Highly stereoselective formal synthesis of rosuvastatin and pitavastatin through Julia-Kocienski olefination using the lactonized statin side-chain precursor

PAPER

▌2333

^pH^api^eg^rhly Stereoselective Formal Synthesis of Rosuvastatin and Pitavastatin

Through Julia–Kocienski Olefination Using the Lactonized Statin Side-Chain

Precursor

Statins via Julia–Kocienski Reaction with Lactonized Precursor

Jan Fabris,^a,bZdenko Časar,*^b,c,dIvana Gazić Smilović,^bMartin Črnugelj^b

a

Cadonic Consultancy Services, LL.C., Cesta na postajo 74, 1351 Brezovica pri Ljubljani, Slovenia

b

Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27,

1234 Mengeš, Slovenia

c

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia

d

Sandoz GmbH, Global Portfolio Management API, Biochemiestrasse 10, 6250 Kundl, Austria

Fax +43(5338)200418; E-mail: zdenko.casar@sandoz.com

Received: 13.03.2014; Accepted after revision: 24.04.2014

mic compound in the class, atorvastatin contains a fully

Abstract: An expedient and simple synthetic approach to pitava-

saturated chiral side-chain motive. The two compounds

statin and rosuvastatin final intermediates is described. The present-

that are both optically pure and contain the C=C spacer

with E-geometry between the heterocyclic core and the

ed approach consists of completely stereoselective Julia–Kocienski

olefination step (E/Z up to 300:1) between lactonized statin side-

chain precursor and sulfone derivative of the corresponding pyrim- chiral side chain are rosuvastatin and pitavastatin

idine and quinoline heterocyclic cores. The desired O-TBS protect-

ed statin lactones were isolated in 66–71% yield and high >97%

purity (HPLC).

(Scheme 1). Nevertheless, both compounds differ signifi-

cantly with respect to the key substituents on the hetero-

cyclic core, which provides unique structural features.

Namely, pitavastatin is the only super-statin, which has a

Key words: stereoselective synthesis, olefination, heterocycles,

sulfones, lactones, aldehydes, drugs

cyclopropyl moiety attached to the heterocyclic core in-

stead of the isopropyl group, while rosuvastatin is the only

group member that contains a polar sulfonamide substitu-

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase (EC 1.1.1.88),¹known as statins,

are one of the most pronounced success stories in modern

medicine.²This is due to their unique ability to efficiently

inhibit the HMG-CoA reductase, the rate-controlling en-

zyme of the mevalonate metabolic pathway that produces

cholesterol.³Consequently, remarkable cholesterol-low-

ering effect is achieved, which renders statins the most ef-

fective hypolipidemic drugs available.⁴Moreover, this

therapeutic group of compounds demonstrated enormous

potential for structural refinement as evidenced by rapid

evolution from pioneering discovery of natural deriva-

tives such as compactin (mevastatin) by Endo et al.⁵and

lovastatin by Alberts et al.⁶to semisynthetic compounds

represented by simvastatin⁷and pravastatin⁸to fully syn-

thetic derivatives. The latter are frequently addressed also

as super-statins^9,10and consist of a heterocyclic core at-

tached to the chiral 3,5-dihydroxyhept-6-enoic or -hepta-

noic acid side-chain residue, which remains as the key

pharmacophore from its naturally derived ancestors.

Nowadays, the group of super-statins that has received

and maintained the marketing authorization by regulatory

authorities on different territories, consists of fluvasta-

tin,¹¹atorvastatin,¹²rosuvastatin,¹³and pitavastatin.¹⁴Al-

though all four compounds share some common structural

features, there are specific structural particularities associ-

ated with each of them. While fluvastatin is the only race-

ent (Scheme 1). These structural particularities give some

unique properties to both compounds in terms of activity

for rosuvastatin¹⁵as well as metabolism and tolerability in

combination with other drugs in the case of pitavastatin.¹⁶

Therefore, both compounds are interesting synthetic tar-

gets. Indeed, many synthetic approaches have been de-

vised to both rosuvastatin^9,17and pitavastatin.^9,18,19The

most frequently applied are, due to their technical simplic-

ity and cost competitiveness, associated with Wittig reac-

tion employing phosphonium salts A (Scheme 1) or

Horner–Wadsworth–Emmons (HWE) olefination using

other phosphorous functionalized heterocyclic precur-

sors.^13,20,21Nevertheless, both Wittig and HWE olefina-

tions are not completely stereoselective and give rise to

the undesirable Z-stereoisomer, which represents a te-

dious to remove impurity in these drugs.

An interesting alternative method for the assembly of ro-

suvastatin and pitavastatin could be the well established

Julia–Kocienski olefination^22,23(Scheme 1). Interestingly,

reports on Julia–Kocienski olefination strategy to super-

statins are much less frequent and are addressed mostly in

the patent literature employing sulfones B and dually pro-

tected open statin side-chain precursor D. Moreover, these

reports provide poor scientific insights and characteriza-

tion details.²⁴The only scientific report on Julia–Kocienski

olefination related to statin chemistry on investigational

drug candidate employs the inverse coupling partners: the

aldehyde E of the corresponding heterocyclic precursor

and sulfone derivative of the dually protected open statin

side-chain derivative F (Scheme 1). This approach pro-

vided initial stereoselectivities of 15:1 for E-olefin, which

SYNTHESIS 2014, 46, 2333–2346

Advanced online publication: 12.06.2014

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

DOI: 10.1055/s-0033-1338648; Art ID: st-2014-t0180-op

2334

J. Fabris et al.

PAPER

OH

O

S

OPG OPG O

N

Het =

N

R

Het₂

OR'

R

O

N

CO₂Ca_1/2

Julia–Kocienski (ref. 25)

O

F

OH

O

S

N

Het₁

OPG OPG

O

E

O

N

OR'

investigational

hepatoselective statin

candidate

Julia–Kocienski (ref. 24)

D

rosuvastatin

moiety

OTBS

R

Julia–

Kocienski

O

Ar

O

S

OTBS

OH

O

CO₂Ca_1/2

O

3 steps

one-pot

this work

Het

N

1

B

O

pitavastatin

moiety

OH

ref.

26 and 27

PR'

₃X

Wittig

Het

rosuvastatin and pitavastatin

R = 4-FC₆H₄

C

Het

ref.

26 and 27

A

Scheme 1 Synthetic strategy towards rosuvastatin and pitavastatin described in this and previous related work

dramatically increased to >100:1 in favor of E-isomer tavastatin and rosuvastatin via highly stereoselective

when the reaction mixture was ‘aged’ after reagents addi- Julia–Kocienski olefination of the lactonized statin side-

tion at noncryogenic temperatures.²⁵Based on the above chain derivative 1 and sulfone derivatives B of the corre-

mentioned shortcomings of other routes to super-statins sponding pyrimidine and quinoline heterocyclic cores to

and our recent success in the first successful assembly of produce known O-TBS-protected super-statin lactones C.

rosuvastatin²⁶and pitavastatin²⁷via lactonized statin side- These are easily transformed to rosuvastatin and pitavas-

chain precursor 1²⁸employing the Wittig reaction, we tatin in a three-step/one-pot sequence in high yields

were prompted to consider the assembly of rosuvastatin (Scheme 1).^26,27

and pitavastatin via Julia–Kocienski olefination employ-

Our first goal was to prepare diverse array of sulfone het-

ing lactone 1. This would also enable us to verify, if the

erocyclic precursors 6 and 7, through a two-step reaction

suboptimal stereoselectivity of our Wittig approach with

pathway, which would allow us a relevant screening for

lactone 1, where an E/Z ratio between 7:1 and 12:1 was

the best performing Julia–Kocienski olefination partners

(Scheme 2). In the first reaction step, the sulfide heterocy-

clic precursors 4 and 5 were prepared via the reaction be-

achieved,^26,27could be improved. Therefore, in this paper

we present a detailed study on the formal synthesis of pi-

Ar =

O

Ar

O

Ar

R

S

R

N

Br

S

a

b

e

f

N

O

N

a

b

O

S

N

O

S

N

O

S

N

O

N

O

N

O

N

2

CF₃

4a (82%) 4e (75%)

4b (88%) 4f (85%)

4c (87%) 4g (84%)

4d (85%) 4h (80%)

6a (18%) 6e (73%)

6b (89%) 6f (86%)

6c (71%) 6g (76%)

6d (50%) 6h (93%)

N

S

R = 4-FC₆H₄

O

Ar

O

Ar

g

h

c

d

R

N

S

R

N

S

R

Br

N

NO₂

a

b

N

3

5a (86%) 5e (79%)

5b (82%) 5f (81%)

5c (85%) 5g (97%)

5d (91%) 5h (87%)

7a (19%) 7e (66%)

7b (76%) 7f (75%)

7c (49%) 7g (69%)

7d (28%) 7h (51%)

N

S

Scheme 2 Synthesis of various sulfide heterocyclic precursors 4a–h and 5a–h and sulfone heterocyclic precursors 6a–h and 7a–h. Reagents

and conditions: (a) ArSH (1.2 equiv), NaOH (1.5 equiv), MeOH or MeOH–THF (2:1), r.t., 18 h; (b) mCPBA (5 equiv), THF, r.t., 17 h. Com-

pounds 4b, 5b, 6b, and 7b were prepared according to the published procedures with comparable yields.^24e

Synthesis 2014, 46, 2333–2346

PAPER

Statins via Julia–Kocienski Reaction with Lactonized Precursor

2335

tween the heterocyclic alkyl bromide 2^26dor 3^27aand proved with IR spectroscopy solely, because a band, typ-

various aromatic and heterocyclic thiols at room tempera- ical for C–N stretch of amines, also lies in the same wave-

ture, where NaOH was used as a base and methanol as a number range.

solvent. When pyrimidine alkyl bromide 2 was used, THF

was also added to the mixture to achieve better solubility.

