Synthesis of atorvastatin lactone linker constructs for target fishing

Article abstract of DOI:10.1002/ejoc.201201154

With the aim of connecting atorvastatin lactone 9 to a linker for affinity-based target fishing, a concise route to the pyrrolecarboxylic acid 8 was developed. Key features of the synthesis of the diol-containing side-chain were a catalytic enantioselecti

Full text of DOI:10.1002/ejoc.201201154

FULL PAPER
DOI: 10.1002/ejoc.201201154
Synthesis of Atorvastatin Lactone Linker Constructs for Target Fishing
Pramod Sawant[a] and Martin E. Maier*[a]
Keywords: Atorvastatin / Vinylogous aldols / 1,3-Diols / Cross metathesis / Amines / Linkers / Inhibitors / Enantio-
selectivity
With the aim of connecting atorvastatin lactone 9 to a linker
for affinity-based target fishing, a concise route to the pyr-
rolecarboxylic acid 8 was developed. Key features of the syn-
thesis of the diol-containing side-chain were a catalytic
enantioselective vinylogous aldol reaction resulting in 5-hy-
droxy-enoate 14 (88% ee). Subsequent intramolecular oxa-
Michael addition and amide reduction furnished key build-
tone is an aniline derivative of acid 7, we prepared two link-
ers having an aniline terminus. For this purpose ethylene
glycol based allyl ethers 20 and 27 were combined with nitro-
styrene 22 by cross-metathesis. After hydrogenation of the
nitro group and the double bond, anilines 25 and 29, respec-
tively, were obtained. The anilines were condensed with
carboxylic acid 8 to afford the corresponding amides 30 and
ing block 5. As we have described previously, Paal–Knorr re- 35. Elaboration of the side-chain then provided atorvastatin
action of amine 5 with diketone 6 led to pyrrole 7, which –
after carboxylation – provided acid 8. Since atorvastatin lac-
lactone linker constructs 34 and 39, respectively.
Introduction
CoA reductase, an atorvastatin probe might be helpful.
Apart from the lactone moiety, the carboxyl function in the
pyrrole appeared as an obvious handle for attachment of a
linker.
Statins are widely prescribed drugs for reducing plasma
cholesterol levels with the aim of lowering the risk of car-
diovascular disease.[1] Their principal mechanism of action
entails inhibition of 3-hydroxy-3-methylglutaryl coen-
zyme A (HMG-CoA) reductase, a key enzyme in the early
steps of cholesterol biosynthesis. The wide use of statins
revealed a range of beneficial side effects including antioxi-
dant and anti-inflammatory effects.[2] In the case of lovasta-
tin (1) and related natural statins, it could be shown that
the anti-inflammatory effect is due to binding of 1 to the
β2 integrin leucocyte function antigen-1 (LFA-1) (Figure 1).
This seems to interfere with the leukocyte adhesion cascade.
LFA-1 is a major integrin receptor on circulating leuko-
cytes. Their corresponding natural ligands on endothelium
cells include intracellular adhesion molecule 1 (ICAM-1)
and vascular adhesion molecule 1 (VCAM-1). They are in-
duced or upregulated by cytokines or C-reactive protein
(CRP). The X-ray structure of the lovastatin/LFA-1 I-do-
main complex shows that the hydroxy lactone form and not
the dihydroxy-carboxylate form is bound by LFA-1.[3] How-
ever, thus far it is not clear whether other statins like atorva-
statin, a natural product mimetic,[4] confer their anti-in-
flammatory effects by the same mechanism (Figure 1). To
detect and identify other cellular targets besides HMG-
Figure 1. Structure of two HMG reductase inhibitors. Lovastatin
(1) is a natural product, whereas atorvastatin (2) is a natural prod-
uct mimetic.
In a previous paper we already outlined a strategy to
generate side-chain amine 5, its Paal–Knorr condensation
with diketone[5] 6 to pyrrole 7, and the carboxylation of
pyrrole 7 by iodination, halogen–metal exchange and reac-
tion with carbon dioxide (Scheme 1).[6] Some routine steps
converted pyrrole-3-carboxylic acid 8 to atorvastatin lac-
tone 9. The stereocenters in the side chain were created by
two sequential asymmetric transfer hydrogenative carbonyl
allylations. In this paper we illustrate an alternative ap-
proach by which to produce side-chain amine 5 and de-
scribe the synthesis of two aniline linkers suitable for con-
densation with acid 8.
[a] Institut für Organische Chemie, Universität Tübingen,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: +49-7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
Homepage: http://www.uni-tuebingen.de/uni/com/welcome.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201154.
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Atorvastatin Lactone Linker Constructs for Target Identification
these resonate at δ = 19.7 and 30.0 ppm, respectively. Sub-
sequently, ester 16 was converted to amide 17 by refluxing
in a mixture of 25% aqueous NH3 and methanol for 24 h,
which provided amide 17 in 76% yield. To complete the
synthesis of the amine side-chain, amide 17 was reduced
with LiAlH4 in refluxing THF to give key amine 5 in 72%
yield {[α]2D0 = –9.1 (c = 1.0, CHCl3), ref.[6] [α]2D0 = –10.0 (c
= 1.0, CHCl3)}. The overall sequence from benzyloxypro-
panal (12) involved five steps with an overall yield of 21%.
By application of the known sequence, amine 5 was con-
densed with diketone 6 to yield pyrrole 7 (Scheme 1).
Scheme 1. Previous strategy to the primary amine 5 and pyrrole-3-
carboxylic acid 8.
Results and Discussion
Scheme 2. Synthesis of primary amine 5 using a tactical sequence
of vinylogous aldol reaction, intramolecular oxa-Michael addition
and amide reduction.
Since the side-chain amine 5 contains a syn-1,3-diol sub-
unit we considered a strategy that would create one of the
secondary hydroxy functions by internal asymmetric induc-
tion. This, for example, is possible by intramolecular oxa-
The plan was then to couple acid 8 with a linker having
Michael addition of hemiacetal anions to electron-poor alk- an aniline terminus. Towards this goal triethylene glycol was
enes.[7] The synthesis of a suitable substrate for this ap- first monoprotected with tert-butyldiphenylsilyl chloride
proach is shown in Scheme 2. Thus, a vinylogous Mukai- using NaH as a base in THF to yield glycol derivative[15]
yama aldol reaction,[8,9] between benzyloxypropanal[10] 12 19 (Scheme 3). The free hydroxy group was then allylated
and O,O-silyl ketene acetal 11 in the presence of trypto- with allyl bromide under phase-transfer conditions[16] using
phan-derived B-phenyloxazaborolidinone Lewis acid 13 led NaOH and tetrabutylammonium hydrogen sulfate
to 5-hydroxyheptenoate 14 in 60% yield.[11] The reaction (TBAHS) in a mixture of benzene and water providing allyl
was run in n-butyronitrile at –78 °C in the presence of ether 20. To attach the aniline part a cross-metathesis of
iPrOH. Mosher analysis of allylic alcohol 14 indicated an allyl ether 20 with nitrostyrene (22) was envisioned. We
ee value of 88% {[α]2D5 = +10.1 (c = 1, CHCl3), ref.[10a] [α]D found the preparation of 22 to be more convenient using
= 7.6 (c = 1.21, CHCl3)}. To generate the desired syn-1,3- Takai–Nozaki chemistry[17] [CH2I2, Zn, Ti(OiPr)4] instead
diol, hydroxy ester 14 was subjected to a base-catalyzed in- of the classical Wittig reaction[18] since the styrene was ob-
tramolecular conjugate addition of the hemiacetal alkoxide tained in high purity (Scheme 3). The cross-metathesis be-
derived from benzaldehyde and alcohol 14. This gave 66% tween styrene 22 and allyl ether 20 turned out to be a criti-
of benzylidene acetal 15 essentially as a single isomer.[12] cal step. The reaction was carried out in dry degassed tolu-
This reaction did not work with acetone directly. After- ene at 70 °C in the presence of Grubbs 2nd generation cata-
wards, transacetalization to acetonide[13] 16 was done in one lyst.[19] After 5 h, a mixture of three isomers could be iso-
step with dimethoxypropane in the presence of pTsOH. The lated in 65% total yield. Besides the trans-allyl ether 23 the
syn-1,3-diol was evident from the chemical shifts of the cis- and trans-enol ether isomers 24-cis and 24-trans were
acetonide methyl groups in the 13C NMR spectrum;[14] also formed.[20] This was inconsequential since, upon cata-
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lytic hydrogenation (H2, Pd/C, MeOH), the mixture con-
verged to aniline 25. The alcohol function at the terminus
of 25 was envisioned to be suitable for immobilization on
an acid or epoxide functionalized resin.
Scheme 4. Synthesis of aniline-based linker system 29 with a
carboxy terminus from nitrostyrene 22.
Scheme 3. Synthesis of aniline-based linker system 25 from nitro-
styrene 22.
Since a range of resins for affinity chromatography con-
tain a primary amine for ligation, we also prepared linker
29 containing the aniline as well as a carboxylic function
(Scheme 4). Accordingly, triethylene glycol was monoallyl-
ated using allyl bromide and NaH in THF to afford allyl
ether 26.[21] This transformation was then followed by alkyl-
ation of the free hydroxy group with tert-butyl bromoacet-
ate under phase-transfer conditions. To our surprise, the
crucial cross-metathesis reaction[18] of allyl ether 27 with
styrene 22 using Grubbs 2nd generation catalyst (5 mol-%)
in CH2Cl2 went quite well; allyl ether 28 was generated as
a single product in 80% yield. Hydrogenation of the nitro
group and the double bond provided aniline derivative 29
in good yield.
In order to prepare an affinity probe with a primary
alcohol at the terminus or the atorvastatin lactone linker
construct, aniline 25 was condensed with acid 8 using bro-
Scheme 5. Synthesis of atorvastatin lactone linker construct 34.
