C, aryl), 139.0 (C, aryl), 139.8 (C,
aryl), 163.8 (C-4, JC,F¼246.6 Hz, 4-FeC6H4), 169.5 (CONH), 174.6
(COO); HRMS (ESI) calcd for C36H39FN2O5 [MþNa]þ 621.27352,
found 621.27359.
version, at doi:10.1016/j.tet.2010.10.028. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
References and notes
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€
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4.16. 5-(4-Fluoro-phenyl)-1-[2-(4-hydroxy-6-oxo-tetrahydro-
pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-
carboxylic acid phenylamide (6)
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A solution of acid 29 (52 mg, 0.08 mmol) and a catalytic amount
of camphor sulphonic acid in THF (2 mL) was stirred at room
temperature for 3 h. The mixture was concentrated and the residue
purified by flash chromatography (diethyl ether/methanol, 50:1) to
afford atorvastatin lactone 6 (38 mg, 90%) as white solid. It was
recrystallized from petroleum ether/ethyl acetate to give an
13. (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2000, 65, 4779e4781; (b) Tararov, V. I.;
Andrushko, N.; Andrushko, V.; Koenig, G.; Spannenberg, A.; Boerner, A. Eur. J.
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amorphous white solid, mp 150e155 ꢀC {Ref. 30: 160e162 ꢀC}. Rf
20
(diethyl ether/methanol, 50:1) 0.25; [
a
]
þ25.5 (c 0.2, CHCl3)
D
23
{Ref. 9: [
a
]
þ24.53 (0.53% in CHCl3), Ref. 10: [
a]
þ26.05 (c 1,
D
D
€
14. For some reviews, see: (a) Muller, M. Angew. Chem. 2005, 117, 366e369; Angew.
CHCl3)}; dH (400 MHz, CDCl3) 1.50e1.53 (m, 6H, CH(CH3)2),
1.55e1.60 (m, 1H, lactone H-4), 1.65e1.77 (m, 2H, lactone H-4,
NCH2CH2), 1.82e1.91 (m, 1H, NCH2CH2), 2.37 (s, 1H, OH), 2.49e2.66
(m, 2H, lactone H-2), 3.48e3.58 (m, 1H, CH(CH3)2), 3.98e4.10 (m,
1H, NCH2), 4.16e4.29 (m, 2H, NCH2, lactone H-3), 4.44e4.54 (m, 1H,
lactone H-5), 6.87 (s, 1H, NH), 6.96e7.20 (m, 13H, aryl), 7.27e7.33
(m, 1H, aryl); dC (100 MHz, CD3OD) 21.7 (CH(CH3)2), 22.0 (CH
(CH3)2), 26.1 (CH(CH3)2), 35.6 (C-4, lactone), 37.0, 37.1 (NCH2CH2),
38.5 (C-2, lactone), 40.7 (NCH2), 62.4 (C-3, lactone), 73.0 (C-5, lac-
tone), 73.1, 115.6 (C-3, JC,F¼22.0 Hz, 4-FeC6H4), 115.6 (C-3, pyrrole),
119.7 (C-2, anilide), 122.1 (C-4, pyrrole), 123.6, 123.7 (C-4, anilide),
126.5, 126.6 (C-4, phenyl), 128.0 (C-1, JC,F¼2.9 Hz, 4-FeC6H4), 128.3,
128.4 (C-3, anilide), 128.4, 128.7 (C-2, anilide), 128.7 (C-5, pyrrole),
130.4 (C-3, phenyl), 131.3, 134.0, 133.1 (C-2, JC,F¼8.1 Hz, 4-FeC6H4),
134.4 (C-1, phenyl), 134.5, 138.2, 138.2 (C-1, anilide), 141.3 (C-2,
pyrrole), 162.3 (C-4, JC,F¼248.8 Hz, 4-FeC6H4), 164.9 (CONH), 169.4
(COO); HRMS (ESI) calcd for C33H33FN2O4 [MþNa]þ 563.23166,
found 563.23154.
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Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged. P.S.
acknowledges a fellowship from the Promotionsverbund ‘Identi-
fizierung und Validierung von Arzneistofftargets’ funded by the
€
€
Eberhard Karls Universitat Tubingen. We also thank the co-
ordinator, Prof. Oliver Werz, and members of the Promo-
tionsverbund for helpful discussions.
ꢀ
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Supplementary data
Supplementary data associated with this article (procedure for
alcohol 13, copies of NMR spectra) can be found in the online