After the workup and recrystallization, the desired prod-

ucts 4 and 5 were obtained in good to excellent yields (75–

To further prove the presence of sulfone functional group

we resorted to MS/MS analysis. Fragmentation behavior

of compound 7c was investigated with atmospheric pres-

sure chemical ionization mass spectrometry in the posi-

97%).

tive ion mode. Mass spectrum displayed a peak at m/z =

Trying to find a general procedure for sulfide oxidation, 408 corresponding to the elimination of SO₂molecule via

three different reaction conditions were tested on the pre- rearrangement³³from the protonated starting compound at

pared sulfides 4 and 5: KMnO₄in AcOH–acetonitrile,^24e,29m/z = 472. The elimination of SO₂molecule obviously

NaIO₄/RuCl₃·H₂O in acetonitrile–H₂O,³⁰and m-chloro- confirmed the presence of sulfone functional group in 7c.

peroxybenzoic acid (mCPBA) in THF.^24e,31In most cases, The m/z = 276 ion resulted from the further loss of N-

the latter oxidizing agent gave the cleanest reaction with methylbenzimidazole fragment (proposed fragmentation

generally good outcomes for desired products 6 and 7. All pathways of 7c and its mass spectrum are both presented

of the sulfides 4 and 5 were therefore oxidized with in Scheme S1 in the Supporting Information).

mCPBA and the major product 6 and 7 was isolated via

Finally, when preparing compound 7d according to the

trituration and/or column chromatography in good to high

discussed procedure, we also managed to isolate the over-

yields (49–93%) except for 6a, 7a, and 7d where low

oxidized product 7d′ (see Figure S1 in the Supporting In-

yields were attained. The known compounds 4b, 5b, 6b,

formation for structure description). Molar mass for 7d′

and 7b were prepared according to the patent literature in

was 16 units higher than for 7d. Comparison of ¹H NMR

similar yields.^24e

spectra between 7d and 7d′ revealed, that the main differ-

The oxidation of sulfides with mCPBA was monitored ence lies in the chemical shifts of CH of cyclopropyl

with LC-MS, which enabled us to study the reaction prog- group (2.50 ppm for 7d and 1.94 ppm for 7d′) and H-8 of

ress. In most cases, as the starting material was slowly ox- quinoline (7.98 ppm for 7d and 8.76 ppm for 7d′). Fur-

1

idized, the firstly formed intermediate had a molar mass ther, H–¹⁵N heteronuclear correlations in HMBC NMR

16 units higher (M + 16) than the starting sulfide, which spectra showed that in both cases chemical shift of the thi-

indicated that this compound could probably be a sulfox- azole nitrogen remains unchanged (334 ppm). However,

ide derivative. Further oxidation of this first intermediate there is a significant chemical shift difference between the

gave the next one, which exhibited the desired molar mass quinoline nitrogen atoms (297 ppm for 7d and 282 ppm

of a sulfone (M + 32). Still, there was also another minor for 7d′). These results clearly indicate that compound 7d′

side-product with a molar mass that was 48 units higher contains sulfone as well as the N-oxide functional group,

(M + 48) than the starting compound. Because all the whereas 7d lacks the latter one. Therefore, when sulfides

starting sulfides 4 and 5 possess at least one nitrogen atom are oxidized, they form sulfones in the first place and the

within the structure, which is capable of being oxidized, corresponding N-oxides only due to the over-oxidation.

the formation of N-oxides could not be excluded. There- At this point we were sure, that all of the newly synthe-

fore, after oxidation of sulfides 4 or 5 to sulfones 6 or 7, sized compounds 6 and 7 have the desired structure and so

there is also a possibility of over-oxidation of the desired were ready for the screening of the Julia–Kocienski olefi-

sulfone, which would produce an unwanted sulfone N-ox- nation.

ide (see Figure S1 in the Supporting Information for struc-

In order to set proper reaction conditions for screening of

ture description). With only that information in hand, a

the Julia–Kocienski olefination with novel sulfone hetero-

reverse order of previously mentioned oxidations could

cyclic precursors (6 and 7) and lactonized statin side-

chain precursor 1, the reaction conditions according to the

also be possible (from the formation of N-oxide to sulfox-

ide and sulfone), which would imply that the product with

already published procedure for the olefination with pre-

desired molar mass would contain the unwanted N-oxide

cursor D were first tried.^24eThe THF solution of com-

functional group. Various spectroscopy techniques, in-

pound 7b and aldehyde 1 (prepared from its hydrate form

1′, see the Experimental Section) was first cooled to

–30 °C, then potassium tert-butoxide was added and the

mixture was left to stir for half an hour. Then, the reaction

cluding IR, NMR, and MS/MS, were required to distin-

guish between the above mentioned functional groups and

to provide insight into step-by-step oxidation reactions of

sulfides 4 and 5.

mixture was warmed to room temperature and stirred for

Therefore, the IR spectroscopy seemed to be an appropri- another hour. After quench and workup, HPLC analysis of

ate method, because every functional group of our interest the crude product surprisingly showed very low ratio of

has its representative infrared absorption bands.³²IR spec- desired product (E)-9 to starting sulfone 7b (1:7) and

tra of all synthesized compounds 6 and 7 with desired mo- many side products (see Scheme S2 in the Supporting In-

lar mass exhibit the absorption bands in the ranges, typical formation for reaction description). Under exact condi-

for sulfones, and lack the strong band, characteristic for tions we repeated the reaction with compound 6b and

sulfoxides. Unfortunately, presence of N-oxides cannot be gained practically the same result.

Synthesis 2014, 46, 2333–2346

2336

J. Fabris et al.

PAPER

Due to the fact that we were unable to apply the reaction

conditions according to the above mentioned procedure, it

was decided to perform a preliminary Julia–Kocienski

olefination between compound 6b and benzaldehyde as a

model substrate at lower temperatures (from –20 to

–80 °C) using sodium hexamethyldisilazide (NaHMDS)

as a base. A THF solution of 6b was cooled and then the

base was added to form red-orange colored solution. After

five minutes, a solution of benzaldehyde (1.2 equiv) in

THF was rapidly added under vigorous stirring. The loss

of color of the solution was immediate. After quench and

workup, ¹H NMR and HPLC analyses of the crude prod-

ucts showed a large ratio of desired product to starting sul-

fone (as high as 17:1) with only minor side products being

present. Encouraged by these results, we decided to per-

form the Julia–Kocienski olefination screening over sul-

fones 6 and 7 according to our preliminary procedure

(Scheme 3). All of the screening reactions took place at

–60 °C, NaHMDS was used as a base, and the lactonized

statin side-chain precursor 1 as the coupling partner. The

crude reaction products of the screening were analyzed by

¹H NMR spectroscopy to gain data on conversion and

yield. The results of the screening are summarized in Ta-

ble 1.

Table 1 Screening of the Olefination Step Between Aldehyde 1 and

Sulfone Heterocyclic Precursors 6a–h and 7a–h

Entry^a

6 or 7

Conversion (%)^b(E)-8 or (E)-9 Yield (%)^b,c

1

2

6a

6b

6c

6d

6e

6f

90

81

56

36

27

28

72

51

86

83

53

65

60

62

54

37

41

64

19

9

3

4

5

nd

5

6

7

6g

6h

7a

7b

7c

7d

7e

7f

8

9

45

63

33

11

nd

10

11

12

13

14

15

16

At the first glance, Table 1 reveals that results for rosuv-

astatin and pitavastatin substrates are very comparable

with each other. In both cases, benzothiazole substrates 6b

and 7b gave the best result with 64% and 63% yield, re-

spectively (Table 1, entries 2 and 10). In addition, there

were only three major compounds in the crude mixture:

desired product (E)-8 or (E)-9, starting sulfone 6 or 7 and

the stoichiometric by-products 10a–h (generally written

as ArOH, for exact structure of aryl moieties see Scheme

2). Interestingly, all three pairs of the uncondensed ring

heterocyclic sulfones 6d,e,h and 7d,e,h (entries 4, 5, 8,

12, 13, and 16) gave very poor results as well as both pairs

of the electron-poor aromatic sulfones 6f,g and 7f,g (en-

tries 6, 7, 14, and 15). In all ten mentioned cases, the yield

was never higher than 11%. On the other hand, both pairs

of the condensed heterocyclic sulfones gave considerably

7g

7h

^aAll reactions were performed in THF on a 0.2 mmol scale and at

–60 °C with 1.1 equiv of NaHMDS and 1.2 equiv of aldehyde 1 (see

Experimental Section).

^bConversions and yields are set by ¹H NMR analysis of the crude re-

action mixtures using 1,3,5-trimethoxybenzene as an internal stan-

dard.

^cThe difference between the yields and conversions goes on the ex-

pense of formed unidentified side-products. nd: not determined.

higher yields (entries 1, 3, 9, and 11). Compounds 6c and

7c gave 19% and 33% yield, whereas 6a and 7a gave 41%

and 45% yield, respectively. Results of the screening re-

vealed that Julia–Kocienski olefination gave better results

Het =

O

R

N

OTBS

N

S

O

N

HO

O

1'

OH

r.t.

CH₂Cl₂

6a–h, (E)-8 and (Z)-8

(rosuvastatin moiety)

1. Base

2.

OTBS

O

R

OTBS

O

TBSO

O

Ar

S

N

1

O

Ar OH

+

O

(Z)

(E)

7a–h, (E)-9 and (Z)-9

temp, solvent

10a–h

Het

(Z)-8

(Z)-9

Het

(pitavastatin moiety)

(E)-8

(E)-9

6a–h

7a–h

R = 4-FC₆H₄

Scheme 3 Study of the olefination step between aldehyde 1 and sulfone heterocyclic precursors 6a–h and 7a–h. Structures of aryl substituents

(Ar) in compounds 10a–h are the same as shown in Scheme 2.

Synthesis 2014, 46, 2333–2346

PAPER

Statins via Julia–Kocienski Reaction with Lactonized Precursor

2337

when sulfones with sterically more hindered substituents higher) in order to make handling with such small

are used. Besides, using substrates with trifluoromethyl amounts of compounds easier. Because the results were

(6f and 7f) and nitro (6g and 7g), substituents on the ben- slightly improved (entry 3), the reactions were continued

zene ring gave similarly poor results as when using sub- on a 0.4 mmol scale. Then we tried to vary some other

strates with the pyridyl functional group 6h and 7h. For bases, but unfortunately all performed less successful (en-

that, it seems that electronic effects of the substituents tries 4 and 5). Lithium hexamethyldisilazide (LiHMDS)

have no significant influence on the reaction outcome. gave lower yield, whereas potassium hexamethyldisila-

With the hit result in hand, we next tried to optimize the zide (KHMDS) gave comparable yield, but many undesir-

reaction conditions in order to improve the reaction yield able side products as well. Variation of the solvent also

and to find the optimal method to purify our desired prod- gave poorer results, for example, using dimethoxyethane

ucts (E)-8 and (E)-9.

gave lower product/reactant ratio, whereas with diethyl

ether almost complete starting material was recovered.

Since in all cases there was some starting material left in

the crude reaction mixture, we thought that basic sulfonyl

carbanion could as well abstract the α-carbonyl proton

from the excess aldehyde 1 to form the starting sulfone

compound again. Therefore, we tried first to lower the

amount of aldehyde 1 and second to lower the amounts of

both aldehyde 1 and base (entries 6 and 7). In both cases,

the results were worse, suggesting that excess aldehyde 1

does not have any major contribution to the starting mate-

rial recovery. Trying to enhance the sulfonyl carbanion

formation, we next raised the excess of the base from 1.1

equivalents to 1.3 equivalents (entry 8). The results

showed significantly higher product/reactant ratio. There

were 7% and 18% higher yields of compounds (E)-8 and

(E)-9, respectively (than in entry 3). Furthermore, the ex-

periment was performed with 1.5 equivalents of aldehyde

1 and 1.3 equivalents of base (entry 9), but the overall out-

come was slightly worse. Finally, using even a higher ex-

cess of the base (1.5 equiv), only poorer result was

obtained (entry 10).