A similar strategy secured atorvastatin derivative 39.
motris(pyrrolidino)phosphonium
hexafluorophosphate
(PyBrOP) in the presence of Hünig’s base (Scheme 5). Next,
the benzyl ether of 30 was cleaved by hydrogenation. A two- Thus, condensation of acid 8 with amino ester 29 led to
step sequence consisting of Dess–Martin oxidation to the amide 35 (Scheme 6). Elaboration of the side chain contain-
aldehyde and further Pinnick oxidation delivered acid 32. ing the 1,3-diol through catalytic hydrogenation and oxi-
Stirring the acid with camphorsulfonic acid in CH2Cl2 in- dation of the resulting alcohol 36 to acid 37 was concluded
duced acetal cleavage and lactonization. A final cleavage of with acid-induced formation of the δ-lactone 38. At this
the silyl ether of the linker terminus provided atorvastatin stage, the tert-butyl ester in the linker could be cleaved using
lactone derivative 34.
a solution of aqueous phosphoric acid in CH2Cl2.[22]
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Atorvastatin Lactone Linker Constructs for Target Identification
immediately. The resulting dark brown solution was stirred at room
temp. for 1 h. The solvent was evaporated under reduced pressure,
and the dark brown foamy solid was dissolved in n-butyronitrile
(44 mL). The solution was cooled to –78 °C before a mixture of
aldehyde 12 (2.01 g, 12.2 mmol), 2-propanol (1.14 mL, 14.7 mmol)
and ketene acetal 11 (3.15 g, 14.7 mmol) in n-butyronitrile (10 mL)
was added dropwise using a syringe pump over 40 min. The reac-
tion mixture was stirred for 4 h, quenched with saturated NaHCO3
solution (30 mL), brought to room temp. and extracted with diethyl
ether (3ϫ 60 mL). The combined organic layers were dried with
MgSO4, filtered and concentrated under vacuum. Purification of
the crude residue by flash chromatography (EtOAc/petroleum
ether, 3:7) afforded δ-hydroxy-α,β-unsaturated ester 14 (1.95 g,
60%, 88% ee by Mosher ester analysis) as a colorless oil. Rf = 0.4
(EtOAc/petroleum ether, 2:3). [α]2D2 = +10.1 (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.68–1.83 (m, 2 H, 6-H), 2.30–2.44
(m, 2 H, 4-H), 3.64 (ddd, J = 9.3, 7.6, 5.0 Hz, 1 H, 7-H), 3.68–3.74
(m, 1 H, 7-H), 3.71 (s, 3 H, OCH3), 3.92–4.01 (m, 1 H, 5-H), 4.51
(s, 2 H, CH2Ph), 5.88 (ddd, J = 15.7, 1.5, 1.3 Hz, 1 H, 2-H), 6.98
(ddd, J = 15.7, 7.6, 7.3 Hz, 1 H, 3-H), 7.25–7.37 (m, 5 H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 35.9 (C-6), 40.5 (C-4), 51.4
(OCH3), 68.9 (C-7), 70.2 (C-5), 73.4 (CH2Ph), 123.2 (C-2), 127.7
(2CH, phenyl), 127.8 (CH, phenyl), 128.5 (2CH, phenyl), 137.7 (C,
phenyl), 145.5 (C-3), 166.7 (C-1) ppm. HRMS (ESI): calcd. for
C15H20O4Na [M + Na]+ 287.12538, found 287.125232.
Methyl 2-{(2S,4S,6S)-6-[2-(Benzyloxy)ethyl]-2-phenyl-1,3-dioxan-4-
yl}acetate (15): To a cooled (salt/ice bath) solution of δ-hydroxy
enoate 14 (2.02 g, 7.6 mmol) in THF (40 mL) under N2 was added
freshly distilled benzaldehyde (0.86 mL, 8.4 mmol), and potassium
tert-butoxide (86 mg, 0.76 mmol). This manipulation was repeated
three times with 15 min intervals. After an additional 30 min of
stirring, the reaction was quenched by addition of phosphate buffer
solution (pH = 7, 30 mL). The mixture was extracted using diethyl
ether (3ϫ 70 mL), the combined organic layers were washed with
saturated NaCl solution, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromatography
(EtOAc/petroleum ether, 1:9 then 1:4) to yield acetal 15 (1.86 g,
66%) as a colorless thick oil. Rf = 0.37 (EtOAc/petroleum ether,
Scheme 6. Synthesis of atorvastatin lactone linker construct 39.
Conclusions
A new strategy to the diol-containing side chain of
atorvastatin lactone has been devised. Key steps include a
vinylogous Mukaiyama aldol reaction to give 5-hydroxy en-
oate 14. The second stereocenter resulted from an intramo-
lecular oxa-Michael reaction. The primary amine could be
obtained by reduction of carboxylic amide 17. Amine build-
ing block 5 was then used for the synthesis of pyrrole-3-
carboxylic acid 8. This acid could be condensed with aniline
derivatives 25 and 29, respectively, which contain linker sys-
tems derived from triethylene glycol. The aniline derivatives
25 and 29 were synthesized through a cross-metathesis reac-
tion between nitrostyrene 22 and suitable allyl ethers.
Atorvastatin constructs 34 and 39 are currently being inves-
tigated in pull–down experiments. Since aniline derivatives
can easily be converted to aryl isothiocyanates, which are
commonly used for ligation in biology, the present linker
systems should be of great value for many purposes.
1
2:3). [α]2D1 = –27.3 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ
= 1.46 (ddd, J = 12.9, 11.4, 11.1 Hz, 1 H, 5-H), 1.73 (ddd, J =
12.9, 2.3, 2.3 Hz, 1 H, 5-H), 1.81–1.99 (m, 2 H, BnOCH2CH2), 2.52
(dd, J = 15.7, 6.1 Hz, 1 H, CH2CO2Me), 2.74 (dd, J = 15.7, 7.1 Hz,
1
H, CH2CO2Me), 3.60 (ddd, J = 9.3, 5.6, 5.6 Hz, 1 H,
BnOCH2CH2), 3.66–3.76 (m, 1 H, BnOCH2CH2), 3.70 (m, 3 H,
OCH3), 4.08 (dddd, J = 10.6, 8.3, 4.5, 2.5 Hz, 1 H, 6-H), 4.32
(dddd, J = 11.1, 8.8, 6.3, 2.3 Hz, 1 H, 4-H), 4.50 (d, J = 11.9 Hz,
1 H, OCH2Ph), 4.54 (d, J = 11.9 Hz, 1 H, OCH2Ph), 5.56 (s, 1 H,
CHPh), 7.23–7.38 (m, 8 H, Ar-H), 7.42–7.47 (m, 2 H, Ar-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 36.0 (BnOCH2CH2), 36.6 (C-
5), 40.3 (CH2CO2Me), 51.7 (OCH3), 65.9 (BnOCH2CH2), 73.0
(OCH2Ph), 73.1 (C-4), 73.6 (C-6), 100.5 (CHPh), 126.0 (2 CH, Ar),
127.6 (CH, Ar), 127.6 (2 CH, Ar), 128.1 (2 CH, Ar), 128.4 (2 CH,
Ar), 128.6 (CH, Ar), 138.4 (2 CH, Ar), 171.1 (CO2Me) ppm.
HRMS (ESI): calcd. for C22H26O5Na [M + Na]+ 393.16725, found
393.167621.
Experimental Section
General: Known compounds ketene acetal[8] 11, propanal deriva-
tive[9] 12, Lewis acid[8] 13, and pyrrole carboxylic acid[6] 8 were
prepared according to literature procedures.
Methyl 2-{(4S,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxan-
4-yl}acetate (16): Acetal 15 (3.04 g, 8.2 mmol) was dissolved in
CH2Cl2 (30 mL) to which 2,2-dimethoxypropane (30 mL) and p-
toluenesulfonic acid monohydrate (312 mg, 0.16 mmol) were
Methyl (R,E)-7-(Benzyloxy)-5-hydroxyhept-2-enoate (14): Di- added. The mixture was heated to reflux for 24 h and brought to
chlorophenylborane (1.61 g, 12.2 mmol) was added to a mixture room temp. The volatiles were evaporated under vacuum, and the
of N-Ts-l-tryptophan 13 (4.39 g, 12.2 mmol) in CH2Cl2 (100 mL) residual mixture was diluted with CH2Cl2 (100 mL), washed with
dropwise at room temp., which led to persistent HCl gas evolution saturated NaHCO3 solution (50 mL), saturated NaCl solution,
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dried with Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (EtOAc/petroleum ether, 1:9) furnished acetonide
ester 16 (2.51 g, 95%) as a colorless oil. Rf = 0.52 (EtOAc/petro-
leum ether, 1:4). [α]2D0 = –18.3 (c = 1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.18 (ddd, J = 12.6, 12.6, 11.6 Hz, 1 H, 5-H), 1.34 (s,
= 11.9 Hz, 1 H, OCH2Ph), 7.26–7.35 (m, 5 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.9 (2-CH3), 30.2 (2-CH3), 36.5
(BnOCH2CH2), 37.0 (C-5), 38.5 (CH2CH2NH2), 39.4
(CH2CH2NH2), 66.0 (C-4), 66.1 (BnOCH2CH2), 67.7 (C-6), 73.0
(OCH2Ph), 127.5 (CH, phenyl), 127.6 (2 CH, phenyl), 128.34 (2
3 H, 2-CH3), 1.43 (m, 3 H, 2-CH3), 1.57 (ddd, J = 12.6, 2.5, 2.3 Hz, CH, phenyl), 138.49 (C, phenyl) ppm. HRMS (ESI): calcd. for
1 H, 5-H), 1.67–1.81 (m, 2 H, BnOCH2CH2), 2.36 (dd, J = 15.4,
6.1 Hz, 1 H, CH2CO2Me), 2.53 (dd, J = 15.4, 6.8 Hz, 1 H,
CH2CO2Me), 3.48–3.62 (m, 2 H, BnOCH2CH2), 3.67 (s, 3 H,
OCH3), 4.05 (dddd, J = 11.4, 6.8, 5.0, 2.8 Hz, 1 H, 6-H), 4.29
(dddd, J = 11.4, 8.6, 4.8, 2.3 Hz, 1 H, 4-H), 4.46 (d, J = 12.1 Hz,
1 H, OCH2Ph), 4.50 (d, J = 12.1 Hz, 1 H, OCH2Ph), 7.24–7.36 (m,
5 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.7 (2-CH3),
30.0 (2-CH3), 36.5 (BnOCH2CH2), 36.6 (C-5), 41.2 (CH2CO2Me),
51.6 (OCH3), 65.9 (C-4), 65.9 (C-6), 66.1 (BnOCH2CH2), 73.0
(OCH2Ph), 98.8 (C-2), 127.5 (CH, phenyl), 127.6 (2 CH, phenyl),
128.3 (2 CH, phenyl), 138.5 (C, phenyl), 171.4 (CO2Me) ppm.
HRMS (ESI): calcd. for C18H26O5Na [M + Na]+ 345.16725, found
345.167000.
C17H27NO3Na [M + H]+ 294.20637, found 294.206401.
