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Synthesis and Chromatographic Evaluation of the New Phase Heptakis
(3-O-pentaluoropropionyl- 2 , 6 - di
-O-pentyl) -
β
- cyclodex trin
Anderson S. Mallmann, Eduardo M. Ethur, Ubiratan F. da Silva, Ionara I. Dalcol and Ademir F. Morel*
Departamento de Química, NPPN, Universidade F ederal de Santa M aria, 9 7 1 0 5 -9 0 0 Santa M aria-R S, Brazil
Neste trab alh o uma nov a f ase estacionária q uiral, h ep taq uis ( 3Op entaluorop rop ionil2,6
-di-O-p entil) -β-ciclodex trina, f oi sintetizada e av aliada f rente uma g rande v ariedade de comp ostos v oláteis q uirais. O nov o deriv ado de ciclodex trina f oi usado p ara a sep aração de comp onentes de óleos essenciais, como h idrocarb onetos, cetonas, aldeídos, álcoois de cadeia long a, comp ostos h alog enados e comp ostos contendo nitrog ênio e enx of re.
I n th is w ork , a new ch iral stationary p h ase h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di
-O-p enty l) -β-cy clodex trin w as sy nth esized and ev aluated w ith a w ide v ariety of v olatile ch iral
comp ounds. A s a result, th e new cy clodex trin deriv ativ e can b e ap p lied to th e sep aration of ch iral comp onents of essential oils, as h y drocarb ons, k etones, aldeh y des, alcoh ols and of v arious classes of sy nth etic ch iral comp ounds, as long ch ain alcoh ols, h alocarb ons, nitrog en and sulf ur containing comp ounds.
K eywords: enantioselectiv e g as ch romatog rap h y , h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di -O-p enty l) -β- cy clodex trin, p entaluorop rop iony l g roup
I ntroduction
C y clodex trins ( C D s) deriv ativ es, esp ecially th ose of α-, β- and γ-cy clodex trins, are used w idely as ch iral
stationary p h ases ( C SPs) in g as ch romatog rap h y ( G C ) as an ef icient meth od f or enantiosep aration of a w ide v ariety
of v olatile comp ounds of dif f erent f unctionality .1-11 Various
ch iral mono and sesq uiterp enes common to essential oils and oth er economically imp ortant p roducts could b e resolv ed on columns coated w ith p er-O-alk y lated/ acy lated
cy clodex trins.11-16 T h e numb er of cy clodex trin deriv ativ es
th at is p rep ared and ev aluated f or enantioselectiv e g as ch romatog rap h y is still declining in recent y ears. T h e most imp ortant ch iral stationary p h ases k now to data, as octak is ( 3-O-b uty ry l-2,6 -di-O-p enty l) -γ-cy clodex trin ( L ip odex E )17, h ep tak is ( 3-O-p enty l-2,6 -di-O-meth y l) -β
-cy clodex trin18 and octak is ( 3-O-meth y l-2,6 -di-O-p enty l) -γ
-cy clodex trin12, w ere ob tained in th e late 8 0’s and 9 0’s. I n th is
w ork w e describ e th e p rep aration and th e enantioseparation ab ility of h ep tak is ( 3-O-p entaf luorop rop iony l-2,6 -di
-O-p enty l) -β-cy clodex trin deriv ativ e w ith p enty l g roup s at th e 2 and 6 p ositions and th e p entaluorop rop ionyl g roup in th e 3 p osition of th eir g lucose unit. T h e p entaluorop rop iony l g roup is used as h y drox y l g roup p rotection in olig omannoside sy nth esis,19 b ut not used y et
as deriv atizing ag ent in C D s. T h e enantioselectiv ity of th e new p h ase w as ev aluated w ith a numb er of natural ch iral comp onents of essential oils as h y drocarb ons, alcohols,
k etones and lactones, and determination of enantiomeric comp osition in asy mmetric sy nth esis. T h e enantiomers of
(+/−) -α-p inene, (+/−) -limonene, alcoh ols as (+/−) -menth ol, (+/−) -neo-menth ol, (+/−) b orneol, ( and its acety l and/ or O -triluoroacety l deriv ativ es) , k etones as (+/−) -carv one, (+/−) -camp h or and (+/−) -α-ionone could b e resolv ed. I n addition, ch iral secondary and tertiary long ch ain alcoh ols, h alocarb ons, nitrog en and sulf ur containing comp ounds may also b e resolv ed.