Because the reaction between both of the benzothiazole

sulfones 6b and 7b and aldehyde 1 gave almost no consid-

erable side products except the by-product 10b, we decid-

ed to analyze crude reaction mixtures of optimization

reactions with HPLC analysis (Table 2). Reactions for

each entry in Table 2 were performed with 6b and 7b in

parallel, which gave the corresponding results for (E)-8,

(Z)-8, 6b and (E)-9, (Z)-9, 7b, respectively. Analytical

standards of compounds (Z)-8 and (Z)-9 were prepared in

accordance with the already published procedures.^26,27

Again, all results for pitavastatin and rosuvastatin deriva-

tives are very comparable with each other. Our first at-

tempt to improve the reaction yield was with the variation

of the temperature (Table 2, entries 1 and 2), which gave

comparable or slightly worse results, so the temperature

was kept constant at –60 °C for further experiments

(HPLC analysis of crude reaction mixtures from entries 2

and 10 in Table 1 showed that (E)-8/6b = 79:21 and (E)-

9/7b = 68:32, respectively). Next, a small scale-up from

0.2 mmol to 0.4 mmol was performed with the same vol-

umes of solvents (concentrations were therefore two-fold

Table 2 Optimization of Reaction Conditions for the Olefination Step Between Aldehyde 1 and Sulfone Heterocyclic Precursors 6b and 7b

Entry^a

1 (equiv) Base (equiv)

Temp (°C) (E)-8 (%)^b(Z)-8 (%)^b6b (%)^b(E)-8/6b^c(E)-9 (%)^b(Z)-9 (%)^b7b (%)^b(E)-9/7b^c

1^d

2^d

3

1.2

0.9

1.2

1.5

1.2

NaHMDS (1.1)

LiHMDS (1.1)

KHMDS (1.1)

NaHMDS (1.1)

NaHMDS (1.0)

NaHMDS (1.3)

NaHMDS (1.5)

–70

–50

–60

45

53

35

51

40

38

60

66

54

0.36

0.44

0.62

0.34

0.33

0.18

0.16

0.45

0.53

0.50

36

31

27

57

13

36

47

18

22

24

71:29

74:26

79:21

54:46

88:12

68:32

61:39

86:14

85:15

81:19

45

29

53

21

47

34

39

71

66

71

0.02

nd

27

57

26

72

6

72:28

44:56

76:24

30:70

93:7

4

0.07

nd

5

6

0.05

nd

35

37

12

16

18

60:40

61:39

90:10

86:14

7

8

0.23

0.14

0.24

9

10

^aReactions were run on a 0.4 mmol scale. For details, see the Experimental Section.

^bYields, set by HPLC analysis of the crude products, are given as the area percentage of the peaks, where no response factors were taken in

account, due to unidentified minor side products. The sum of the products is lower than 100% owing to the presence of unidentified minor side

products. Standards for (Z)-8 and (Z)-9 were prepared according to the literature data.^26,27nd: not determined.

^cProduct to reactant ratios are set by HPLC analysis of the crude reaction mixtures. The values are calculated taking response factors into ac-

count and are normalized to 100.

^dReactions were run on a 0.2 mmol scale.

Synthesis 2014, 46, 2333–2346

2338

J. Fabris et al.

PAPER

Melting points were determined with a Mettler Toledo DSC822e

apparatus (heating rate 10 °C/min) and are referred to as onset val-

ues and peak values. IR spectra were recorded on a Thermo Nicolet

Nexus FTIR spectrometer; only noteworthy absorptions are listed.

High-resolution mass spectra were obtained with a VG-Analytical

AutospecQ instrument and a Q-TOF Premier instrument. All reac-

tions involving air or moisture-sensitive reagents were performed

under N₂in oven-dried glassware by using syringe/septum cap tech-

niques.

The best result was hence obtained on a 0.4 mmol scale at

–60 °C using 1.3 equivalents of the base, 1.2 equivalents

of aldehyde 1, and THF as a solvent. Both of the hit results

(Table 2, entry 8,) gave practically complete stereoselec-

tive reactions, where (E)-8/(Z)-8 is >130:1 and (E)-9/(Z)-

9 is >300:1. Having determined the best reaction condi-

tions, the scale up of the reaction was attempted at a 1.0

mmol scale, where the molar ratio for all compounds in-

volved in the reaction remained the same. Completing the

reactions, NMR analyses of the crude reaction mixtures

showed that 71% and 78% yield was obtained for (E)-8

and (E)-9, respectively, whereas HPLC analyses revealed

that no other impurity was on the higher level than 2 ar-

ea%. Compounds (E)-8 and (E)-9 were purified via col-

umn chromatography to give 66% and 71% isolated yield,

respectively. According to HPLC analysis, the purity of

both desired compounds was >97%.

Sulfide Heterocyclic Precursors; General Procedure

Aq 1 M NaOH (9 mL, 1.5 equiv) was added to a stirred MeOH (20

mL) solution of the appropriate aromatic thiol (7.2 mmol, 1.2

equiv). The solution was stirred at r.t. for 15 min and then the het-

erocyclic alkyl bromide 2 or 3 (6 mmol, 1 equiv) was added. When

rosuvastatin moiety bromides 2 were used, THF (10 mL) was also

added to the mixture to improve solubility. After 18 h, the solvent

was evaporated, the residue was dissolved in CH₂Cl₂(50 mL), and

washed with H₂O (100 mL). The aqueous phase was additionally

extracted with CH₂Cl₂(2 × 25 mL). The combined organic phases

were dried (MgSO₄) and the solvent was evaporated. The residue

was recrystallized and the isolated product was dried in vacuum

overnight at 60 °C below 50 mbar to give the pure sulfide heterocy-

clic precursor 4 or 5 in 75–97% yield.

To conclude, we have presented in depth study on the

preparation of sulfides 4 and 5 and sulfones 6 and 7. Fur-

thermore, a practical and simple synthetic approach, via

Julia–Kocienski olefination, was developed towards O-

TBS protected pitavastatin and rosuvastatin lactones (E)-

8 and (E)-9 which are known to be easily converted into

the corresponding drugs.^26,27For the first time, the Julia–

Kocienski olefination step between the lactonized statin

side-chain precursor 1 and the sulfone substrate is de-

scribed. Extending the scope of olefinations towards su-

per-statins using the lactonized aldehyde 1, allowed us

straightforward comparison between Wittig and Julia–

Kocienski approach. Whereas Wittig route^26,27utilizes

high yield single step preparation of the phosphorous pre-

cursors from the same starting compounds 2 and 3 and fa-

cilitates the olefination at reasonably higher temperature,

the main advantage of the Julia–Kocienski method is as-

sociated with complete stereoselectivity of the olefination

step with almost none of the other side products. Gratify-

ingly, both methods provide very good and comparable

yields of the olefination step. Nevertheless, due to the

more favorable impurity profile of the Julia–Kocienski

olefination reaction, this approach seems to be better suit-

ed for larger scale production of rosuvastatin and pitava-

statin.

N-{5-[(Benzo[d]oxazol-2-ylthio)methyl]-4-(4-fluorophenyl)-6-

isopropylpyrimidin-2-yl}-N-methylmethanesulfonamide (4a)

Prepared according to the general procedure; recrystallized from

MeOH–THF (3:1) to give a brown crystalline product after drying;

yield: 2.38 g (82%); mp 147.7 °C (onset), 149.5 °C (peak).

IR (KBr): 3439, 2964, 2929, 2870, 1553, 1504, 1455, 1376, 1337,

1150, 1140, 956, 741, 575, 509 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.34–1.41 (m, 6 H), 3.49–3.56 (m,

4 H), 3.58 (s, 3 H), 4.60 (s, 2 H), 7.12–7.18 (m, 2 H), 7.25–7.35 (m,

2 H), 7.43–7.48 (m, 1 H), 7.57–7.62 (m, 1 H), 7.69–7.76 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.4, 30.8, 31.9, 33.3, 42.6, 110.2,

115.9 (d, J = 21.8 Hz), 116.0, 118.6, 124.5, 124.7, 130.9 (d, J = 8.4

Hz), 133.8 (d, J = 3.2 Hz), 141.7, 151.9, 158.2, 163.1, 163.7 (d, J =

250.3 Hz), 166.9, 177.6.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₄FN₄O₃S₂: 487.1268;

found: 487.1264.

N-{5-[(Benzo[d]thiazol-2-ylthio)methyl]-4-(4-fluorophenyl)-6-

isopropylpyrimidin-2-yl}-N-methylmethanesulfonamide (4b)

Prepared according to the procedure described in the literature with

comparable yield;^24emp 134.3 °C (onset), 137.9 °C (peak) (Lit.^24e

132–135 °C).

IR (KBr): 3432, 2969, 2929, 2869, 1605, 1554, 1510, 1455, 1430,

1380, 1330, 1215, 1162, 967, 913, 843, 774, 749, 707, 618, 565, 511

cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.32–1.39 (m, 6 H), 3.48–3.56 (m,

4 H), 3.58 (s, 3 H), 4.64 (s, 2 H), 7.09–7.16 (m, 2 H), 7.30–7.35 (m,

1 H), 7.40–7.46 (m, 1 H), 7.70–7.76 (m, 2 H), 7.76–7.80 (m, 1 H),

7.82–7.86 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.4, 31.8, 31.9, 33.2, 42.6, 115.7

(d, J = 21.7 Hz), 116.6, 121.2, 121.7, 124.7, 126.4, 130.9 (d, J = 8.5

Hz), 133.9 (d, J = 3.1 Hz), 135.2, 153.0, 158.1, 163.6 (d, J = 250.1

Hz), 164.8, 166.6, 177.5.

Reagents and solvents were acquired from commercial sources and

were used without further purification. Reactions were monitored

by using analytical TLC plates (Merck; silica gel 60 F254, 0.25

mm), and compounds were visualized with UV radiation. Silica gel

grade 60 (70–230 mesh, Merck) was used for column chromatogra-

phy. HPLC analysis were performed with MeCN–H₂O as the mo-

bile phase (MeCN gradient 5–90%) on a Waters 2695 instrument

with photodiode array detector and a Waters X Bridge (150 × 4.6

mm, 3.5 μm) column. LC-MS analyses were performed on Agilent

1200 instrument with diode array detector and a YMC-Triart C18

(100 × 2.0 mm I.D., S-1.9 μm, 12 nm) column. Mass spectra were

obtained with a Bruker HCT esquire ion trap with atmospheric pres-

sure chemical ionization. All the NMR spectra were recorded with

a Bruker Avance III 500 MHz spectrometer at 25 °C. ¹H NMR spec-

tra were obtained at 500 MHz, ¹³C NMR spectra were obtained at

125 MHz. Chemical shifts are reported in ppm relative to the peak

of the residual nondeuterated solvent, CDCl₃(7.26 ppm for ¹H and

77.16 ppm for ¹³C). The coupling constants (J) are given in Hertz.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₄FN₄O₂S₃: 503.1040;

found: 503.1038.