1-Nitro-4-vinylbenzene (22): Diiodomethane (13.43 mL, 0.17 mol)
was carefully added dropwise (sudden exotherm is possible after
addition) to a well-stirred mixture of zinc powder (19.57 g,
0.30 mol) in THF (300 mL) while cooling the reaction mixture in
an ice bath. The mixture was stirred at room temp. for 30 min, then
Ti(OiPr)4 (9.96 mL, 0.033 mol) was added over 20 min, and stirring
was continued for 30 min before 4-nitrobenzaldehyde (21) (5.0 g,
0.033 mol) in THF (50 mL) was added dropwise to the reaction
mixture. After having been stirred at room temp. for 3 h, excess of
zinc was removed by filtration through Celite, and the filtrate was
diluted with diethyl ether (100 mL). Then, HCl (1 n) was added to
the solution until a clear orange-red color persisted. The organic
layer was separated, and the aqueous layer extracted with diethyl
ether (3ϫ 40 mL). The combined organic layers were washed with
saturated NaHCO3 solution, saturated NaCl solution, dried with
MgSO4, and concentrated in vacuo. Purification of the residue by
flash chromatography (petroleum ether/diethyl ether, 25:1) afforded
styrene 22 (4.69 g, 94%) as a yellowish liquid, which solidified at
low temperature. Rf = 0.36 (petroleum ether/diethyl ether, 25:1). 1H
NMR (400 MHz, CDCl3): δ = 5.48 (d, J = 10.9 Hz, 1 H,
CH=CH2), 5.92 (d, J = 17.4 Hz, 1 H, CH=CH2), 6.77 (dd, J =
10.9, 17.4 Hz, 1 H, CH=CH2), 7.52 (d, J = 8.6 Hz, 2 H, Ar-H), 8.17
(d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 118.6 (CH=CH2), 123.9 (2 CH, Ar), 126.8 (2 CH, Ar), 135.0
(CH=CH2), 143.8 (C, Ar) ppm.
2-{(4S,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxan-4-yl}-
acetamide (17): Ester 16 (450 mg, 1.4 mmol) was heated in a screw-
cap bottle in a mixture of 25% aq. NH4OH solution (5 mL) and
methanol (10 mL) for 48 h. The mixture was cooled to room temp.
and extracted with ethyl acetate (3ϫ 20 mL). The combined or-
ganic layers were washed with saturated NaCl solution (5 mL),
dried with anhydrous MgSO4, and filtered. The filtrate was concen-
trated and purified by flash chromatography (methanol/CH2Cl2,
1:20) to yield amide 17 (327 mg, 76%) as a viscous yellowish oil.
Rf = 0.31 (methanol/CH2Cl2, 1:20). [α]2D0 = –5.34 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.24 (ddd, J = 12.6, 11.6,
11.6 Hz, 1 H, 5-H), 1.37 (s, 3 H, 2-CH3), 1.43 (s, 3 H, 2-CH3),
1.52 (ddd, J = 12.9, 2.5, 2.3 Hz, 1 H, 5-H), 1.65–1.80 (m, 2 H,
BnOCH2CH2), 2.32 (dd, J = 15.4, 4.0 Hz, 1 H, CH2CONH2), 2.39
(dd, J = 15.1, 7.6 Hz, 1 H, CH2CONH2), 3.46–3.62 (m, 2 H,
BnOCH2CH2), 4.05 (dddd, J = 11.9, 7.6, 5.0, 2.3 Hz, 1 H, 4-H),
4.21 (dddd, J = 11.4, 7.3, 4.3, 2.8 Hz, 1 H, 6-H), 4.45 (d, J =
12.1 Hz, 1 H, OCH2Ph), 4.49 (d, J = 11.9 Hz, 1 H, OCH2Ph), 5.74
(s, 1 H, CONH2), 6.31 (s, 1 H, CONH2), 7.23–7.38 (m, 5 H, Ar-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.8 (2-CH3), 30.1
(2-CH3), 36.2 (C-5), 36.3 (BnOCH2CH2), 42.8 (CH2CO2Me), 65.9
(BnOCH2CH2), 65.9 (C-4), 66.2 (C-6), 73.0 (OCH2Ph), 98.9 (C-2),
127.5 (CH, phenyl), 127.6 (2 CH, phenyl), 128.3 (2 CH, phenyl),
138.4 (C, phenyl), 173.2 (C=O, amide) ppm. HRMS (ESI): calcd.
for C17H25NO4Na [M + Na]+ 330.16758, found 330.167335.
Nitrostyrenes 23 and 24 by Cross-Metathesis between Alkene 22 and
Allyl Ether 20: A solution of Grubbs 2nd generation catalyst
(198 mg, 5 mol-%) in toluene (3 mL) was added at room temp. to
a mixture of allyl ether 20 (2.01 g, 4.7 mmol) and 4-nitrostyrene
(22) (2.1 g, 14.0 mmol) in dry and degassed toluene (20 mL). The
reaction mixture was heated to 70 °C for 5 h before it was concen-
trated under vacuum. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 17:3) to afford a mixture
of isomers of cross-metathesis products 23, 24-cis and 24-trans
(1.67 g, 65%) as a yellow red oil. Rf = 0.16 (23), 0.29 (24-trans),
0.33 (24-cis) (petroleum ether/EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): 24-cis: δ = 1.04 [s, 9 H, SiC(CH3)3], 3.49 (d, J = 7.6 Hz, 2
2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxan-4-yl}- H, CH=CHCH2Ar), 3.59–3.70 (m, 8 H, OCH2), 3.80 (dd, J = 5.6,
ethanamine (5): Amide 17 (350 mg, 0.14 mmol) in THF (1.5 mL)
was added dropwise to a cooled (0 °C) solution of LiAlH4 in THF
(2 mL) under nitrogen. The reaction mixture was refluxed over-
night (ca. 12 h), cooled to room temp., followed by the addition of
3 n KOH (2 mL). After 2 h of stirring, the mixture was extracted
with ethyl acetate (3ϫ 10 mL). The combined organic layers were
dried with MgSO4, filtered, and concentrated in vacuo. Purification
by flash chromatography (CH2Cl2/MeOH/Et3N, 9.5:0.4:0.1) af-
5.0 Hz, 2 H, CH2OTBDPS), 3.91–3.94 (m, 2 H, OCH2), 4.51 (ddd,
J = 7.6, 7.3, 6.3 Hz, 1 H, OCH=CHCH2), 6.15 (ddd, J = 6.1, 1.3,
1.3 Hz, 1 H, OCH=CHCH2), 7.33–7.42 (m, 8 H, Ar-H), 7.66–7.68
(m, 4 H, Ar-H), 8.10 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 24-trans: δ
=
1.03 [s, 9 H, SiC(CH3)3], 3.33 (d, J = 7.3 Hz, 2 H,
CH=CHCH2Ar), 3.60 (dd, J = 5.6, 5.0 Hz, 2 H, OCH2), 3.62–3.68
(m, 4 H, OCH2), 3.71–3.73 (m, 2 H, OCH2), 3.79–3.83 (m, 4 H,
OCH2), 4.86 (ddd, J = 12.6, 7.6, 5.0 Hz, 1 H, OCH=CHCH2), 6.41
forded amine 5 (240 mg, 72%) as a colorless oil. Rf = 0.29 (CH2Cl2/ (d, J = 12.6 Hz, 1 H, OCH=CH), 7.32–7.42 (m, 8 H, Ar-H), 7.66–
MeOH/Et3N, 9.5:0.4:0.1). [α]2D0 = –9.1 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.19 (ddd, J = 12.6, 11.6, 11.6 Hz, 1 H, 5-
H), 1.35 (s, 3 H, 2-CH3), 1.41 (s, 3 H, 2-CH3), 1.44 (ddd, J = 12.6,
7.68 (m, 4 H, Ar-H), 8.12 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 23: δ =
1.03 [s, 9 H, SiC(CH3)3], 3.58–3.71 (m, 10 H, OCH2), 3.80 (dd, J
= 5.3, 5.3 Hz, 2 H, OCH2), 4.22 (dd, J = 5.6, 1.5 Hz, 2 H,
2.5, 2.3 Hz,
1 H, 5-H), 1.53–1.80 (m, 4 H, BnOCH2CH2, OCH2CH=CH), 6.45 (ddd, J = 16.2, 5.6, 5.3 Hz, 1 H,
CH2CH2NH2), 1.97 (br. s, 2 H, NH2), 2.80, (d, J = 6.8, 6.6 Hz, 2 OCH2CH=CH), 6.67 (d, J = 16.2 Hz, 1 H, OCH2CH=CH), 7.33–
H, CH2CH2NH2), 3.51 (ddd,
BnOCH2CH2), 3.54–3.61 (m, 1 H, BnOCH2CH2), 3.94 (dddd, J =
11.4, 7.3, 4.8, 2.8 Hz, 1 H, 4-H), 4.02 (dddd, J = 11.4, 7.6, 5.0,
J
=
9.3, 5.8, 5.8 Hz,
1
H,
7.42 (m, 6 H, Ar-H), 7.47 (d, J = 8.8 Hz, 2 H, Ar-H), 7.66–7.68
(m, 4 H, Ar-H), 8.15 (d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): 24-cis: δ = 19.2 [SiC(CH3)3], 26.8 [SiC(CH3)3],
2.5 Hz, 1 H, 6-H), 4.45 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.49 (d, J 30.1 (CH2Ar), 63.4 (OCH2), 70.4 (OCH2), 70.8 (OCH2), 70.9
6580
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6576–6585

Atorvastatin Lactone Linker Constructs for Target Identification
(OCH2), 71.6 (OCH2), 72.5 (OCH2), 103.4 (OCH=CH), 123.5 (2 CH2Cl2 (5 mL) was added dropwise at room temp. over 10 min,
CH, Ar), 127.6 (4 CH, Ar), 129.0 (2 CH, Ar), 129.6 (2 CH, Ar), and the reaction mixture was heated to reflux for 6 h. After com-
133.6 (2 C, Ar), 135.6 (4 CH, Ar), 146.2 (C, Ar), 146.8 (OCH=CH),
149.8 (C, Ar) ppm. 24-trans: δ = 19.2 [SiC(CH3)3], 26.8 [SiC(CH3)
3], 33.9 (CH2Ar), 63.4 (OCH2), 68.6 (OCH2), 69.8 (OCH2), 70.8
(2ϫ OCH2), 72.5 (OCH2), 101.1 (CH=CHCH2), 123.6 (2 CH, Ar),
127.6 (4 CH, Ar), 129.0 (2 CH, Ar), 129.6 (2 CH, Ar), 133.7 (2 C,
plete conversion, the reaction mixture was concentrated under vac-
uum and the residue purified by flash chromatography (petroleum
ether/EtOAc, 1:1) to furnish the nitrostyrene derivative 28 (2.43 g,
80%) as a reddish brown oil. Rf = 0.2 (petroleum ether/EtOAc,
1:1). 1H NMR (400 MHz, CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 3.63–
Ar), 135.6 (4 CH, Ar), 146.5 (C, Ar), 148.3 (CH=CHCH2), 149.4 3.69 (m, 12 H, OCH2), 3.98 (s, 2 H, OCH2CO2tBu), 4.21 (dd, J =
(C, Ar) ppm. 23: δ = 19.2 [SiC(CH3)3], 26.8 [SiC(CH3)3], 63.4 5.6, 1.5 Hz, 2 H, ArCH=CHCH2), 6.44 (ddd, J = 15.9, 5.6, 5.5 Hz,
(OCH2), 70.0 (OCH2), 70.7 (OCH2), 70.8 (2 OCH2), 71.2 (OCH2), 1 H, ArCH=CHCH2), 6.66 (d, J = 16.2 Hz, 1 H, ArCH=CHCH2),
72.5 (OCH2), 124.0 (OCH2CH=CH), 126.9 (2 CH, Ar), 127.6 (4 7.47 (d, J = 8.6 Hz, 2 H, Ar-H), 8.13 (d, J = 8.6 Hz, 2 H, Ar-
CH, Ar), 129.5 (C, Ar), 129.6 (2 CH, Ar), 133.7 (2 C, Ar), 135.6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0 [C(CH3)3], 68.9
(4 CH, Ar), 143.3 (OCH2CH=CH), 146.9 (C, Ar) ppm. HRMS
(ESI): calcd. for C31H39NO6SiNa [M + Na]+ 572.24389, found
572.243999.