R esults and D iscussion
l-Sy nth esis and C h romatog rap h ic E v aluation of th e New Ph ase H ep tak isJ. Braz. Chem. Soc. 2006
2,6 -di-O-p enty l) -β-cy clodex trin. T h e g reat dif f erence in reactiv ity of th e 2- and 6 -O H g roup s vs. th e 3-O H
g roup s ( low reactiv ity ) , allow s reg ioselectiv e p enty lation of th e p ositions 2 and 6 , f ollow ed b y acy lation w ith th e p entaluorop rop iony l g roup in p osition 3.
T h e new ly sy nth esized cy clodex trin p h ase h as demonstrated g ood selectiv ity f or a w ide v ariety of ch iral
comp ounds of v arious ch emical classes, as h y drocarbons, k etones, alcoh ols, lactones, h alocarb ons, nitrog en and sulf ur containing comp ounds. F ig ure 1 sh ow s th e G C sep aration of (+/−) -α-p inene and (+/−) -limonene.
F ig ure 2 illustrate th e G C sep aration of (+/−) -carv one, (+/−) -camp h or and (+/−) -α-ionone, resp ectiv ely . F ig ure 3 sh ow s th e G C of (−) -menth y lacetate. T h is clearly indicates
an adulteration w ith th eir enantiomer (+) -menth y lacetate. O n th is p h ase, not only can b e underiv atized alcoh ols b e resolv ed, b ut also th e corresp ondent acetates and trif luoroacetates. T h e ch romatog ram p resented in F ig ure 4 illustrates th e sep arations of th e enantiomers of (+/−) -b orneol, (+/−) -b orneol-O-A c, (+/−) -b orneol-O-T F A .
T h is p h ase can b e ap p lied to th e sep aration of racemates of secondary and tertiary long ch ain alcoh ols. F ig ure 5 illustrates th e sep aration of (+/−) -decanol-O-A c, (+/−) -decanol-O-T F A , (+/−) -undecanol-O-A c and
(+/−) -undecanol-O-T F A , resp ectiv ely . O ne ex amp le of discrimination b eing af f ected b y structural p rop erties is th e sep aration of tertiary acety l alcoh ols. F ig ure 6 sh ow s th e sep aration of (+/−) -2-p h eny lb utanol-O-A c,
(+/−) -2-p h eny lp entanol-O-A c, (+/−) -2-p h eny lh ex anol-O-A c
and (+/−) -2-p h eny lh ep tanol-O-A c, resp ectiv ely . I n
th is case, th e increased size of th e alcoh ol causes a decrease in sep aration ef f iciency . T h e ef f iciency of th is p h ase f or th e sep aration of nitrog en and sulf ur containing comp ounds is of p articular interest. F igure 7 sh ow s th e sep aration of D,L-alanine-O-E t and of
R,S-(E) -eth y l-2-( 4 -ox op ent-2-en-2-y lamino) p rop anoate,
comp ound ob tained sy nth etically f rom alanine. F inally , F ig ures 8 and 9 illustrated th e use of th is p h ase f or th e sep aration of sulf ur-containing comp ounds. T h e enantiomers (+/−) -cy cloh ex y lb enzenesulf inate a n d (+/−) - 1 - c h l o r o - 3 - ( e t h y l s u l f i n y l ) b e n z e n e ( F ig ure 8 ) and of (+/−) -cy cloh ex y lb enzenesulf inate,
Scheme 1. Sy nth etic p ath w ay to h ep tak is ( 3Op entaluorop rop iony l2,6
-di-O-p enty l) -β-cy clodex trin.
F igure 2. E nantiomeric sep aration of ( + /−) -carv one: 4 0-18 0 °C ( 2° min−1) , ( + /−) -camp h or: 50-18 0 °C ( 1° min−1) , and ( + /−) -α-ionone: 4 0-18 0 °C ( 1° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
F igure 3. E nantiomeric sep aration of ( + /−) -menth ol-O-A c: 35-18 0 °C ( 1° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
(+/−) -meth y lsuliny lb enzene, (+/−) -eth y lsuliny lb enzene, (+/−) - 1 - m e t h y l - 4 - ( m e t h y l s u l f i ny l ) b e n z e n e a n d (+/−) -1-eth y l-4 -( meth y lsuliny l) b enzene, resp ectiv ely ( F ig ure 9 ) h av e b een resolv ed.