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(1-methyl-1H-ben-

zo[d]imidazol-2-ylthio)methyl]pyrimidin-2-yl}-N-methylmeth-

anesulfonamide (4c)

Prepared according to the general procedure; recrystallized from

MeOH–THF (3:1) to give a white crystalline product after drying;

yield: 2.60 g (87%); mp 153.6 °C (onset), 155.1 °C (peak).

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Statins via Julia–Kocienski Reaction with Lactonized Precursor

2339

IR (KBr): 3434, 2967, 2925, 2870, 1550, 1374, 1150, 956, 743, 574

cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.35–1.40 (m, 6 H), 3.53–3.58 (m,

4 H), 3.60 (s, 3 H), 3.70 (s, 3 H), 4.66 (s, 2 H), 7.10–7.16 (m, 2 H),

7.24–7.33 (m, 3 H), 7.64–7.69 (m, 1 H), 7.69–7.75 (m, 2 H).

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(4-nitrophenyl-

thio)methyl]pyrimidin-2-yl}-N-methylmethanesulfonamide

(4g)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a yellow crystalline product after dry-

ing; yield: 2.46 g (84%); mp 203.7 °C (onset), 205.7 °C (peak).

¹³C NMR (125 MHz, CDCl₃): δ = 22.4, 30.2, 31.0, 31.8, 33.3, 42.7,

108.8, 115.8 (d, J = 21.7 Hz), 116.9, 118.4, 122.2, 122.4, 130.9 (d,

J = 8.3 Hz), 134.0 (d, J = 2.5 Hz), 136.8, 143.4, 150.7, 158.1, 163.6

(d, J = 250.0 Hz), 166.7, 177.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₇FN₅O₂S₂: 500.1585;

found: 500.1578.

IR (KBr): 3439, 2966, 2927, 1546, 1510, 1377, 1338, 1228, 1157,

853, 777, 740 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.37 (d, J = 6.6 Hz, 6 H), 3.46

(sept, J = 6.6 Hz, 1 H), 3.52 (s, 3 H), 3.58 (s, 3 H), 4.20 (s, 2 H),

7.10–7.17 (m, 2 H), 7.29–7.34 (m, 2 H), 7.73–7.79 (m, 2 H), 8.12–

8.17 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.5, 31.2, 31.9, 33.3, 42.7, 115.8

(d, J = 21.7 Hz), 116.1, 124.3, 126.6, 130.9 (d, J = 8.4 Hz), 133.9

(d, J = 2.8 Hz), 145.7, 146.3, 158.2, 163.8 (d, J = 250.6 Hz), 166.4,

177.4.

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(thiazol-2-ylthio)meth-

yl]pyrimidin-2-yl}-N-methylmethanesulfonamide (4d)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give an off-white crystalline product after

drying; yield: 2.32 g (85%); mp 97.2 °C (onset), 101.3 °C (peak).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₂₄FN₄O₄S₂: 491.1218;

IR (KBr): 3433, 3096, 2976, 2957, 2925, 1548, 1512, 1377, 1148,

968, 912, 774, 522 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.33–1.40 (m, 6 H), 3.47–3.56 (m,

4 H), 3.59 (s, 3 H), 4.49 (s, 2 H), 7.13–7.19 (m, 2 H), 7.29 (d, J =

3.4 Hz, 1 H), 7.69 (d, J = 3.4 Hz, 1 H), 7.73–7.78 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.4, 31.8, 32.8, 33.2, 42.6, 115.7

(d, J = 21.7 Hz), 116.9, 119.7, 131.0 (d, J = 8.4 Hz), 133.9 (d, J =

2.8 Hz), 143.0, 158.0, 162.7, 163.6 (d, J = 250.0 Hz), 166.5, 177.4.

found: 491.1215.

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(pyridin-2-ylthio)meth-

yl]pyrimidin-2-yl}-N-methylmethanesulfonamide (4h)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a white crystalline product after dry-

ing; yield: 2.14 g (80%); mp 129.0 °C (onset), 132.4 °C (peak).

IR (KBr): 3440, 2975, 2934, 1550, 1511, 1383, 1220, 1152, 957,

754 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.29–1.37 (m, 6 H), 3.45–3.55 (m,

4 H), 3.57 (s, 3 H), 4.41 (s, 2 H), 7.00–7.07 (m, 1 H), 7.07–7.15 (m,

2 H), 7.15–7.23 (m, 1 H), 7.49–7.57 (m, 1 H), 7.72–7.80 (m, 2 H),

8.36–8.42 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.4, 28.5, 31.7, 33.3, 42.6, 115.5

(d, J = 21.6 Hz), 118.1, 120.0, 122.0, 131.1 (d, J = 8.4 Hz), 134.3

(d, J = 2.7 Hz), 136.3, 149.7, 157.8, 158.1, 163.6 (d, J = 249.6 Hz),

166.3, 177.4.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₉H₂₂FN₄O₂S₃: 453.0883;

found: 453.0885.

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(1-methyl-1H-imidazol-

2-ylthio)methyl]pyrimidin-2-yl}-N-methylmethanesulfon-

amide (4e)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a white crystalline product after dry-

ing; yield: 2.01 g (75%); mp 153.4 °C (onset), 155.6 °C (peak).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₁H₂₄FN₄O₂S₂: 447.1319;

found: 447.1320.

IR (KBr): 3432, 2994, 2971, 1551, 1377, 1334, 1232, 1152, 971,

956, 864, 779 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.29–1.36 (m, 6 H), 3.45–3.57 (m,

10 H), 4.26 (s, 2 H), 6.92 (d, J = 1.3 Hz, 1 H), 7.00 (d, J = 1.3 Hz, 1

H), 7.07–7.16 (m, 2 H), 7.61–7.71 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.2, 31.6, 32.4, 33.1, 33.1, 42.4,

115.4 (d, J = 21.7 Hz), 117.6, 122.7, 129.6, 130.7 (d, J = 8.4 Hz),

133.9 (d, J = 2.6 Hz), 139.9, 157.6, 163.3 (d, J = 249.7 Hz), 166.1,

177.2.

2-({[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}thio)benzo[d]oxazole (5a)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a green crystalline product after dry-

ing; yield: 2.20 g (86%); mp 160.6 °C (onset), 162.3 °C (peak).

IR (KBr): 3396, 3058, 3000, 2948, 2852, 1604, 1577, 1514, 1493,

1452, 1239, 1213, 1122, 1090, 920, 765, 743, 603, 558 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.09–1.16 (m, 2 H), 1.38–1.44 (m,

2 H), 2.48–2.56 (m, 1 H), 4.74 (s, 2 H), 7.16–7.23 (m, 2 H), 7.23–

7.38 (m, 6 H), 7.41–7.45 (m, 1 H), 7.57–7.61 (m, 1 H), 7.62–7.68

(m, 1 H), 7.98–8.03 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.2, 15.1, 32.5, 110.1, 115.8 (d,

J = 21.6 Hz), 118.5, 124.2, 124.5, 124.7, 125.9, 126.4, 129.1, 129.6,

131.1 (d, J = 8.1 Hz), 132.0 (d, J = 2.7 Hz), 141.9, 147.4, 147.7,

151.9, 161.7, 162.8 (d, J = 248.1 Hz), 164.2.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₀H₂₅FN₅O₂S: 450.1428;

found: 450.1421.

N-(5-{[(3,5-Bis(trifluoromethyl)phenylthio]methyl}-4-(4-fluo-

rophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesul-

fonamide (4f)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a white crystalline product after dry-

ing; yield: 2.96 g (85%); mp 169.8 °C (onset), 171.3 °C (peak).

HRMS-ESI: m/z [M + H]⁺calculated for C₂₆H₂₀FN₂OS: 427.1275;

found: 427.1269.

IR (KBr): 3441, 2979, 2936, 1554, 1381, 1355, 1277, 1120, 966,

818, 771, 682 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.38 (d, J = 6.6 Hz, 6 H), 3.46

(sept, J = 6.6 Hz, 1 H), 3.53 (s, 3 H), 3.58 (s, 3 H), 4.21 (s, 2 H),

7.10–7.17 (m, 2 H), 7.60–7.64 (m, 2 H), 7.67–7.75 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.5, 32.0, 32.2, 33.3, 42.6, 115.8

(d, J = 21.7 Hz), 116.5, 120.3, 123.0 (q, J = 273.0 Hz), 128.3, 130.8

(d, J = 8.4 Hz), 132.6 (q, J = 33.6 Hz), 133.9 (d, J = 2.8 Hz), 139.7,

158.2, 163.7 (d, J = 250.8 Hz), 166.5, 177.3.

2-({[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}thio)benzo[d]thiazole (5b)

Prepared according to the procedure described in the literature with

comparable yield;^24emp 147.3 °C (onset), 149.6 °C (peak) (Lit.^24e

122–124 °C).

IR (KBr): 3433, 3062, 3039, 2997, 1606, 1512, 1491, 1462, 1430,

1217, 1160, 1058, 987, 921, 839, 765, 729, 558 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.07–1.17 (m, 2 H), 1.37–1.48 (m,

2 H), 2.50–2.59 (m, 1 H), 4.81 (s, 2 H), 7.15–7.22 (m, 2 H), 7.26–

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₃F₇N₃O₂S₂: 582.1114;

found: 582.1111.

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J. Fabris et al.

PAPER

7.38 (m, 5 H), 7.41–7.47 (m, 1 H), 7.62–7.68 (m, 1 H), 7.74–7.78

(m, 1 H), 7.83–7.88 (m, 1 H), 8.00–8.05 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.1, 15.1, 33.5, 115.7 (d, J = 21.6

Hz), 121.1, 121.6, 124.5, 125.3, 125.8, 126.2, 126.4, 126.4, 129.1,

129.4, 131.1 (d, J = 7.9 Hz), 132.1 (d, J = 2.7 Hz), 135.3, 147.3,

147.4, 153.1, 161.8, 162.7 (d, J = 247.6 Hz), 166.0.

3-{[3,5-Bis(trifluoromethyl)phenyl)thio]methyl}-2-cyclopro-

pyl-4-(4-fluorophenyl)quinoline (5f)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:10) to give a brown crystalline product after dry-

ing; yield: 2.53 g (81%); mp 146.8 °C (onset), 148.5 °C (peak).