(OCH2CO2tBu), 69.9 (OCH2), 70.5 (2 OCH2), 70.6 (3 OCH2), 71.1
(OCH2), 81.4 [C(CH3)3], 123.9 (2 CH, Ar), 126.8 (2 CH, Ar), 129.4
(ArCH=CHCH2), 131.3 (ArCH=CHCH2), 143.2 (C, Ar), 146.8 (C,
Ar), 169.5 (CH2COO) ppm. HRMS (ESI): calcd. for
C21H31NO8Na [M + Na]+ 448.19419, found 448.194519.
4-(2,2-Dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silahexadec-16-
yl)aniline (25): An isomeric mixture of metathesis products 23, 24-
cis and 24-trans (1.52 g, 2.8 mmol) in methanol (15 mL) was hydro-
genated under balloon pressure in the presence of a catalytic
amount of 10% Pd/C at room temp. After 24 h (TLC control), the
reaction mixture was filtered through a pad of Celite to remove the
catalyst, and the filtrate was concentrated under vacuum. The resi-
due was purified by flash chromatography (petroleum ether/EtOAc,
3:2) to afford aniline 25 (1.14 g, 79%) as a yellow red oil. Rf = 0.37
(petroleum ether/EtOAc, 3:2). 1H NMR (400 MHz, CDCl3): δ =
1.04 [s, 9 H, SiC(CH3)3], 1.78–1.88 (m, 2 H, OCH2CH2CH2Ar),
2.56 (dd, J = 7.8, 7.3 Hz, 2 H, OCH2CH2CH2Ar), 3.43 (dd, J =
6.6, 6.3 Hz, 2 H, OCH2CH2CH2Ar), 3.54–3.65 (m, 10 H, OCH2),
3.80 (dd, J = 5.6, 5.0 Hz, 2 H, OCH2), 6.68 (d, J = 8.3 Hz, 2 H,
Ar-H), 6.98 (d, J = 8.3 Hz, 2 H, Ar-H), 7.34–7.43 (m, 6 H, Ar-H),
7.66–7.69 (m, 4 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.2 [SiC(CH3)3], 26.8 [SiC(CH3)3], 31.3 (2 CH2), 63.4 (OCH2),
70.1 (OCH2), 70.5 (OCH2), 70.6 (OCH2), 70.7 (OCH2), 70.8
(OCH2), 72.4 (OCH2), 116.0 (2 CH, Ar), 127.6 (4 CH, Ar), 129.3
(2 CH, Ar), 129.6 (2 CH, Ar), 133.1 (C, Ar), 133.7 (2 C, Ar), 135.6
(4 CH, Ar), 142.5 (C, Ar) ppm. HRMS (ESI): calcd. for
C31H43NO4SiNa [M + Na]+ 544.28536, found 544.285897.
tert-Butyl 15-(4-Aminophenyl)-3,6,9,12-tetraoxapentadecan-1-oate
(29): A solution of nitro compound 28 (2.55 g, 5.5 mmol) in dry
EtOAc (40 mL) was hydrogenated under balloon pressure in the
presence of a catalytic amount of 10% Pd/C overnight (ca. 14 h).
The catalyst was filtered through a pad of Celite, and the filtrate
was concentrated in vacuo. The crude oil was purified by flash
chromatography (petroleum ether/EtOAc, 2:3) to furnish amine 29
(2.3 g, 96%) as a slightly green oil. Rf = 0.2 (petroleum ether/
EtOAc, 2:3). 1H NMR (400 MHz, CDCl3): δ = 1.46 [s, 9 H, C(CH3)
3], 1.79–1.86 (m, 2 H, CH2CH2Ar), 2.55 (dd, J = 7.8, 7.3 Hz, 2 H,
CH2CH2Ar), 3.43 (dd, J = 6.6, 6.6 Hz, 2 H, OCH2CH2CH2Ar),
3.55–3.58 (m, 4 H, NH2, OCH2), 3.61–3.71 (m, 10 H, OCH2), 4.00
(m, 2 H, OCH2CO2tBu), 6.60 (d, J = 8.3 Hz, 2 H, Ar-H), 6.95 (d,
J = 8.3 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
28.1 [C(CH3)3], 31.3 (CH2), 31.4 (CH2), 69.0 (OCH2CO2tBu), 70.1
(OCH2), 70.5 (OCH2), 70.6 (4 OCH2), 70.7 (OCH2), 81.5 [C(CH3)
3], 115.2 (2 CH, Ar), 129.2 (2 CH, Ar), 131.9 (C, Ar), 144.2 (C,
Ar), 169.7 (OCH2CO2tBu) ppm. HRMS (ESI): calcd. for
C21H35NO6Na [M + Na]+ 420.23566 found 420.235325.
1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxan-4-yl}-
ethyl)-N-[4-(2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silahexa-
dec-16-yl)phenyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyr-
role-3-carboxamide (30): To a cooled solution of acid[6] 8 (440 mg,
0.73 mmol) and amine 25 (382 mg, 0.73 mmol) in CH2Cl2 (10 mL)
at 0 °C were added ethyldiisopropylamine (376 μL, 2.2 mmol) and
PyBrOP (410 mg, 0.88 mmol) successively. The mixture was stirred
at room temp. for 12 h, then diluted with CH2Cl2 (10 mL), and
washed with saturated NaHCO3 solution (10 mL) and saturated
NaCl solution. The organic layer was dried with Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatog-
raphy to afford amide 30 (540 mg, 73%) as a viscous yellowish oil.
Rf = 0.32 (EtOAc/petroleum ether, 3:7). [α]2D0 = –0.6 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.95–1.07 (m, 1 H, 5Ј-H), 1.04
[s, 9 H, SiC(CH3)3], 1.22 (ddd, J = 12.9, 2.5, 2.3 Hz, 1 H, 5Ј-H),
1.29 (s, 3 H, 2Ј-CH3), 1.33 (s, 3 H, 2Ј-CH3), 1.52 [d, J = 7.1 Hz, 6
H , C H ( CH 3 ) 2 ] , 1 . 6 0 – 1 . 7 4 ( m , 4 H , C H 2 , N C H2 CH 2 ,
CH2CH2OBn), 1.77–1.87 (m, 2 H, OCH2CH2CH2Ar), 2.56 (dd, J
= 8.1, 7.3 Hz, 2 H, OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.3 Hz, 2
H, OCH2CH2CH2Ar), 3.44–3.68 [m, 14 H, 4Ј-H, CH(CH3)2,
OCH2], 3.75–3.85 (m, 1 H, NCH2CH2), 3.80 (dd, J = 5.6, 5.3 Hz,
2 H, CH2CH2OBn), 3.93 (dddd, J = 11.6, 7.3, 5.0, 2.3 Hz, 1 H, 6Ј-
H), 3.99–4.11 (m, 1 H, NCH2CH2), 4.45 (d, J = 12.1 Hz, 1 H,
tert-Butyl 3,6,9,12-Tetraoxapentadec-14-en-1-oate (27): To a mix-
ture of alcohol 26 (4.5 g, 23.6 mmol), tert-butyl bromoacetate
(11.2 mL, 70.9 mmol) and tetra-n-butylammonium hydrogen sul-
fate (2.0 g, 5.9 mmol) in benzene (23 mL) a 50% aq. solution of
NaOH (25 mL) was added slowly at room temp. The reaction mix-
ture was stirred at room temp. for 5 h (TLC control) before it was
neutralized with a 1 n HCl solution to pH ≈ 5 and extracted with
ethyl acetate (3ϫ 100 mL). The combined organic layers were dried
with MgSO4, filtered, and concentrated under vacuum. The crude
concentrate was purified by flash chromatography (petroleum
ether/EtOAc, 1:1) to give O-alkylated compound 27 (6.95 g, 96%)
1
as a colorless oil. Rf = 0.3 (petroleum ether/EtOAc, 3:2). H NMR
(400 MHz, CDCl3): δ = 1.45 [s, 9 H, C(CH3)3], 3.56–3.59 (m, 2 H,
OCH2), 3.62–3.71 (m, 10 H, OCH2), 3.98–4.02 (m,
2 H,
OCH2CH=CH2), 4.00 (s, 2 H, OCH2CO), 5.13–5.18 (m, 1 H,
CH=CH2), 5.25 (dddd, J = 17.2, 1.8, 1.5, 1.5 Hz, 1 H, CH=CH2),
5.84–5.94 (m, 1 H, CH=CH2) ppm. 13C NMR (100 MHz, CDCl3):
δ = 28.1 [C(CH3)3], 69.0 (OCH2CO), 69.4 (OCH2), 70.6 (4 OCH2),
70.7 (OCH2), 72.2 (OCH2CH=CH2), 81.5 [C(CH3)3], 117.0
(CH=CH2), 134.7 (CH=CH2), 169.6 (CO2tBu) ppm. HRMS (ESI):
calcd. for C15H28O6Na [M + Na]+ 327.17781, found 327.17765.