Conclusions
-Sy nth esis and C h romatog rap h ic E v aluation of th e New Ph ase H ep tak isJ. Braz. Chem. Soc. 2008
F igure 4 . E nantiomeric sep aration of ( + /−) -b orneol, ( + /−) -b orneol-O-A c and ( + /−) -b orneol-O-T F A : 4 0-18 0 °C ( 2° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
F igure 5. E nantiomeric sep aration of ( + /−) -decanol-O-A c: 50-18 0 °C ( 4° min−1) , ( + /−) -decanol-O-T F A : 50 °C ( 10 min) and 50-18 0 °C ( 4 ° min−1) ,
( + /−) -undecanol-O-A c: 30-18 0 °C ( 1° min−1) , and ( + /−) -undecanol-O-T F A : 4 0-18 0 °C ( 1° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
O-p enty l) -β-cy clodex trin rep resents a v ersatile stationary p h ase f or th e enantiosep aration of dif f erent classes of
comp ounds b y h ig h -resolution g as ch romatog rap h y . T he sep aration of sulf ur containing comp ounds in F ig ure 8 and 9 are only tw o ex amp les of th e contrib ution of th e new h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β
-cy clodex trin to th is class of ch iral sy nth etic comp ounds. A noth er imp ortant p rop erty is th e cap ab ility of th is p h ase to resolv e th e enantiomers of a w ide rang e of secondary and tertiary long ch ain alcoh ols ( in its acety l and/ or
O-triluoroacety l deriv ativ es) , as sh ow in F ig ure 5 and
6 . M oreov er, th e new p h ase sh ow ed a g ood p erf ormance
in th e resolution of ch iral comp ounds commonly f ound in many essential oils, as h y drocarb ons, alcoh ols and k etones.
Ex perimental
I nstrumentation
C ap illary G C w as p erf ormed on a Varian C P 38 00 eq uip p ed w ith F I D , using cap illary column ( 25 m) of f used silica. H y drog en w as used as carrier g as. 1H and 13C NM R
sp ectra w ere recorded on a Bruk er D PX 4 00/ 100 M H z, w ith deuteroch lorof orm and tetrameth y lsilane as internal standard. C h emical sh if ts (d) are g iv en in p p m and coup ling constants (J) in H z.
Sy nthesis of heptak is ( 2 ,6 -di-O-penty l ) -b-cy cl odex trin2
F igure 6 . E nantiomeric sep aration of ( + /−) -2-p h eny lb utanol-O-A c, ( + /−) -2-p h eny lp entanol-O-A c, ( + /−) -2-p h eny lh ex anol-O-A c, and ( + /−) -2-p h eny lh ep tanol-O-A c:
30 °C ( 10 min) and 30-18 0 °C ( 1° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
F igure 7. E nantiomeric sep aration of D ,L -alanine-O-E t and R,S-(E) -eth y l-2-( 4 -ox op ent-2-en-2-y lamino) p rop anoate: 50-18 0 °C ( 1.5° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
h y drox ide ( 5.0 g ; 125.0 mmol) , and dry dimeth y lsulf ox ide at 0 °C . Stirring w as continued f or 4 day s, at room temp erature, p rotected f rom lig h t. T h e mix ture w as tak en up in diisop rop y l eth er and w ash ed w ith w ater. T h e org anic lay er w as dried ov er anh y drous mag nesium and concentrate
Sy nth esis and C h romatog rap h ic E v aluation of th e New Ph ase H ep tak isJ. Braz. Chem. Soc. 2010
F igure 8. E nantiomeric sep aration of ( + /−) -cy cloh ex y lb enzenesulinate: 35-18 0 °C ( 1° min−1) and ( + /−) -1-ch loro-3-( eth y lsuliny l) b enzene: 4 0-18 0 °C ( 2° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as, h y drog en 7 p si.
F igure 9. E nantiomeric sep aration of ( + /−) -meth y lsuliny lb enzene and ( + /−) -eth y lsuliny lb enzene: 35-18 0 °C ( 1° min−1) , ( + /−) -1-meth y l-4 -( meth y lsuliny l) b enzene and ( + /−) -1-eth y l-4 -( meth y lsuliny l) b enzene: 4 0-18 0 °C ( 2° min−1) on a 25 m × 0.25 mm C C SF coated w ith h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β-cy clodex trin in O V 17 01; carrier g as: h y drog en 7 p si.