IR (KBr): 3436, 3068, 3052, 1515, 1493, 1355, 1275, 1187, 1131,

844, 771, 680 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.12–1.22 (m, 2 H), 1.42–1.52 (m,

2 H), 2.48–2.58 (m, 1 H), 4.38 (s, 2 H), 7.19–7.27 (m, 2 H), 7.28–

7.35 (m, 3 H), 7.36–7.42 (m, 1 H), 7.60–7.65 (m, 2 H), 7.65–7.71

(m, 1 H), 7.71–7.74 (m, 1 H), 8.02–8.08 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.2, 15.1, 34.3, 115.8 (d, J = 21.6

Hz), 120.0, 123.1 (q, J = 273.1 Hz), 125.2, 125.9, 126.4, 126.4,

128.7, 129.1, 129.5, 131.2 (d, J = 7.9 Hz), 132.1 (d, J = 3.0 Hz),

132.3 (q, J = 33.4 Hz), 140.6, 147.2, 147.4, 161.5, 162.8 (d, J =

248.5 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₆H₂₀FN₂S₂: 443.1046; found:

443.1044.

2-Cyclopropyl-4-(4-fluorophenyl)-3-[(1-methyl-1H-ben-

zo[d]imidazol-2-ylthio)methyl]quinoline (5c)

Prepared according to the general procedure; recrystallized from

MeCN–THF (2:1) to give a white crystalline product after drying;

yield: 2.25 g (85%); mp 162.1 °C (onset), 163.7 °C (peak).

IR (KBr): 3437, 3054, 3010, 2933, 1512, 1492, 1445, 1420, 1279,

1215, 924, 738, 733 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.04–1.11 (m, 2 H), 1.36–1.43 (m,

2 H), 2.50–2.58 (m, 1 H), 3.62 (s, 3 H), 4.76 (s, 2 H), 7.12–7.19 (m,

2 H), 7.20–7.37 (m, 7 H), 7.60–7.70 (m, 2 H), 7.98–8.02 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.3, 15.0, 30.1, 32.8, 108.7,

115.7 (d, J = 21.5 Hz), 118.4, 122.1, 122.2, 125.5, 125.7, 126.4,

129.0, 129.4, 131.2 (d, J = 7.8 Hz), 132.2 (d, J = 1.8 Hz), 136.7,

143.4, 147.3, 147.3, 151.5, 162.1, 162.7 (d, J = 247.7 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₇H₁₉F₇NS: 522.1121; found:

522.1123.

2-Cyclopropyl-4-(4-fluorophenyl)-3-{[(4-nitrophe-

nyl)thio]methyl}quinoline (5g)

Prepared according to the general procedure; recrystallized from

MeCN to give a yellow crystalline product after drying; yield: 2.51

g (97%); mp 167.4 °C (onset), 169.6 °C (peak).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₇H₂₃FN₃S: 440.1591; found:

440.1593.

IR (KBr): 3433, 3103, 3014, 3061, 1575, 1507, 1335, 1224, 1092,

925, 838, 770, 742 cm^–1.

2-({[(2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}thio)thiazole (5d)

Prepared according to the general procedure; recrystallized from

CH₂Cl₂–hexane (1:1) to give a dark red crystalline product after

drying; yield: 2.14 g (91%); mp 140.5 °C (onset), 143.1 °C (peak).

¹H NMR (500 MHz, CDCl₃): δ = 1.08–1.16 (m, 2 H), 1.39–1.45 (m,

2 H), 2.45–2.53 (m, 1 H), 4.35 (s, 2 H), 7.19–7.25 (m, 2 H), 7.25–

7.31 (m, 3 H), 7.34–7.40 (m, 3 H), 7.64–7.70 (m, 1 H), 8.00–8.04

(m, 1 H), 8.10–8.16 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.1, 15.0, 32.9, 115.7 (d, J = 21.5

Hz), 124.1, 124.6, 124.7, 125.9, 126.4, 126.5, 129.1, 129.5, 131.1

(d, J = 7.8 Hz), 132.0 (d, J = 3.0 Hz), 145.4, 147.3, 147.3, 147.5,

161.6, 162.8 (d, J = 248.3 Hz).

IR (KBr): 3432, 3067, 3015, 1603, 1551, 1491, 1388, 1219, 1017,

927, 770, 712, 596, 559 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.09–1.15 (m, 2 H), 1.38–1.45 (m,

2 H), 2.50–2.59 (m, 1 H), 4.64 (s, 2 H), 7.17–7.26 (m, 3 H), 7.26–

7.30 (m, 1 H), 7.30–7.38 (m, 3 H), 7.61–7.69 (m, 2 H), 7.99–8.04

(m, 1 H).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₅H₂₀FN₂O₂S: 431.1224;

found: 431.1217.

2-Cyclopropyl-4-(4-fluorophenyl)-3-[(pyridin-2-ylthio)meth-

yl]quinoline (5h)

Prepared according to the general procedure; recrystallized from

MeOH–THF (1:1) to give a white crystalline product after drying;

yield: 2.02 g (87%); mp 168.3 °C (onset), 169.6 °C (peak).

¹³C NMR (125 MHz, CDCl₃): δ = 10.0, 14.9, 34.4, 115.5 (d, J = 21.5

Hz), 119.2, 125.4, 125.6, 126.2, 126.2, 128.9, 129.2, 131.0 (d, J =

8.0 Hz), 131.9 (d, J = 3.0 Hz), 142.7, 147.0, 147.1, 161.6, 162.5 (d,

J = 247.6 Hz), 163.8.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₈FN₂S₂: 393.0890; found:

393.0888.

IR (KBr): 3426, 3039, 3002, 2953, 1578, 1515, 1493, 1451, 1412,

1220, 1122, 926, 767, 754 cm^–1.

2-Cyclopropyl-4-(4-fluorophenyl)-3-[(1-methyl-1H-imidazol-2-

ylthio)methyl]quinoline (5e)

Prepared according to the general procedure; CH₂Cl₂–hexane (1:2)

to give a brown crystalline product after drying; yield: 1.85 g (79%);

mp 127.3 °C (onset), 129.6 °C (peak).

¹H NMR (500 MHz, CDCl₃): δ = 1.02–1.12 (m, 2 H), 1.34–1.47 (m,

2 H), 2.50–2.60 (m, 1 H), 4.60 (s, 2 H), 6.96–7.03 (m, 1 H), 7.10–

7.25 (m, 3 H), 7.25–7.40 (m, 4 H), 7.44–7.52 (m, 1 H), 7.59–7.68

(m, 1 H), 7.97–8.06 (m, 1 H), 8.34–8.43 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.0, 15.0, 30.0, 115.5 (d, J = 21.5

Hz), 119.6, 121.8, 125.6, 126.2, 126.5, 126.9, 129.0, 129.0, 131.3

(d, J = 8.0 Hz), 132.5 (d, J = 2.9 Hz), 136.0, 146.8, 147.0, 149.5,

158.8, 162.1, 162.6 (d, J = 247.1 Hz).

IR (KBr): 3429, 3066, 2999, 2961, 1513, 1493, 1280, 1221, 1159,

841, 765, 729, 604, 559 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.01–1.10 (m, 2 H), 1.28–1.37 (m,

2 H), 2.44–2.53 (m, 1 H), 3.33 (s, 3 H), 4.32 (s, 2 H), 6.86 (d, J =

1.2 Hz, 1 H), 7.01 (d, J = 1.2 Hz, 1 H), 7.12–7.21 (m, 5 H), 7.23–

7.29 (m, 1 H), 7.52–7.58 (m, 1 H), 7.90–7.95 (m, 1 H).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₀FN₂S: 387.1326; found:

387.1327.

Sulfone Heterocyclic Precursors; General Procedure

¹³C NMR (125 MHz, CDCl₃): δ = 10.2, 14.7, 33.1, 34.5, 115.4 (d,

J = 21.5 Hz), 122.6, 125.5, 126.1, 126.2, 126.3, 128.8, 129.0, 129.6,

131.0 (d, J = 7.9 Hz), 132.1 (d, J = 2.9 Hz), 140.4, 146.5, 146.9,

161.8, 162.4 (d, J = 247.6 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₁FN₃S: 390.1428; found:

390.1435.

mCPBA (77%, 2.24 g, 10 mmol, 5 equiv) was added to a THF (25

mL) solution of a sulfide heterocyclic precursor 4 or 5 (2 mmol, 1

equiv) and left to stir at r.t. for 17 h. After quenching the reaction

with sat. aq Na₂S₂O₃(25 mL), THF was evaporated. EtOAc (50 mL)

was added to the residue and the aqueous phase was separated. The

organic phase was washed with H₂O (25 mL), sat. aq NaHCO₃(2 ×

25 mL), and brine (25 mL), respectively. The organic layer was

dried (MgSO₄) and the solvent was evaporated in vacuo to give an

impure solid or oily residue. Subsequent purification by recrystalli-

zation or silica gel column chromatography provided pure products

Synthesis 2014, 46, 2333–2346

PAPER

Statins via Julia–Kocienski Reaction with Lactonized Precursor

2341

6 or 7, which were dried in vacuum overnight at 60 °C below 50

mbar.

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(thiazol-2-ylsulfo-

nyl)methyl]pyrimidin-2-yl}-N-methylmethanesulfonamide (6d)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) and triturated with Et₂O to provide a white

crystalline product after drying; yield: 484 mg (50%); mp 141.7 °C

(onset), 145.6 °C (peak).

N-{5-[(Benzo[d]oxazol-2-ylsulfonyl)methyl]-4-(4-fluorophe-

nyl)-6-isopropylpyrimidin-2-yl}-N-methylmethanesulfon-

amide (6a)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) and recrystallized from MeOH to provide a

yellow crystalline product after drying; yield: 184 mg (18%); mp

161.8 °C (onset), 168.0 °C (peak).

IR (KBr): 3440, 2967, 2943, 1604, 1552, 1510, 1380, 1332, 1225,

1161, 1130, 957, 913, 772, 765, 540 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.29–1.40 (m, 6 H), 3.49 (s, 3 H),

3.51–3.58 (m, 4 H), 4.94 (s, 2 H), 7.06–7.14 (m, 2 H), 7.41–7.48 (m,

2 H), 7.71 (d, J = 3.0 Hz, 1 H), 7.92 (d, J = 3.0 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.8, 33.3, 42.6, 53.6, 109.5,

115.8 (d, J = 21.7 Hz), 126.9, 131.0 (d, J = 8.4 Hz), 133.6 (d, J = 2.6

Hz), 145.5, 158.5, 163.4 (d, J = 250.1 Hz), 165.0, 168.3, 178.8.

IR (KBr): 3431, 2974, 2960, 2870, 1607, 1548, 1511, 1377, 1349,

1154, 1124, 968, 798, 746, 704, 575, 524, 509 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.33–1.43 (m, 6 H), 3.48 (s, 3 H),

3.50–3.57 (m, 4 H), 5.08 (s, 2 H), 6.79–6.89 (m, 2 H), 7.24–7.30 (m,

2 H), 7.50–7.62 (m, 3 H), 7.80–7.85 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.0, 32.9, 33.3, 42.6, 53.6, 108.7,

112.1, 115.7 (d, J = 21.8 Hz), 122.4, 126.6, 129.1, 130.6 (d, J = 8.4

Hz), 133.1 (d, J = 2.8 Hz), 139.6, 151.3, 157.6, 158.6, 163.2 (d, J =

250.5 Hz), 167.9, 179.0.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₉H₂₂FN₄O₄S₃: 485.0782;

found: 485.0782.