tert-Butyl (E)-15-(4-Nitrophenyl)-3,6,9,12-tetraoxapentadec-14-en- OCH2Ph), 4.48 (d, J = 12.1 Hz, 1 H, OCH2Ph), 6.80 (br., s, 1 H,
1-oate (28): To a solution of O-allyl TEG 27 (2.2 g, 7.2 mmol) and
4-nitrostyrene (22) (3.23 g, 21.7 mmol) in CH2Cl2 (55 mL, dry and
degassed) Grubb’s 2nd generation catalyst (307 mg, 5 mol-%) in
NH), 6.92–7.03 (m, 6 H, Ar-H), 7.09–7.21 (m, 7 H, Ar-H), 7.26–
7.43 (m, 11 H, Ar-H), 7.64–7.71 (m, 4 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.2 [SiC(CH3)3], 19.8 (2Ј-CH3), 21.6
Eur. J. Org. Chem. 2012, 6576–6585
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6581

P. Sawant, M. E. Maier
FULL PAPER
[CH(CH3)2], 21.7 [CH(CH3)2], 26.1 [CH(CH3)2], 26.8 [SiC(CH3)3], 0.10 mmol), which was dissolved in tert-butyl alcohol (6 mL), and
30.0 (2Ј-CH3), 31.2 (OCH2CH2CH2Ar), 31.6 (OCH2CH2CH2Ar), 2-methyl-2-butene (0.6 mL) was added. Then, a mixture of NaClO2
36.4 (C-5Ј), 36.5 (NCH2CH2), 38.1 (CH2CH2OBn), 40.8
(19 mg, 0.21 mmol) and NaH2PO4·2H2O (97 mg, 0.62 mmol) in
(NCH2CH2), 63.4 (CH2CH2OBn), 65.7 (C-6Ј), 66.0 (OCH2), 66.5 water (6 mL) was added dropwise to the reaction mixture at room
(C-4Ј), 70.1 (OCH2), 70.4 (OCH2), 70.6 (OCH2), 70.7 (OCH2), 70.8
(OCH2), 72.4 (OCH2), 72.9 (OCH2Ph), 98.5 (C-2Ј), 115.3 (d, JCF
temp., and the resulting biphasic reaction mixture was stirred for
6 h. The organic layer was separated and the aqueous layer ex-
= 22.0 Hz, 2 CH, Ar), 115.4 (C, Ar), 119.7 (2 CH, Ar), 121.7 (C, tracted with ethyl acetate (3ϫ 10 mL), dried with MgSO4, filtered,
Ar), 126.5 (CH, Ar), 127.6 (7 CH, Ar), 128.3 (C, Ar), 128.3 (4 CH,
Ar), 128.6 (2 CH, Ar), 128.7 (C, Ar), 129.6 (2 CH, Ar), 130.5 (2
and concentrated under vacuum. The residue on purification by
flash chromatography (EtOAc/petroleum ether/AcOH, 1:1:0.001)
CH, Ar), 133.2 (d, JCF = 8.0 Hz, 2 CH, Ar), 133.7 (C, Ar), 134.7 provided acid 32 (104 mg, 74%, two steps) as a yellowish sticky
(C, Ar), 135.6 (4 CH, Ar), 136.1 (C, Ar), 137.2 (C, Ar), 138.5 (2
C, Ar), 141.3 (C, Ar), 162.9 (d, JCF = 377.6 Hz, C, Ar), 163.5
solid. Rf = 0.29 (EtOAc/petroleum ether/AcOH, 1:1:0.001). [α]2D0
+1.8 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.00–1.11
=
1
(C=O, amide) ppm. HRMS (ESI): calcd. for C68H83FN2O8SiNa (m, 1 H, 5Ј-H), 1.03 [s, 9 H, SiC(CH3)3], 1.29–1.39 (m, 1 H, 5Ј-H),
[M + Na]+ 1125.579493, found 1125.579667.
1.31 (s, 3 H, 2Ј-CH3), 1.36 (s, 3 H, 2Ј-CH3), 1.51 [d, J = 7.1 Hz, 6
H, CH(CH3)2], 1.59–1.73 (m, 2 H, NCH2CH2), 1.76–1.86 (m, 2 H,
OCH2CH2CH2Ar), 2.38 (dd, J = 15.9, 5.8 Hz, 1 H, CH2COOH),
2.52 (dd, J = 15.9, 6.8 Hz, 1 H, CH2COOH), 2.56 (dd, J = 8.1,
7.3 Hz, 2 H, OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.6 Hz, 2 H,
OCH2CH2CH2Ar), 3.48–3.73 [m, 12 H, 4Ј-H, CH(CH3)2, OCH2],
3.79 (dd, J = 5.6, 5.0 Hz, 2 H, OCH2), 3.83 (ddd, J = 15.9, 9.6,
6.3 Hz, 1 H, NCH2CH2), 4.07 (ddd, J = 14.9, 9.8, 5.6 Hz, 1 H,
NCH2CH2), 4.14–4.24 (m, 1 H, 6Ј-H), 6.81 (s, 1 H, CONH), 6.92–
7.04 (m, 6 H, Ar-H), 7.10–7.21 (m, 7 H, Ar-H), 7.31–7.43 (m, 6 H,
Ar-H), 7.62–7.71 (m, 4 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.2 [SiC(CH3)3], 19.6 (2Ј-CH3), 21.6 [CH(CH3)2], 21.8
[CH(CH3)2], 26.1 [CH(CH3)2], 26.8 [SiC(CH3)3], 29.8 (2Ј-CH3),
31.2 (OCH2 CH2 CH2 Ar), 31.6 (OCH2 CH2 CH2 Ar), 35.7
(NCH2CH2), 37.8 (C-5Ј) 40.7 (NCH2CH2, CH2COOH), 63.4
(OCH2), 65.5 (C-6Ј), 66.4 (C-4Ј), 70.1 (OCH2), 70.4 (OCH2), 70.6
N-[4-(2,2-Dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silahexadec-
16-yl)phenyl]-5-(4-fluorophenyl)-1-{2-[(4R,6S)-6-(2-hydroxyethyl)-
2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-2-isopropyl-4-phenyl-1H-pyr-
role-3-carboxamide (31): A solution of benzyl ether 30 (550 mg,
0.50 mmol) in dry ethyl acetate (15 mL) was hydrogenated under
balloon pressure in the presence of 20 % Pd(OH)2 on carbon
(110 mg, 20 wt.-%) for 8 h. The mixture was filtered through a pad
of Celite, the filtrate was concentrated under reduced pressure, and
the residue purified by passing it through a short filtration column
(EtOAc/petroleum ether, 1:1) to afford alcohol 31 (438 mg, 87%)
as a viscous yellowish oil. Rf = 0.27 (EtOAc/petroleum ether, 1:1).
[α]2D0 = –0.6 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.03
[s, 9 H, SiC(CH3)3], 1.12 (ddd, J = 12.9, 11.4, 11.1 Hz, 1 H, 5Ј-H),
1.21 (ddd, J = 12.9, 2.8, 2.5 Hz, 1 H, 5Ј-H), 1.25 (s, 1 H, OH), 1.31
(s, 3 H, 2Ј-CH3), 1.36 (s, 3 H, 2Ј-CH3), 1.52 [d, J = 7.1 Hz, 6 H,
CH(CH3)2], 1.58–1.71 (m, 4 H, NCH2CH2, CH2CH2OH), 1.76–
1.87 (m, 2 H, OCH2CH2CH2Ar), 2.56 (dd, J = 8.1, 7.3 Hz, 2 H,
OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.3 Hz, 2 H, OCH2CH2-
CH2Ar), 3.51–3.76 [m, 14 H, 4Ј-H, CH2CH2OH, CH(CH3)2,
OCH2], 3.79 (dd, J = 5.5, 5.3 Hz, 2 H, OCH2), 3.78–3.87 (m, 1 H,
NCH2CH2), 3.95–4.12 (m, 2 H, NCH2CH2, 6Ј-H), 6.81 (s, 1 H,
CONH), 5.92–7.04 (m, 6 H, Ar-H), 7.10–7.21 (m, 7 H, Ar-H),
7.32–7.44 (m, 6 H, Ar-H), 7.64–7.70 (m, 4 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.2 [SiC(CH3)3], 19.8 (2Ј-CH3),
21.6 [CH(CH3)2], 21.8 [CH(CH3)2], 26.1 [CH(CH3)2], 26.8
[SiC(CH3)3], 30.0 (2Ј-CH3), 31.2 (OCH2CH2CH2Ar), 31.6
(OCH2CH2 CH2Ar), 36.1 (C-5Ј), 38.0 (NCH2CH2 ), 38.0
(CH2CH2OH), 40.8 (NCH2CH2), 60.6 (CH2CH2OH), 63.4
(OCH2), 66.5 (C-4Ј), 68.8 (C-6Ј), 70.1 (OCH2), 70.4 (OCH2), 70.6
(OCH2), 70.7 (2 OCH2), 72.4 (OCH2), 99.0 (C-2Ј), 115.4 (d, JCF
=
21.2 Hz, 2 CH, Ar), 115.5 (C, Ar), 119.8 (2 CH, Ar), 121.8 (C, Ar),
126.5 (CH, Ar), 127.6 (4 CH, Ar), 128.1 (d, JCF = 3.7 Hz, C, Ar),
128.3 (C, Ar), 128.3 (2 CH, Ar), 128.6 (2 CH, Ar), 128.7 (C, Ar),
129.6 (2 CH, Ar), 130.4 (2 CH, Ar), 133.1 (d, JCF = 8.0 Hz, 2 CH,
Ar), 133.7 (C, Ar), 134.5 (C, Ar), 135.6 (4 CH, Ar), 136.0 (C, Ar),
137.3 (C, Ar), 141.1 (C, Ar), 163.0 (d, JCF = 393.0 Hz, C, Ar),
163.5 (CONH) ppm. HRMS (ESI): calcd. for C61H75FN2O9SiNa
[M + Na]+ 1049.51181, found 1049.511774.