Sy nthesis of heptak is ( 3 -O-pentaluoropropiony l -2 ,6 - di-O-penty l ) -b-cy cl odex trin
H ep tak is ( 2,6 -di-O-p enty l) -β-cy clodex trin ( 100 mg ; 4 7 .25 µmol) w as dissolv ed in dry mix ture of ch lorof orm
w as w ash ed w ith 100 mL of 5% H C l solution, 100 mL of NaH C O3 saturated solution and 100 mL of w ater. A f ter
dry ov er anh y drous sodium sulf ate th e org anic lay er w as concentrated. T h e crude p roduct w as ch romatog rap h ed on silica g el column w ith eth y l acetate/ h ex ane 1: 9 ( v /v ) , to g iv e h ep tak is ( 3-O-p entaluorop rop iony l-2,6 -di-O-p enty l) -β -cy clodex trin ( 2,6 -Pe-3-PF P-β-C D ; 116 mg , 7 8 % ) .1H NM R
( C D C l3,4 00 M H z) : d 0.8 6 ( t, 6 H , J 6 .36 H z; 2 × ε-C H3) ; 1.17 -1.30 ( m, 8 H , 2 × d-C H2; 2 × γ-C H2) ; 1.4 4 -1.57 ( m, 4 H , 2 × β-C H2) ; 3.33-3.4 7 ( m, 6 H , H -2, 2 × α-C H2; H -6 ’) ; 3.8 7 -3.9 9 ( m, 3H , H -4 , H -5, H -6 ) ; 5.01( d, 1H , J 2.8 0 H z;
H -1) ; 5.37 ( t, 1H , J 8 .24 H z; H -3) ;13C NM R ( C D C l
3/ T M S,
100 M H z) : d 13.7 , 13.9 ( 2 × ε-C H3) ; 22.3, 22.5 ( 2 × d-C H2) ; 27 .6 , 27 .9 ( 2 × γ-C H2) ; 28 .3, 29 .1 ( 2 × β-C H2) ; 6 9 .1 ( C -6 ) ; 7 1.2 ( C -5) ; 7 1.8 , 7 1.9 ( 2 × α-C H2) ; 7 5.9 ( C -4 ) ; 7 6 .7 ( C -3) ; 7 7 .4 ( C -2) ; 9 7 .9 ( C -1) ; 105.8 7 ( C F2, J1 26 4 .9 H z, J3 38 .4
H z) ; 117 .7 ( C F3, J1 28 5.3 H z, J3 34 .2 H z) ; 115.4 ( C = O , J3 29 .1 H z) . Peak assig nments w ere made w ith th e aid of
tw o-dimensional 1H -1H and 1H -13C correlation ( C O SY and
H M QC ) tech niq ues.
Col umn preparation
F used silica columns ( 25 m × 0.25 mm i.d.) w ere p rep ared b y static coating .18 T h e inner surf ace of th e f used
silica tub ing w as sub mitting to a mild leach ing w ith H C l. T h e 25% of th e cap illary is illed w ith a 2% aq ueous H C l ( 0.5 mL ) . A f ter th e liq uid h as lef t th e cap illary b oth ends are sealed w ith a h ig h temp erature lame ( microlame g as torch ) . T h e cap illary is treated f or 6 h at 220 °C in a G C ov en. T h en small p ieces at th e end of th e cap illary are cut of , 1mL of 2% aq ueous H C l solution and sub seq uently 1 mL of meth anol are illed into and p ush ed th roug h th e column w ith nitrog en ( 30 min) until th e column ap p ears dry . T h e column is ag ain installed in a G C ov en and conditioned f or 2 h at 250 °C under nitrog en low to ensure deh y dratation of th e surf ace. C olumns w ere deactiv ated w ith dip h eny ltetrameth y ldisilazane ( 50% in p entane) . F or th is, th e solution is slow ly p ush ed th roug h th e column and th e ends are sealed immediately . T h en th e column is h eated f or 6 h in a G C ov en at 330 °C . A f ter cutting of f
th e ends of th e cap illary its v olume is illed w ith M eO H ( 1 mL ) and f ollow ed b y dieth y l eth er ( 1 mL ) . T h e solv ent w as remov ed b y a nitrog en low and th e cap illary is lush ed
1 h w ith nitrog en. T h e cap illary is th en illed w ith a 0.2% solution of th e cy clodex trine deriv ativ e and O V 17 01
( 1: 1; m m−1) according to th e p rocedure describ ed
p rev iously .2
A cknowledgements
F inancial sup p ort f or th is w ork w as p rov ided b y th e C NPq ( C onselh o Nacional de D esenv olv imento C ientíico e T ecnológ ico-Brazil) . T h e auth ors th ank Prof . A nita J . M arsaioli at th e C h emistry I nstitute of th e State U niv ersity of C amp inas, Brazil, to sup p ly th e racemic sulf ur comp ounds.