N-(4-(4-Fluorophenyl)-6-isopropyl-5-{[(1-methyl-1H-imidazol-

2-yl)sulfonyl]methyl}pyrimidin-2-yl)-N-methylmethanesulfon-

amide (6e)

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₄FN₄O₅S₂: 519.1167;

Prepared according to the general procedure, but on a 1.50 mmol

scale (the molar ratio of all compounds involved in the reaction re-

mained the same). The crude reaction mixture was purified by silica

gel column chromatography (EtOAc–hexane, 1:1) to provide a

white crystalline product after drying; yield: 527 mg (73%); mp

183.8 °C (onset), 185.3 °C (peak).

found: 519.1162.

N-{5-[(Benzo[d]thiazol-2-ylsulfonyl)methyl]-4-(4-fluorophe-

nyl)-6-isopropylpyrimidin-2-yl}-N-methylmethanesulfon-

amide (6b)

Prepared according to procedure described in the literature with

comparable yield;^24emp 187.4 °C (onset), 189.0 °C (peak) (Lit.^24e

189–190 °C).

IR (KBr): 3434, 2964, 2937, 1604, 1548, 1509, 1379, 1327, 1224,

1124, 974, 959, 836, 761, 618, 528 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.27–1.36 (m, 6 H), 3.49 (s, 3 H),

3.50–3.53 (m, 1 H), 3.54 (s, 3 H), 3.59 (s, 3 H), 4.95 (s, 2 H), 6.93

(d, J = 0.9 Hz, 1 H), 7.03 (d, J = 0.9 Hz, 1 H), 7.07–7.13 (m, 2 H),

7.40–7.45 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.7, 33.3, 34.9, 42.6, 53.3,

109.4, 115.7 (d, J = 21.7 Hz), 126.3, 129.7, 131.0 (d, J = 8.4 Hz),

133.8 (d, J = 2.7 Hz), 141.3, 158.4, 163.4 (d, J = 250.1 Hz), 168.3,

178.9.

IR (KBr): 3425, 3038, 3005, 2971, 2930, 2872, 1606, 1550, 1511,

1433, 1402, 1373, 1339, 1331, 1227, 1154, 1124, 1066, 969, 908,

853, 836, 775, 758, 604, 563, 506 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.31–1.42 (m, 6 H), 3.47 (s, 3 H),

3.54 (s, 3 H), 3.55–3.62 (m, 1 H), 5.06 (s, 2 H), 6.75–6.82 (m, 2 H),

7.20–7.26 (m, 2 H), 7.58–7.67 (m, 2 H), 7.94–7.98 (m, 1 H), 8.04–

8.09 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.8, 33.2, 42.5, 53.5, 109.5,

115.5 (d, J = 21.8 Hz), 122.3, 125.7, 127.9, 128.4, 130.6 (d, J = 8.4

Hz), 133.2 (d, J = 2.3 Hz), 137.3, 152.6, 158.4, 163.1 (d, J = 250.1

Hz), 164.9, 167.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₀H₂₅FN₅O₄S₂: 482.1327;

found: 482.1320.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₄FN₄O₄S₃: 535.0938;

found: 535.0939.

N-[5-({[3,5-Bis(trifluoromethyl)phenyl]sulfonyl}methyl)-4-(4-

fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethane-

sulfonamide (6f)

N-(4-(4-Fluorophenyl)-6-isopropyl-5-{[(1-methyl-1H-ben-

zo[d]imidazol-2-yl)sulfonyl]methyl}pyrimidin-2-yl)-N-methyl-

methanesulfonamide (6c)

Prepared according to the general procedure. The crude reaction

mixture was triturated with Et₂O to provide a white crystalline prod-

uct after drying; yield: 755 mg (71%); mp 141.7 °C (onset),

146.2 °C (peak).

Prepared according to the general procedure. The crude reaction

mixture was triturated with Et₂O to provide a white crystalline prod-

uct after drying; yield: 1054 mg (86%); mp 218.1 °C (onset),

219.2 °C (peak).

IR (KBr): 3433, 3085, 3055, 2960, 1556, 1516, 1340, 1284, 1156,

1134, 964, 908, 841, 776, 582 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.30–1.48 (m, 6 H), 3.49 (s, 3 H),

3.52–3.61 (m, 4 H), 4.74 (s, 2 H), 6.97–7.05 (m, 2 H), 7.13–7.22 (m,

2 H), 7.80–7.89 (m, 2 H), 8.04–8.12 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.9, 33.3, 42.6, 54.6, 109.5,

116.0 (d, J = 21.9 Hz), 122.2 (q, J = 273.6 Hz), 127.8, 128.5, 130.5

(d, J = 8.3 Hz), 133.3, 133.4 (q, J = 34.9 Hz), 141.8, 158.6, 163.4

(d, J = 252.0 Hz), 167.7, 178.8.

IR (KBr): 3435, 2971, 2932, 1608, 1547, 1513, 1442, 1377, 1338,

1333, 1156, 1132, 964, 910, 744, 564 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.25–1.45 (m, 6 H), 3.47 (s, 3 H),

3.50–3.64 (m, 4 H), 3.72 (s, 3 H), 5.15 (s, 2 H), 6.77–6.88 (m, 2 H),

7.16–7.29 (m, 2 H), 7.32–7.43 (m, 2 H), 7.43–7.52 (m, 1 H), 7.69–

7.80 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.0, 31.3, 32.8, 33.2, 42.6, 53.2,

109.0, 110.7, 115.5 (d, J = 21.8 Hz), 121.9, 124.3, 126.4, 130.6 (d,

J = 8.4 Hz), 133.3 (d, J = 2.2 Hz), 136.3, 140.9, 146.5, 158.5, 163.2

(d, J = 250.2 Hz), 168.0, 179.2.

HRMS-ESI: m/z [M – H]^–calcd for C₂₄H₂₁F₇N₃O₄S₂: 612.0867;

found: 612.0857.

N-(4-(4-Fluorophenyl)-6-isopropyl-5-{[(4-nitrophenyl)sulfo-

nyl]methyl}pyrimidin-2-yl)-N-methylmethanesulfonamide (6g)

Prepared according to the general procedure. The crude reaction

mixture was triturated with Et₂O to provide a bright yellow crystal-

line product after drying; yield: 794 mg (76%); mp 191.0 and

201.2 °C (onset), 196.6 and 203.5 °C (peak).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₇FN₅O₄S₂: 532.1483;

found: 532.1479.

Synthesis 2014, 46, 2333–2346

2342

J. Fabris et al.

PAPER

IR (KBr): 3435, 3112, 2963, 1606, 1534, 1376, 1227, 1157, 967,

611 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.28–1.46 (m, 6 H), 3.48 (s, 3 H),

3.52–3.60 (m, 4 H), 4.71 (s, 2 H), 6.97–7.07 (m, 2 H), 7.16–7.24 (m,

2 H), 7.57–7.67 (m, 2 H), 8.16–8.25 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.7, 15.7, 56.0, 115.5 (d, J = 21.6

Hz), 118.0, 122.3, 125.5, 125.9, 126.3, 126.6, 127.8, 128.2, 129.1,

130.1, 131.5 (br s), 137.0, 147.7, 149.6, 152.6, 162.2, 162.5 (d, J =

248.3 Hz), 166.2.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₆H₂₀FN₂O₂S₂: 475.0945;

found: 475.0944.

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.9, 33.3, 42.7, 54.3, 109.5,

115.8 (d, J = 21.7 Hz), 124.5, 129.6, 130.8 (d, J = 8.3 Hz), 133.5 (d,

J = 2.7 Hz), 144.3, 151.1, 158.5, 163.3 (d, J = 251.4 Hz), 167.4,

178.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₂₄FN₄O₆S₂: 523.1116;

found: 523.1111.

2-Cyclopropyl-4-(4-fluorophenyl)-3-{[(1-methyl-1H-ben-

zo[d]imidazol-2-yl)sulfonyl]methyl}quinoline (7c)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) to provide a bright yellow crystalline product

after drying; yield: 462 mg (49%); mp 198.2 °C (onset), 199.3 °C

(peak).

N-{4-(4-Fluorophenyl)-6-isopropyl-5-[(pyridin-2-ylsulfo-

nyl)methyl]pyrimidin-2-yl}-N-methylmethanesulfonamide (6h)

Prepared according to the general procedure. The crude reaction

mixture was triturated with Et₂O to provide a white crystalline prod-

uct after drying; yield: 889 mg (93%); mp 178.5 °C (onset),

180.7 °C (peak).

IR (KBr): 3434, 2924, 1513, 1334, 1229, 1162, 1130, 816, 759, 744,

630, 582 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.87–0.98 (m, 2 H), 1.18–1.35 (m,

2 H), 2.42–2.52 (m, 1 H), 3.75 (s, 3 H), 5.32 (s, 2 H), 6.97–7.09 (m,

2 H), 7.15–7.24 (m, 3 H), 7.29–7.36 (m, 1 H), 7.35–7.44 (m, 2 H),

7.45–7.52 (m, 1 H), 7.62–7.70 (m, 1 H), 7.78–7.85 (m, 1 H), 7.95–

8.03 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.7, 15.4, 31.5, 55.8, 110.6,

115.6 (d, J = 21.6 Hz), 117.6, 122.0, 124.3, 126.0, 126.3, 126.4,

126.6, 129.2, 130.2, 131.7 (d, J = 2.9 Hz), 131.7 (br s), 136.4, 140.9,

147.8, 150.1, 162.4, 162.7 (d, J = 248.4 Hz).

IR (KBr): 3436, 3085, 2970, 2932, 1606, 1550, 1510, 1378, 1337,

1230, 1167, 1153, 977, 607 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.34 (d, J = 6.5 Hz, 6 H), 3.48 (s,

3 H), 3.54 (s, 3 H), 3.59 (sept, J = 6.5 Hz, 1 H), 4.92 (s, 2 H), 7.00–

7.09 (m, 2 H), 7.37–7.44 (m, 2 H), 7.48–7.53 (m, 1 H), 7.82–7.91

(m, 2 H), 8.50–8.56 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 32.7, 33.2, 42.6, 50.4, 110.2,

115.6 (d, J = 21.7 Hz), 122.4, 127.7, 131.0 (d, J = 8.4 Hz), 133.9,

138.3, 150.4, 157.2, 158.3, 163.2 (d, J = 249.7 Hz), 167.9, 178.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₇H₂₃FN₃O₂S: 472.1490;

found: 472.1488.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₁H₂₄FN₄O₄S₂: 479.1218;

found: 479.1220.