N-[4-(2,2-Dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silahexadec-
16-yl)phenyl]-5-(4-fluorophenyl)-1-{2-[(2R,4R)-4-hydroxy-6-oxotetra-
hydro-2H-pyran-2-yl]ethyl}-2-isopropyl-4-phenyl-1H-pyrrole-3-carb-
oxamide (33): A mixture of acetonide acid 32 (126 mg, 0.12 mmol)
and camphorsulfonic acid (57 mg, 0.24 mmol) in CH2Cl2 (4 mL)
was stirred at room temp. for 3 h. The mixture was diluted with
CH2Cl2 (10 mL), washed with water (3ϫ 10 mL) and saturated
NaCl solution (10 mL). The organic layer was dried with Na2SO4,
filtered, and concentrated in vacuo. The crude residue was purified
by flash chromatography to afford pure lactone 33 (105 mg, 90%)
as a sticky yellowish solid. Rf = 0.22 (EtOAc/petroleum ether, 7:3).
[α]2D0 = +13.2 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.03 [s, 9 H, SiC(CH3)3], 1.50 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 1.51
[d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.55–1.61 (m, 1 H, 3Ј-H), 1.67–
1.92 (m, 6 H, NCH2CH2, 3Ј-H, OCH2CH2CH2Ar, OH), 2.48–2.60
(m, 3 H, 5Ј-H, OCH2CH2CH2Ar), 2.64 (dd, J = 17.7, 4.8 Hz, 1 H,
5Ј-H), 3.40 (dd, J = 6.6, 6.6 Hz, 2 H, OCH2CH2CH2Ar), 3.46–3.68
[m, 11 H, CH(CH3)2, OCH2], 3.79 (dd, J = 5.3, 5.3 Hz, 2 H,
OCH2), 4.01 (ddd, J = 14.9, 9.1, 4.8 Hz, 1 H, 1-H), 4.20 (ddd, J =
14.9, 9.8, 4.5 Hz, 1 H, 1-H), 4.26–4.32 (m, 1 H, 4Ј-H), 4.51 (dddd,
J = 11.4, 8.6, 3.3, 3.0 Hz, 1 H, 2Ј-H), 6.82 (s, 1 H, CONH), 6.92–
(OCH2), 70.7 (2 OCH2), 72.4 (OCH2), 98.6 (C-2Ј), 115.3 (d, JCF
=
21.2 Hz, 2 CH, Ar), 119.7 (2 CH, Ar), 121.7 (C, Ar), 126.5 (CH,
Ar), 127.6 (4 CH, Ar), 128.4 (d, JCF = 3.7 Hz, C, Ar), 128.3 (C,
Ar), 128.3 (2 CH, Ar), 128.6 (2 CH, Ar), 128.7 (C, Ar), 129.6 (2
CH, Ar), 130.4 (2 CH, Ar), 133.2 (d, JCF = 8.0 Hz, 2 CH, Ar),
133.7 (C, Ar), 134.6 (C, Ar), 135.6 (4 CH, Ar), 136.1 (C, Ar), 137.2
(C, Ar), 141.2 (C, Ar), 162.9 (d, JCF = 376.9 Hz, C, Ar), 163.5
(CONH) ppm. HRMS (ESI): calcd. for C61H77FN2O8SiNa [M +
Na]+ 1035.53254, found 1035.532117.
2-{(4R,6R)-6-[2-(3-{[4-(2,2-Dimethyl-3,3-diphenyl-4,7,10,13-tetra-
oxa-3-silahexadec-16-yl)phenyl]carbamoyl}-5-(4-fluorophenyl)-2-iso-
propyl-4-phenyl-1H-pyrrol-1-yl)ethyl]-2,2-dimethyl-1,3-dioxan-4-yl}-
acetic Acid (32): Dess–Martin periodinane (69 mg, 0.16 mmol) was
added in one portion to a solution of alcohol 31 (138 mg,
0.14 mmol) in CH2Cl2 (3 mL) at 0 °C. The mixture was stirred at
room temp. for 1 h, diluted with CH2Cl2 (5 mL), washed success-
ively with saturated NaHCO3 (5 mL), 1 m Na2S2O3 (5 mL), and 7.04 (m, 6 H, Ar-H), 7.09–7.22 (m, 7 H, Ar-H), 7.31–7.43 (m, 6 H,
saturated NaCl solution. The organic layer was dried with Na2SO4,
filtered, and the residue purified by passing it through a short flash
Ar-H), 7.62–7.70 (m, 4 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.2 [SiC(CH3)3], 21.7 [CH(CH3)2], 22.0 [CH(CH3)2],
chromatography column to yield pure aldehyde (105 mg, 26.2 [CH(CH3)2], 26.8 [SiC(CH3)3], 31.2 (OCH2CH2CH2Ar), 31.6
6582
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6576–6585

Atorvastatin Lactone Linker Constructs for Target Identification
(OCH2CH2CH2Ar), 35.6 (C-3Ј), 37.1 (NCH2CH2), 38.5 (C-5Ј), [d, J = 7.3 Hz, 6 H, CH(CH3)2], 1.56–1.76 (m, 4 H, NCH2CH2,
40.7 (NCH2CH2), 62.5 (C-4Ј), 63.4 (OCH2), 70.1 (OCH2), 70.4 CH2CH2OBn), 1.77–1.87 (m, 2 H, OCH2CH2CH2Ar), 2.57 (dd, J
(OCH2), 70.6 (OCH2), 70.7 (2 OCH2), 72.4 (OCH2), 73.0 (C-2Ј), = 8.1, 7.3 Hz, 2 H, OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.6 Hz, 2
115.6 (d, JCF = 22.0 Hz, 2 CH, Ar), 115.8 (C, Ar), 119.8 (2 CH,
H, OCH2CH2CH2Ar), 3.44–3.59 [m, 5 H, CH2CH2 OBn,
Ar), 122.0 (C, Ar), 126.6 (CH, Ar), 127.6 (4 CH, Ar), 128.0 (d, JCF CH(CH3)2, OCH2], 3.59–3.73 (m, 11 H, 4Ј-H, OCH2), 3.79 (ddd,
= 3.7 Hz, C, Ar), 128.3 (2 CH, Ar), 128.6 (2 CH, Ar), 129.6 (2 CH, J = 14.9, 10.1, 6.3 Hz, 1 H, NCH2CH2), 3.93 (dddd, J = 11.6, 7.3,
Ar), 130.3 (2 CH, Ar), 133.1 (d, JCF = 133.1 Hz, 2 CH, Ar), 133.1
(2 C, Ar), 134.4 (C, Ar), 135.6 (4 CH, Ar), 136.0 (C, Ar), 137.4 (C,
Ar), 141.2 (C, Ar), 162.9 (d, JCF = 374.0 Hz, C, Ar), 163.5
(CONH), 169.4 (C=O, lactone) ppm. HRMS (ESI): calcd. for
C58H69FN2O8SiNa [M + Na]+ 991.46994, found 991.469476.
4.8, 2.3 Hz, 1 H, 6Ј-H), 4.00 (s, 2 H, OCH2CO2tBu), 4.05 (ddd, J
= 14.9, 9.1, 4.8 Hz, 1 H, NCH2CH2), 4.46 (d, J = 12.1 Hz, 1 H,
OCH2Ph), 4.47 (d, J = 12.4 Hz, 1 H, OCH2Ph), 6.80 (s, 1 H,
CONH), 6.93–7.02 (m, 5 H, Ar-H), 7.10–7.21 (m, 7 H, Ar-H),
7.23–7.35 (m, 6 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.8 (2Ј-CH3 ), 21.6 [CH(CH3)2], 21.7 [CH(CH3 )2 ], 26.1
[CH(CH3)2], 28.1 [C(CH3)3], 30.0 (2Ј-CH3), 31.1 (OCH2CH2-
CH2Ar), 31.6 (OCH2CH2CH2Ar), 36.4 (C-5Ј), 36.4 (NCH2CH2),
38.1 (CH2CH2OBn), 40.8 (NCH2CH2), 65.7 (C-6Ј), 66.0 (OCH2),
66.5 (C-3), 69.0 (C-7), 70.1 (OCH2CO2tBu), 70.4 (OCH2), 70.6
(OCH2), 70.6 (3 OCH2), 70.7 (OCH2), 72.9 (OCH2), 81.5
[C(CH3)3], 98.5 (C-2Ј), 115.3 (d, JCF = 21.2 Hz, 2CH, Ar), 115.4
(C, Ar), 119.7 (2 CH, Ar), 121.7 (C, Ar), 126.5 (CH, Ar), 127.6 (4
CH, Ar), 128.2 (C, Ar), 128.3 (3 CH, Ar), 128.6 (2 CH, Ar), 128.7
(C, Ar), 130.4 (2 CH, Ar), 133.2 (d, JCF = 8.0 Hz, 2 CH, Ar), 134.7
(C, Ar), 136.1 (C, Ar), 137.2 (C, Ar), 138.5 (C, Ar), 141.3 (C, Ar),
162.9 (d, JCF = 379.8 Hz, C, Ar), 163.5 (CONH), 169.7 (CO2tBu)
ppm. HRMS (ESI): calcd. for C58H75FN2O10Na [M + Na]+
1001.52980, found 1001.530129.
5-(4-Fluorophenyl)-1-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyr-
an-2-yl]ethyl}-N-[4-(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}-
propyl)phenyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxamide (34):
HF·pyridine complex (53 μL, 1.86 mmol, 70%) was added to a
cooled (0 °C) solution of silyl ether 33 (120 mg, 0.125 mmol) in
THF (3 mL) in a plastic tube, and the mixture was stirred over-
night. The mixture was diluted with ethyl acetate (10 mL), washed
with saturated NaHCO3 solution (5 mL), 10% CuSO4·5H2O solu-
tion (2ϫ 5 mL), followed by washing with saturated NaCl solution.