R eferences
1. H edg es, R . A .; Chem. R ev. 1 9 9 8, 9 8, 2035.
2. K önig , W . A .; G as Chromatog raphic E nantioseparation w ith
M odiied Cy cl odex trins; H eidelb erg : H ueth ig Verlag , G ermany ,
19 9 2.
3. Sch urig , V.; Now otny , P.; A ng ew . Chem., I nt. E d. 1 9 9 0, 2 9, 9 39 . 4 . Sch urig V.; J. Chromatog r., A 2 0 0 2, 9 6 5, 315.
5. Sch urig , V.; Sch midt, R .; J. Chromatog r., A 2 0 0 3, 1 0 0 0, 311. 6 . Sing h , M .; Sh arma, R .; Banerj ee, U . C .; Biotechnol . A dv. 2 0 0 2,
2 0, 34 1.
7 . Sp anik , I .; K rup cik , J .; Scacani, I .; Sandra, P.; A rmstrong , D . W .;
J. Chromatog r., A 2 0 0 5, 1 0 7 1, 59 . 8 . Szetj li, J .; Chem. R ev. 1 9 9 8, 9 8, 17 4 3. 9 . W ard, T . J .; A nal . Chem. 2 0 0 2, 7 4, 28 6 3.
10. G risales, J . O .; L eb ed, P. J .; K eunch k arian, S.; G onzález, F . R .; C astells, C . B.; J. Chromatog r., A 2 0 0 9, 1 2 1 6, 6 8 4 4 .
11. Bicch i, C .; C ag liero, C .; L ib erto, E .; Sg orb ini, B.; M artina, K .;
C rav otto, G .; R ub iolo, P.; J. Chromatog r., A 2 0 1 0, 1 2 1 7, 1106 .
12. K önig , W . A .; G eh rck e, B.; I ch eln, D .; E v ers, P.; D önneck e, J .; W ang , W .; H R C- J. H ig h. R esol ut. Chromatog r. 1 9 9 2, 1 5, 36 7 .
13. Bicch i, C .; A rtuf f o, G .; D ’A mato, A .; M anzin, V.; G alli, A .; G alli, M .; H R C- J. H ig h. R esol . Chromatog r. 1 9 9 3, 1 6, 209 .
14 . Bicch i, C .; D ’A mato, A .; M anzin, V.; G alli, A .; G alli, M .;
J. Chromatog r., A 1 9 9 4, 6 6 6, 137 .
15. K önig , W . A .; H och muth , D . H .; J. Chromatog r. Sci. 2 0 0 4, 4 2, 4 02.
16 . Bicch i, C .; Blumb erg , L .; C ag liero, C .; C ordero, C .; R ub iolo, P.; L ib erto, E .; J. Chromatog r., A 2 0 1 0, 1 2 1 7, 1530.
17 . K önig , W . A .; K reb b er R .; W enz, G .; H R C- J. H ig h. R esol ut.
Chromatog r. 1 9 8 9, 1 2, 6 4 1.
18 . K önig , W . A .; I ch eln, D .; R ung e, T .; Pf orr, I .; K reb s, A .; H R C- J.
H ig h. R esol ut. Chromatog r. 1 9 9 0, 1 3, 7 02.
19 . T ak atani, M .; M atsuo, I .; I to, Y .; Carb ohy dr. R es. 2 0 0 3, 3 3 8, 107 3.
20. G rob , K .; M ak ing and M anipul ating Col umns f or G as
Chromatog raphy, H eidelb erg : H ueth ig Verlag , G ermany , 19 8 6 .
Sub mitted: Septemb er 1 7 , 2 0 0 9