2-({[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}sulfonyl)thiazole (7d)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) to provide a white crystalline product after

drying; yield: 237 mg (28%); mp 182.3 °C (onset), 183.5 °C (peak).

2-({[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}sulfonyl)benzo[d]oxazole (7a)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) and triturated with Et₂O to provide white

crystalline product after drying; yield: 174 mg (19%); mp 173.1 °C

(onset), 174.8 °C (peak).

IR (KBr): 3447, 3083, 1604, 1513, 1492, 1330, 1222, 1147, 1053,

922, 838, 767, 744, 712, 656, 597 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.02–1.10 (m, 2 H), 1.21–1.38 (m,

2 H), 2.45–2.53 (m, 1 H), 5.08 (s, 2 H), 7.13–7.28 (m, 5 H), 7.30–

7.35 (m, 1 H), 7.62–7.68 (m, 1 H), 7.70 (d, J = 3.0 Hz, 1 H), 7.97

(d, J = 3.0 Hz, 1 H), 7.98–7.99 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.7, 15.6, 56.2, 115.7 (d, J = 21.5

Hz), 118.0, 126.0, 126.5, 126.6, 126.7, 129.1, 130.2, 131.7 (d, J =

2.9 Hz), 131.7 (br s), 145.3, 147.8, 149.9, 162.1, 162.7 (d, J = 248.1

Hz), 166.1.

IR (KBr): 3438, 3095, 3007, 2991, 1604, 1515, 1492, 1447, 1342,

1227, 1145, 1125, 799, 765, 627, 603 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.95–1.11 (m, 2 H), 1.21–1.41 (m,

2 H), 2.44–2.56 (m, 1 H), 5.21 (s, 2 H), 6.91–7.09 (m, 2 H), 7.15–

7.24 (m, 3 H), 7.28–7.37 (m, 1 H), 7.48–7.56 (m, 1 H), 7.56–7.63

(m, 2 H), 7.63–7.71 (m, 1 H), 7.81–7.89 (m, 1 H), 7.94–8.04 (m, 1

H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.6, 15.7, 56.3, 112.1, 115.7 (d,

J = 21.6 Hz), 117.3, 122.4, 126.1, 126.4, 126.5, 126.6, 128.9, 129.2,

130.4, 131.5 (br s), 139.6, 147.9, 149.9, 151.2, 158.6, 162.0, 162.7

(d, J = 248.6 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₈FN₂O₂S₂: 425.0788;

found: 425.0781.

2-Cyclopropyl-4-(4-fluorophenyl)-3-[(thiazol-2-ylsulfo-

nyl)methyl]quinoline 1-Oxide (7d′)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) to provide a bright yellow product after dry-

ing; yield: 238 mg (27%); mp 200.1 °C (onset), 203.5 °C (peak).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₆H₂₀FN₂O₃S: 459.1173;

found: 459.1169.

2-({[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-

yl}sulfonyl)benzo[d]thiazole (7b)

Prepared according to procedure described in the literature with

comparable yield;^24emp 160.9 °C (onset), 162.9 °C (peak) (Lit.^24e

159–161 °C).

IR (KBr): 3425, 3115, 2960, 1599, 1508, 1381, 1364, 1323, 1219,

1176, 1143, 1063, 841, 763, 705, 556 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.92–1.07 (m, 2 H), 1.27–1.37 (m,

2 H), 1.89–1.99 (m, 1 H), 5.11 (s, 2 H), 7.10–7.30 (m, 5 H), 7.43–

7.50 (m, 1 H), 7.68–7.75 (m, 2 H), 7.91–7.97 (m, 1 H), 8.73–8.79

(m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 9.7, 11.8, 56.1, 115.8 (d, J = 21.6

Hz), 121.3, 127.0, 127.4, 128.5, 128.6, 130.7 (d, J = 3.0 Hz), 131.1,

132.3 (br s), 139.3, 141.6, 145.3, 147.8, 162.8 (d, J = 249.1 Hz),

165.3.

IR (KBr): 3434, 3074, 3017, 2998, 2929, 1603, 1513, 1492, 1469,

1398, 1332, 1314, 1225, 1160, 1141, 1124, 1023, 920, 869, 840,

767, 730, 707, 601, 556, 521, 506, 490 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.98–1.10 (m, 2 H), 1.21–1.43 (br

s, 2 H), 2.53–2.63 (m, 1 H), 5.22 (s, 2 H), 6.88–7.03 (m, 2 H), 7.12–

7.21 (m, 3 H), 7.27–7.35 (m, 1 H), 7.55–7.61 (m, 1 H), 7.61–7.69

(m, 2 H), 7.92–8.02 (m, 2 H), 8.09–8.15 (m, 1 H).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₈FN₂O₃S₂: 441.0737;

found: 441.0742.

Synthesis 2014, 46, 2333–2346

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Statins via Julia–Kocienski Reaction with Lactonized Precursor

2343

2-Cyclopropyl-4-(4-fluorophenyl)-3-{[(1-methyl-1H-imidazol-

2-yl)sulfonyl]methyl}quinoline (7e)

IR (KBr): 3434, 3049, 2991, 1512, 1493, 1306, 1222, 1145, 1110,

923, 840, 764, 592 cm^–1.

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:1) and triturated with Et₂O to provide a white

crystalline product after drying; yield: 556 mg (66%); mp 167.6 °C

(onset), 169.4 C (peak).

¹H NMR (500 MHz, CDCl₃): δ = 0.99–1.09 (m, 2 H), 1.23–1.39 (m,

2 H), 2.53–2.64 (m, 1 H), 5.07 (s, 2 H), 7.04–7.13 (m, 2 H), 7.12–

7.24 (m, 3 H), 7.27–7.34 (m, 1 H), 7.47–7.54 (m, 1 H), 7.58–7.66

(m, 1 H), 7.82–7.92 (m, 2 H), 7.93–8.00 (m, 1 H), 8.56–8.64 (m, 1

H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.6, 15.7, 53.1, 115.5 (d, J = 21.5

Hz), 119.0, 122.2, 125.8, 126.5, 126.5, 127.5, 129.1, 129.9, 131.7

(br s), 131.9, 138.2, 147.6, 149.3, 150.3, 158.1, 162.4, 162.5 (d, J =

247.7 Hz).

IR (KBr): 3433, 3141, 2936, 1604, 1513, 1492, 1325, 1243, 1157,

922, 776, 720, 601, 490 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.98–1.10 (m, 2 H), 1.15–1.44 (m,

2 H), 2.35–2.48 (m, 1 H), 3.57 (s, 3 H), 5.10 (s, 2 H), 6.91–7.02 (m,

1 H), 7.10–7.16 (m, 1 H), 7.16–7.30 (m, 5 H), 7.32–7.40 (m, 1 H),

7.62–7.72 (m, 1 H), 7.95–8.04 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.6, 15.2, 34.9, 56.0, 115.5 (d,

J = 21.5 Hz), 117.9, 126.0, 126.2, 126.4, 126.6, 129.0, 129.5, 130.1,

131.8 (d, J = 2.8 Hz), 131.8 (br s), 142.3, 147.7, 150.1, 162.2, 162.7

(d, J = 248.2 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₀FN₂O₂S: 419.1224;

found: 419.1228.

Screening of the Olefination Step Between Aldehyde 1 and Sul-

fone-Derivatized Heterocyclic Precursors 6 and 7

A solution of 1′ (66 mg, 0.24 mmol, 1.2 equiv) in anhydrous CH₂Cl₂

(10 mL) was stirred at r.t. for 2 h. Then, it was warmed to 50 °C and

purged with N₂to remove the mixture of CH₂Cl₂and released H₂O.

THF (5 mL) was then added to the resulting residue to form an an-

hydrous solution of pure aldehyde 1. A three-necked reaction flask

containing the sulfone heterocyclic precursor (0.2 mmol, 1 equiv)

was dried at 85 °C under vacuum for 2 h and then cooled to r.t. un-

der N₂. Sulfone 6 or 7 was dissolved in anhydrous THF (10 mL) and

the flask was cooled in a cryostated EtOH bath to –60 °C. A solu-

tion of 1 M NaHMDS in THF (220 μL, 0.22 mmol, 1.1 equiv) was

then added to the mixture to form a colored solution. After 5 min,

the formerly prepared solution of aldehyde 1 was rapidly added to

the reaction mixture with vigorous stirring. The reaction was com-

pleted within few seconds, which was indicated by loss of color.

Sat. aq NH₄Cl (5 mL) was added to the mixture, which was then

slowly warmed to r.t. THF was evaporated under reduced pressure

and EtOAc (50 mL) was added to the residue. The organic phase

was washed with H₂O (25 mL) and sat. aq NaHCO₃(25 mL), dried

(MgSO₄) and concentrated in vacuo. The crude reaction product

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₂₁FN₃O₂S: 422.1333;

found: 422.1332.

3-({[3,5-Bis(trifluoromethyl)phenyl]sulfonyl}methyl)-2-cyclo-

propyl-4-(4-fluorophenyl)quinoline (7f)

Prepared according to the general procedure. The crude reaction

mixture was triturated with Et₂O to provide a white crystalline prod-

uct after drying; yield: 830 mg (75%); mp 163.5 °C (onset),

164.5 °C (peak).

IR (KBr): 3433, 1513, 1494, 1360, 1340, 1276, 1151, 1107, 910,

843, 767, 681, 587 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.00–1.18 (m, 2 H), 1.18–1.50 (m,

2 H), 2.47–2.60 (m, 1 H), 4.82 (s, 2 H), 7.10–7.25 (m, 5 H), 7.31–

7.39 (m, 1 H), 7.64–7.72 (m, 1 H), 7.92–8.05 (m, 3 H), 8.08–8.15

(m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.9, 15.7, 57.7, 115.9 (d, J = 21.6

Hz), 117.8, 122.3 (q, J = 273.3 Hz), 126.2, 126.5, 127.5, 128.6,

129.3, 130.4, 131.7 (br s), 131.7, 133.4 (q, J = 34.5 Hz), 143.0,

148.0, 149.7, 161.8, 162.8 (d, J = 250.1 Hz).

1

was analyzed with HPLC and H NMR spectroscopy. Results of

these reactions are gathered in Table 1.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₇H₁₉F₇NO₂S: 554.1019;

found: 554.1017.