The organic layer was dried with MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography (meth-
anol/CH2Cl2, 1:20) to afford lactone 34 (78 mg, 87%) as a colorless
sticky solid. Rf = 0.21 (methanol/CH2Cl2, 1:20). [α]2D0 = +14.4 (c =
1
1, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.50 [d, J = 6.8 Hz,
3 H, CH(CH3)2], 1.51 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 1.54–1.61
(m, 1 H, 3Ј-H), 1.64–1.96 (m, 6 H, NCH2CH2, 3Ј-H, OCH2CH2-
tert-Butyl 2-[2-(2-{3-[4-(5-(4-Fluorophenyl)-1-{2-[(4R,6S)-6-(2-
hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-2-isopropyl-4-
CH2Ar, OH), 2.48–2.60 (m, 3 H, 5Ј-H, OCH2CH2CH2Ar), 2.62 phenyl-1H-pyrrole-3-carboxamido)phenyl]propoxy}ethoxy)ethoxy]-
(dd, J = 17.9, 4.8 Hz, 1 H, 5Ј-H), 3.41 (dd, J = 6.6, 6.3 Hz, 2 H, acetate (36): A solution of benzyl ether 35 (650 mg, 0.07 mmol) in
OCH2CH2CH2Ar), 3.46–3.74 [m, 13 H, CH(CH3)2, OCH2], 4.00 dry ethyl acetate (7 mL) was hydrogenated under balloon pressure
(ddd, J = 15.2, 10.1, 5.8 Hz, 1 H, NCH2CH2), 4.19 (ddd, J = 14.9,
in the presence of a catalytic amount of 20% Pd(OH)2 on carbon
10.4, 4.8 Hz, 1 H, NCH2CH2), 4.27 (m, 1 H, 4Ј-H), 4.50 (dddd, J for 6 h. The mixture was filtered through a pad of Celite and the
= 11.4, 8.6, 3.3, 3.0 Hz, 1 H, 2Ј-H), 6.84 (s, 1 H, CONH), 6.92–
filtrate concentrated in vacuo. The residue was purified by flash
7.05 (m, 6 H, Ar-H), 7.07–7.22 (m, 7 H, Ar-H) ppm. 13C NMR chromatography (ethyl acetate only) to afford alcohol 36 (540 mg,
(100 MHz, CDCl3): δ = 21.7 [CH(CH3)2], 22.0 [CH(CH3)2], 26.1 82%) as a colorless oil. Rf = 0.25 (EtOAc/petroleum ether, 7:3).
[CH(CH3)2], 31.1 (OCH2CH2CH2Ar), 31.5 (OCH2CH2CH2Ar), [α]2D0 = –2.8 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
35.6 (C-3Ј), 37.1 (NCH2CH2), 38.5 (C-5Ј), 40.7 (NCH2CH2), 61.7
1.12 (ddd, J = 12.9, 11.9, 11.1 Hz, 1 H, 5Ј-H), 1.21 (ddd, J = 12.9,
(OCH2), 62.4 (C-4Ј), 70.0 (OCH2), 70.3 (OCH2CH2CH2Ar), 70.4 2.8, 2.5 Hz, 1 H, 5Ј-H), 1.30 (s, 3 H, 2Ј-CH3), 1.35 (s, 3 H, 2Ј-CH3),
(OCH2), 70.5 (OCH2), 70.6 (OCH2), 72.5 (OCH2), 73.0 (C-3), 115.6 1.45 [s, 9 H, C(CH3)3], 1.51 [d, J = 7.1 Hz, 6 H, CH(CH3)2], 1.57–
(d, JCF = 21.2 Hz, 2CH, Ar), 115.7 (C, Ar), 119.8 (2 CH, Ar), 122.0
(C, Ar), 126.6 (CH, Ar), 128.0 (d, JCF = 2.9 Hz, C, Ar), 128.3 (2
1.73 (m, 4 H, NCH2CH2, CH2CH2OH), 1.76–1.87 (m, 2 H,
OCH2CH2CH2Ar), 2.39 (br. s, 1 H, OH), 2.56 (dd, J = 7.8, 7.3 Hz,
2 H, OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.3 Hz, 2 H, OCH2CH2-
CH, Ar), 128.6 (2 CH, Ar), 130.3 (2 CH, Ar), 133.1 (d, JCF
=
8.0 Hz, 2 CH, Ar), 134.4 (C, Ar), 136.0 (C, Ar), 137.4 (C, Ar), CH2Ar), 3.49–3.58 [m, 3 H, CH(CH3)2, CH2CH2OH], 3.59–3.76
141.1 (C, Ar), 162.9 (d, JCF = 378.4 Hz, C, Ar), 163.5 (CONH), (m, 11 H, 4Ј-H, OCH2), 3.81 (ddd, J = 14.9, 10.1, 6.3 Hz, 1 H,
169.5 (C=O, lactone) ppm. HRMS (ESI): calcd. for
NCH2CH2), 3.94–4.02 (m, 1 H, 6Ј-H), 4.00 (s, 2 H, OCH2CO2tBu),
4.06 (ddd, J = 14.9, 10.1, 4.8 Hz, 1 H, NCH2CH2), 6.81 (s, 1 H,
CONH), 6.92–7.02 (m, 6 H, Ar-H), 7.09–7.22 (m, 7 H, Ar-H) ppm.
1 3 C NMR (100 MHz, CDCl3 ): δ = 19. 7 (2Ј-CH3 ), 21.6
[CH(CH3)2], 21.7 [CH(CH3)2], 26.1 [CH(CH3)2], 28.1 [C(CH3)3],
30.0 (2Ј-CH3), 31.1 (OCH2CH2CH2Ar), 31.6 (OCH2CH2CH2Ar),
36.1 (C-5Ј), 38.0 (NCH2 CH2 ), 38.0 (CH2CH2 OH), 40.8
(NCH2CH2), 60.6 (OCH2), 66.5 (C-4Ј), 68.8 (C-6Ј), 69.0 (OCH2-
CO2tBu), 70.1 (CH2CH2OH), 70.4 (OCH2CH2CH2Ar), 70.5 (2
OCH2), 70.6 (2 OCH2), 70.7 (OCH2), 81.5 [C(CH3)3], 98.6 (C-2Ј),
115.3 (d, JCF = 21.2 Hz, 2 CH, Ar), 115.4 (C, Ar), 119.7 (2 CH,
Ar), 121.7 (C, Ar), 126.5 (CH, Ar), 128.3 (2 CH, Ar), 128.3 (C,
Ar), 128.6 (2 CH, Ar), 128.7 (C, Ar), 128.4 (d, JCF = 3.7 Hz, C,
Ar), 130.4 (2 CH, Ar), 133.1 (d, JCF = 8.0 Hz, 2 CH, Ar), 134.6
(C, Ar), 136.1 (C, Ar), 137.2 (C, Ar), 162.9 (d, JCF = 378.4 Hz, C,
Ar), 163.4 (CONH), 169.7 (CO2tBu) ppm. HRMS (ESI): calcd. for
C51H69FN2O10Na [M + Na]+ 911.48285, found 911.483546.
C42H51FN2O8Na [M + Na]+ 753.35217, found 753.352783.
tert-Butyl 2-{2-[2-(3-{4-[1-(2-{(4R,6S)-6-[2-(Benzyloxy)ethyl]-2,2-di-
methyl-1,3-dioxan-4-yl}ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phen-
yl-1H-pyrrole-3-carboxamido]phenyl}propoxy)ethoxy]ethoxy}acet-
ate (35): A mixture of acid 8 (520 mg, 0.87 mmol) and amine 29
(306 mg, 0.87 mmol) in CH2Cl2 (15 mL) was cooled to 0 °C fol-
lowed by the addition of DIPEA (0.44 mL, 2.6 mmol) and PyBrOP
(606 mg, 1.3 mmol). The mixture was stirred at room temp. over-
night (ca. 12 h) before it was diluted with CH2Cl2 (10 mL), washed
with saturated NaHCO3 solution (10 mL), water (2ϫ 10 mL) and
saturated NaCl solution. The organic layer was dried with anhy-
drous Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (EtOAc/petroleum ether, 2:3) provided
amide 35 (705 mg, 87 %) as a colorless sticky solid. Rf = 0.38
(EtOAc/petroleum ether, 3:2). [α]2D0 = –0.6 (c = 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 0.99 (ddd, J = 12.4, 11.9, 11.6 Hz,
1 H, 5Ј-H), 1.22 (ddd, J = 12.9, 2.5, 2.3 Hz, 1 H, 5Ј-H), 1.29 (s, 3 2-{(4R,6R)-6-[2-(3-{[4-(2,2-Dimethyl-4-oxo-3,6,9,12-tetraoxapenta-
H, 2Ј-CH3), 1.32 (s, 3 H, 2Ј-CH3), 1.46 [s, 9 H, C(CH3)3], 1.51 decan-15-yl)phenyl]carbamoyl}-5-(4-fluorophenyl)-2-isopropyl-4-
Eur. J. Org. Chem. 2012, 6576–6585
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6583

P. Sawant, M. E. Maier
FULL PAPER
phenyl-1H-pyrrol-1-yl)ethyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic
Acid (37): To a cooled solution (ice/water bath) of alcohol 36
(540 mg, 0.60 mmol) in CH2Cl2 (20 mL) was added Dess–Martin
periodinane (335 mg, 0.78 mmol) in one portion. The mixture was
stirred at room temp. for 1 h, washed with saturated NaHCO3
(10 mL), 1 m Na2S2O3 (10 mL), and saturated NaCl solution. The
organic layer was dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by passing it through
a short flash column (EtOAc/petroleum ether, 3:2) to afford inter-
mediate aldehyde (400 mg, 0.45 mmol), which was dissolved in tert-
buyl alcohol (15 mL). 2-Methyl-2-butene (2 mL) was added fol-
lowed by the addition of an aqueous solution (15 mL) of
NaH2PO4·2H2O (422 mg, 2.7 mmol) and NaClO2 (81 mg,
0.90 mmol). The mixture was stirred at room temp. for 6 h and
then extracted with ethyl acetate (3ϫ 15 mL). The combined or-
ganic layers were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (methanol/CH2Cl2/AcOH, 1:20:0.001) to furnish acid 37
(390 mg, 96%) as a viscous yellowish oil. Rf = 0.11 (methanol/
CH2Cl2/AcOH, 1:20:0.001). [α]2D0 = 3.8 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.05 (dd, J = 12.4, 11.9 Hz, 1 H, 5Ј-H),
1.30 (s, 3 H, 2Ј-CH3), 1.30–1.36 (m, 1 H, 5Ј-H), 1.36 (s, 3 H, 2Ј-
CH3 ), 1.45 [s, 9 H, C(CH3 )3 ], 1.51 [d, J = 7.1 Hz, 6 H,
CH(CH3)2], 1.57–1.72 (m, 2 H, NCH2CH2), 1.76–1.90 (m, 2 H,
OCH2CH2CH2Ar), 2.37 (dd, J = 15.9, 5.8 Hz, 1 H, CH2COOH),
2.52 (dd, J = 15.9, 6.8 Hz, 1 H, CH2COOH), 2.57 (dd, J = 8.1,
7.3 Hz, 2 H, OCH2CH2CH2Ar), 3.41 (dd, J = 6.6, 6.6 Hz, 2 H,
OCH2CH2CH2Ar), 3.47–3.59 [m, 3 H, CH(CH3)2, OCH2], 3.59–
3.74 (m, 11 H, 4Ј-H, OCH2), 3.82 (ddd, J = 14.9, 9.6, 6.1 Hz, 1 H,
NCH2CH2), 4.00 (s, 2 H, OCH2CO2tBu), 4.07 (ddd, J = 14.9, 9.3,
5.0 Hz, 1 H, NCH2CH2), 4.18 (dddd, J = 11.9, 9.6, 5.3, 3.3 Hz, 1
H, 6Ј-H), 6.82 (s, 1 H, CONH), 6.91–7.05 (m, 6 H, Ar-H), 7.09–
7.21 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.6
(2Ј-CH3), 21.6 [CH(CH3)2], 21.8 [CH(CH3)2], 26.1 [CH(CH3)2],
29.8 (2Ј-CH3), 31.1 (OCH2CH2CH2Ar), 31.6 (OCH2CH2CH2Ar),
35.7 (C-5Ј), 37.8 (NCH2 CH2 ), 40.8 (NCH2 CH2 ), 40.8
(CH2COOH), 65.5 (C-6Ј), 66.4 (C-4Ј), 69.0 (OCH2CO2tBu), 70.1
(OCH2), 70.4 (OCH2), 70.5 (2 OCH2), 70.6 (OCH2), 70.6
(OCH2CH2CH2Ar), 70.7 (OCH2), 81.5 [C(CH3)3], 99.0 (C-2Ј),
115.4 (d, JCF = 21.9 Hz, 2CH, Ar), 115.5 (C, Ar), 119.8 (2 CH,
Ar), 121.8 (C, Ar), 126.5 (CH, Ar), 128.3 (C, Ar), 128.3 (2 CH,
Ar), 128.6 (2 CH, Ar), 128.7 (C, Ar), 130.4 (2 CH, Ar), 133.1 (d,
JCF = 8.0 Hz, 2 CH, Ar), 134.5 (C, Ar), 136.0 (C, Ar), 137.3 (C,
Ar), 141.1 (C, Ar), 162.9 (d, JCF = 393.7 Hz, C, Ar), 163.5
(CONH), 169.7 (CO2tBu) ppm. HRMS (ESI): calcd. for
C51H67FN2O11Na [M + Na]+ 925.46211, found 925.462059.
3.41 (dd, J = 6.6, 6.6 Hz, OCH2CH2CH2Ar), 3.47–3.57 [m, 3 H,
CH(CH3)2, OCH2], 3.59–3.72 (m, 10 H, OCH2), 3.95–4.06 (m, 1
H, NCH2CH2), 4.00 (s, 2 H, OCH2CO2tBu), 4.19 (ddd, J = 14.9,
10.1, 4.8 Hz, 1 H, NCH2CH2), 4.24–4.31 (m, 1 H, 4Ј-H), 4.50
(dddd, J = 11.4, 8.6, 3.3, 3.0 Hz, 1 H, 2Ј-H), 6.83 (s, 1 H, CONH),
6.91–7.04 (m, 6 H, Ar-H), 7.08–7.22 (m, 7 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.7 [CH(CH3)2], 22.0 [CH-
(CH3)2], 26.1 [CH(CH3)2], 28.1 [C(CH3)3], 31.1 (OCH2CH2-
CH2Ar), 31.6 (OCH2CH2CH2Ar), 35.6 (C-3Ј), 37.1 (NCH2CH2),
38.5 (C-5Ј), 40.7 (NCH2CH2), 62.3 (C-4Ј), 69.0 (OCH2CO2tBu),
70.1 (OCH2), 70.4 (OCH2CH2CH2Ar), 70.5 (3 OCH2), 70.6
(OCH2), 70.7 (OCH2), 73.0 (C-3), 81.5 [C(CH3)3], 115.6 (d, JCF
=
21.9 Hz, 2 CH, Ar), 115.7 (C, Ar), 119.8 (2 CH, Ar), 122.0 (C, Ar),
126.6 (CH, Ar), 128.0 (d, JCF = 3.7 Hz, C, Ar), 128.3 (2 CH, Ar),
128.6 (2 CH, Ar), 130.3 (2 CH, Ar), 133.0 (d, JCF = 8.0 Hz, 2 CH,
Ar), 134.4 (C, Ar), 135.9 (C, Ar), 137.4 (C, Ar), 141.1 (C, Ar),
162.9 (d, JCF = 377.6 Hz, C, Ar), 163.5 (CONH), 169.5 (C=O, lac-
tone), 169.7 (C=O, ester) ppm. HRMS (ESI): calcd. for
C48H61FN2O10Na [M + Na]+ 867.42025, found 867.420241.
2-[2-(2-{3-[4-(5-(4-Fluorophenyl)-1-{2-[(2R,4R)-4-hydroxy-6-oxote-
trahydro-2H-pyran-2-yl]ethyl}-2-isopropyl-4-phenyl-1H-pyrrole-3-carb-
oxamido)phenyl]propoxy}ethoxy)ethoxy]acetic Acid (39): Aqueous
phosphoric acid (58 μL, 0.5 mmol, 85 wt.-%) was added to a solu-
tion of ester 38 (85 mg, 0.1 mmol) in CH2Cl2 (2 mL). The reaction
mixture was stirred at room temp. for ca. 8 h. After completion,
the reaction mixture was diluted with water (2 mL) and extracted
with CH2Cl2 (3ϫ 5 mL). The combined organic layers were dried
with anhydrous Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by flash chromatography (acetone/
CH2Cl2/AcOH, 1:1:0.01) to afford atorvastatin lactone TEG acid
39 (45 mg, 84%) as a viscous oil. Rf = 0.40 (acetone/CH2Cl2/
AcOH, 3:7:0.01). [α]2D0 = 15.5 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.50 [d, J = 6.8 Hz, 6 H, CH(CH3)2], 1.53–
1.62 (m, 1 H, 3Ј-H), 1.67–1.91 (m, 5 H, NCH2CH2, 3Ј-H,
OCH2CH2CH2Ar), 2.48–2.59 (m, 3 H, 5Ј-H, OCH2CH2CH2Ar),
2.62 (dd, J = 17.7, 4.8 Hz, 1 H, 5Ј-H), 3.42 (dd, J = 6.6, 6.6 Hz, 2
H, OCH2CH2CH2Ar), 3.46–3.74 [m, 13 H, CH(CH3)2, OCH2],
4.01 (ddd, J = 14.9, 8.8, 5.0 Hz, 1 H, NCH2CH2), 4.10 (s, 2 H,
OCH2CO2tBu), 4.18 (ddd, J = 14.9, 9.9, 4.8 Hz, 1 H, NCH2CH2),
4.24–4.30 (m, 1 H, 4Ј-H), 4.45–4.55 (m, 1 H, 2Ј-H), 6.86 (s, 1 H,
CONH), 6.92–7.04 (m, 6 H, Ar-H), 7.07–7.23 (m, 8 H, Ar-H) ppm.
13C NMR (100 MHz, CDCl3):
δ = 21.7 [CH(CH3)2], 22.0
[CH(CH3)2], 26.1 [CH(CH3)2], 30.8 (OCH2CH2CH2Ar), 31.4
(OCH2CH2CH2Ar), 35.6 (C-3Ј), 37.1 (NCH2CH2), 38.4 (C-5Ј),
40.7 (NCH2CH2), 62.3 (C-4Ј), 69.2 (OCH2CO2tBu), 70.0 (OCH2),
70.2 (2 OCH2), 70.3 (OCH2), 70.4, 70.5, 71.1 (3 OCH2), 73.0 (C-
2Ј), 115.6 (d, JCF = 22.0 Hz, 2 CH, Ar), 115.7 (C, Ar), 120.0 (2
CH, Ar), 122.0 (C, Ar), 126.6 (CH, Ar), 128.0 (d, JCF = 3.7 Hz, C,
Ar), 128.3 (2 CH, Ar), 128.7 (2 CH, Ar), 128.7 (C, Ar), 130.3 (2
CH, Ar), 133.1 (d, JCF = 8.0 Hz, 2 CH, Ar), 134.4 (C, Ar), 135.9
(C, Ar), 137.3 (C, Ar), 141.0 (C, Ar), 163.0 (d, JCF = 395.9 Hz, C,
Ar), 163.5 (C=O, amide), 163.8 (C=O, lactone), 169.6 (C=O, acid)
ppm. HRMS (ESI): calcd. for C44H52FN2O10 [M – H]– 787.36115,
found 787.361297.
tert-Butyl 2-[2-(2-{3-[4-(5-(4-Fluorophenyl)-1-{2-[(2R,4R)-4-hy-
droxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-2-isopropyl-4-phenyl-
1H-pyrrole-3-carboxamido)phenyl]propoxy}ethoxy)ethoxy]acetate
(38): Camphorsulfonic acid (195 mg, 0.84 mmol) was added to a
solution of acetonide acid 37 (380 mg, 0.42 mmol) in CH2Cl2
(5 mL). The reaction was completed within 3 h (TLC control). The
solution was washed with saturated NaHCO3 solution (5 mL),
water (5 mL), and saturated NaCl solution. The organic layer was
dried with anhydrous Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (methanol/CH2Cl2/AcOH,
3:97:0.001) provided lactone 38 (240 mg, 68%) as a colorless sticky
Supporting Information (see footnote on the first page of this arti-
1
cle): This material contains copies of H and 13C NMR spectra of
new compounds.
solid. Rf = 0.33 (methanol/CH2Cl2/AcOH, 3:97:0.001). [α]2D0
+17.5 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.45 [s,
9 H, C(CH3)3], 1.50 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.51 [d, J =
6.6 Hz, 3 H, CH(CH3)2], 1.54–1.61 (m, 1 H, 3Ј-H), 1.66–1.91 (m,
=
1
Acknowledgments
6 H, NCH2CH2, 3Ј-H, OCH2CH2CH2Ar, OH), 2.50–2.59 (m, 3 H, Financial support by the Deutsche Forschungsgemeinschaft and
5Ј-H, OCH2CH2CH2Ar), 2.62 (dd, J = 17.9, 4.8 Hz, 1 H, 5Ј-H), the Fonds der Chemischen Industrie is gratefully acknowledged.
6584
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6576–6585

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Published Online: October 15, 2012
Eur. J. Org. Chem. 2012, 6576–6585
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6585