Optimization of the Olefination Step Between Sulfone Precur-

sors 6b and 7b with Aldehyde 1

A solution of 1′ (0.90–1.50 equiv) in anhydrous CH₂Cl₂(10 mL)

was stirred at r.t. for 2 h. Then, it was warmed to 50 °C and purged

with N₂to remove the mixture of CH₂Cl₂and released H₂O. Solvent

(5 mL) was then added to the resulting residue to form an anhydrous

solution of pure aldehyde 1. A three-necked reaction flask contain-

ing the sulfone precursor 6b or 7b (1 equiv) was dried at 85 °C un-

der vacuum for 2 h and then cooled to r.t. under N₂. Sulfone 6b or

7b was dissolved in anhydrous solvent (10 mL) and the flask was

cooled in a cryostated EtOH bath to –50, –60, or –70 °C. A solution

of base (1.1–1.5 equiv) was then added to the mixture to form a col-

ored solution. After 5 min, the formerly prepared solution of alde-

hyde 1 was rapidly added to the reaction mixture with vigorous

stirring. The reaction was completed within few seconds, which was

indicated by loss of color. Sat. aq NH₄Cl (5 mL) was added to the

reaction mixture, which was then slowly warmed to r.t. The solvent

was evaporated under reduced pressure and EtOAc (50 mL) was

added to the residue. The organic phase was washed with H₂O (25

mL) and sat. aq NaHCO₃(25 mL), dried (MgSO₄), and concentrated

in vacuo. The crude reaction product was analyzed with HPLC [6b,

t_R= 22.8 min; 7b, t_R= 25.0 min; (E)-8, t_R= 27.0 min; (Z)-8, t_R=

25.5 min; (E)-9, t_R= 34.0 min; (Z)-9, t_R= 33.5 min; ArOH t_R= 14.5

min]. Results of these reactions are collected in Table 2 (see also the

discussion part for the solvents used).

2-Cyclopropyl-4-(4-fluorophenyl)-3-{[(4-nitrophenyl)sulfo-

nyl]methyl}quinoline (7g)

Compound was prepared according to the general procedure. The

crude reaction mixture was purified by silica gel column chroma-

tography (EtOAc–hexane, 1:4) to provide a white crystalline prod-

uct after drying; yield: 638 mg (69%); mp 180.5 °C (onset),

182.6 °C (peak).

IR (KBr): 3436, 2924, 1606, 1533, 1349, 1306, 1159, 1144, 1084,

924, 855, 872, 765 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.98–1.09 (m, 2 H), 1.17–1.39 (m,

2 H), 2.44–2.52 (m, 1 H), 4.79 (s, 2 H), 7.13–7.23 (m, 5 H), 7.31–

7.37 (m, 1 H), 7.64–7.70 (m, 1 H), 7.74–7.79 (m, 2 H), 7.96–8.01

(m, 1 H), 8.26–8.32 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 10.9, 15.7, 57.3, 115.8 (d, J = 21.5

Hz), 117.9, 124.5, 126.2, 126.3, 126.6, 129.2, 129.8, 130.3, 131.7

(d, J = 3.1 Hz), 131.8 (br s), 145.6, 147.8, 149.7, 151.0, 161.8, 162.7

(d, J = 249.1 Hz).

HRMS-ESI: m/z [M + H]⁺calcd for C₂₅H₂₀FN₂O₄S: 463.1122;

found: 463.1122.

2-Cyclopropyl-4-(4-fluorophenyl)-3-[(pyridin-2-ylsulfo-

nyl)methyl]quinoline (7h)

Prepared according to the general procedure. The crude reaction

mixture was purified by silica gel column chromatography

(EtOAc–hexane, 1:4) to provide a white crystalline product after

drying; yield: 426 mg (51%); mp 152.3 °C (onset), 153.4 °C (peak).

The Final Preparative Process of the Olefination Between Ben-

zothiazole Sulfone Precursors 6b and 7b with Aldehyde 1 on a 1

mmol scale; General Procedure

A solution of 1′ (0.330 g, 1.20 mmol, 1.20 equiv) in anhydrous

CH₂Cl₂(25 mL) was stirred at r.t. for 2 h. Then it was warmed to

Synthesis 2014, 46, 2333–2346

2344

J. Fabris et al.

PAPER

50 °C and purged with N₂to remove the mixture of CH₂Cl₂and re-

leased H₂O. THF (12.5 mL) was then added to the resulting residue

to form an anhydrous solution of pure aldehyde 1. A three-necked

reaction flask containing compound 6b or 7b (1 mmol, 1 equiv) was

dried at 85 °C under vacuum for 2 h and then cooled to r.t. under N₂.

Sulfone 6b or 7b was dissolved in anhydrous THF (25 mL) and the

flask was cooled in a cryostated EtOH bath to –60 °C. A solution of

1 M NaHMDS in THF (1.30 mL, 1.30 mmol, 1.30 equiv) was then

added to the mixture to form a colored solution. After 5 min the for-

merly prepared solution of aldehyde 1 was rapidly added to the re-

action mixture with vigorous stirring. The reaction was completed

within few seconds, which was indicated by the loss of color. Sat.

aq NH₄Cl (15 mL) was added to the mixture, which was then slowly

warmed to r.t. THF was evaporated under reduced pressure and

EtOAc (50 mL) was added to the residue. The organic phase was

washed with H₂O (50 mL) and sat. aq NaHCO₃(50 mL), dried

(MgSO₄), and concentrated in vacuo.

Acknowledgment

L. Kolenc, T. Tome, S. Borišek, and M. Borišek are acknowledged

for assistance in some analytical work. D. Orkič is gratefully ack-

nowledged for support on LC-MS and MS-MS analyses as well as

Dr. D. Urankar (University of Ljubljana) for HRMS analysis, and

Prof. J. Košmrlj (University of Ljubljana) for valuable discussions.

The authors thank Lek Pharmaceuticals d.d. and EN-FIST Centre of

Excellence for support of this project. J. Fabris thanks Public Agen-

cy for Technology of the Republic of Slovenia (TIA) for a young re-

searcher fellowship (MR-10/75). Operation part was financed by

the European Union, European Social Fund.

Supporting Information for this article is available online

at

http://www.thieme-connect.com/products/ejournals/journal/

10.1055/s-00000084.SunogIpimrfiantoSuIpg

n

fonirtat

ori

N-(5-{(E)-2-[(2S,4R)-4-(tert-Butyldimethylsilyloxy)-6-oxotetra-

hydro-2H-pyran-2-yl]vinyl}-4-(4-fluorophenyl)-6-isopropyl-

pyrimidin-2-yl)-N-methylmethanesulfonamide [(E)-8)]

Synthesized according to the above described preparative general

procedure. The desired product was purified by silica gel column

chromatography (Et₂O–methylcyclohexane, 1:3) to provide a white

amorphous solid after drying at 60 °C below 50 mbar; yield: 381 mg

(66%); HPLC purity: 97.1 area%.

References

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IR (KBr): 3443, 3071, 2957, 2929, 2855, 1731, 1547, 1511, 1442,

1383, 1234, 1156, 1076, 968, 839, 777, 615, 564 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89

(s, 9 H), 1.27 (d, J = 6.7 Hz, 6 H), 1.51–1.83 (m, 2 H), 2.53–2.68

(m, 2 H), 3.34 (sept, J = 6.7 Hz, 1 H), 3.51 (s, 3 H), 3.58 (s, 3 H),

4.23–4.33 (m, 1 H), 5.12–5.25 (m, 1 H), 5.49 (dd, J = 16.1, 5.8 Hz,

1 H), 6.70 (dd, J = 16.1, 1.3 Hz, 1 H), 7.03–7.17 (m, 2 H), 7.55–7.70

(m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = –4.90, –4.82, 18.0, 21.6, 21.7,

25.7, 32.3, 33.1, 36.4, 39.4, 42.5, 63.3, 75.4, 115.1 (d, J = 21.7 Hz),

120.6, 125.5, 132.1 (d, J = 8.4 Hz), 134.3 (d, J = 3.3 Hz), 134.8,

157.6, 163.3 (d, J = 250 Hz), 163.7, 169.6, 175.0.

(6) Also known as mevinolin, with a brand name of Mevacor^®

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HRMS-ESI (+): m/z [M + H]⁺calcd for C₂₈H₄₁FN₃O₅SSi: 578.2520;

found: 578.2540.

(4R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-6-{(E)-2-[2-cyclopro-

pyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}tetrahydro-2H-py-

ran-2-one [(E)-9]

Synthesized according to the above described preparative general

procedure. The desired product was purified by silica gel column

chromatography (MTBE–methylcyclohexane, 1:5) to provide a

white crystalline solid after drying at 60 °C below 50 mbar; yield:

369 mg (71%); mp 157.0 °C (onset) and 159.3 °C (peak) [Lit.^27a

157.2 °C (onset) and 159.2 °C (peak)]; HPLC purity: 98.4 area%.

(7) Also known as velostatin, with a brand name of Zocor^®

(Merck & Co). For selected literature, see: Hoffman, W. F.;

Alberts, A. W.; Anderson, P. S.; Chen, J. S.; Smith, R. L.;

Willard, A. K. J. Med. Chem. 1986, 29, 849.

(8) FDA approved in 1996, also known as eptastatin with a

brand name of Pravachol^®(Bristol–Myers Squibb). For

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Y.; Tanzawa, K.; Arai, M.; Kaneko, I.; Tanaka, M.; Masuda,

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IR (KBr): 3440, 3065, 3003, 2950, 2926, 2895, 2855, 1741, 1606,

1516, 1492, 1344, 1252, 1241, 1222, 1163, 1074, 1046, 930, 847,

837, 775, 767 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.86

(s, 9 H), 0.99–1.06 (m, 2 H), 1.29–1.36 (m, 2 H), 1.48 (ddd, J = 2.6,

11.2, 13.9 Hz, 1 H), 1.56–1.63 (m, 1 H), 2.35–2.43 (m, 1 H), 2.49–

2.60 (m, 2 H), 4.20–4.26 (m, 1 H), 5.07–5.15 (m, 1 H), 5.63 (dd, J =

6.6, 16.2 Hz, 1 H), 6.65 (dd, J = 1.2, 16.2 Hz, 1 H), 7.11–7.22 (m, 4

H), 7.29 (ddd, J = 1.2, 6.7, 8.2 Hz, 1 H), 7.34 (dd, J = 1.1, 8.4 Hz, 1

H), 7.57 (ddd, J = 1.5, 6.7, 8.3 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = –4.7 (d, J = 10.7 Hz), 10.6 (d, J =

5.4 Hz), 16.0, 18.1, 25.8, 36.8, 39.4, 63.5, 76.1, 115.5 (dd, J = 11.4

Hz, J = 21.4 Hz), 125.7, 126.0, 126.2, 128.4, 128.8, 129.1, 129.1,

132.0 (dd, J = 7.8 Hz, J = 43.5 Hz), 133.4 (d, J = 3.2 Hz), 135.1,

144.7, 147.2, 160.7, 162.4 (d, J = 247.4 Hz), 170.0.

HRMS-ESI (+): m/z [M + H]⁺calcd for C₃₁H₃₇FNO₃Si: 518.2521;

found: 518.2519.

Synthesis 2014, 46, 2333–2346

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Statins via Julia–Kocienski Reaction with Lactonized Precursor

2345

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Article Doi

Highly stereoselective formal synthesis of rosuvastatin and pitavastatin through Julia-Kocienski olefination using the lactonized statin side-chain precursor

DOI: 10.1055/s-0033-1338648

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