Stereoselectivity in micellar and vesicular reactions

Letters,Vol.23,No.l9,pp In Creat Brltam

1985-1988,1982

Tetrahedron

Prmted

STEREOSELECTIVITY Robert A. Moss*, Department

IN MICELLAR

Takayuki

0040-4039/82/191985-04$03.00/O 01982 Pergamon Press Ltd.

AND VESICULAR

Taguchi,

REACTIONS

and George 0. Bizzigotti

of Chemistry, Rutgers, the State University New Brunswick, New Jersey 08903

of New Jersey,

Summary. The diastereoselectivity of esterolytic cleavage of certain dipeptide and tripeptide activated esters is lower in thiol-functionalized vesicles than in comparable micelles. This is thought to be a mechanism-specific effect related to the greater molecular ordering in vesicular systems. Efforts

to realize

tive reactions

between

dlastereoselectlve

stereoselective

reactions

12 2 enantioselectivity phenyl

reactions

choral nucleophlles between

attending

nucleophilic

the cleavage

(PNP) esters by E-(Z)-(&)-Leu-(&)-His

and the 32-fold -LL/DL stereoselectivity a functional present

thiochollne

records

surfactant,

The current

(vs

emphasis

However,

greater

surfactant

substrates

because

the enhanced

on reactions

relative

the origins

molecular

dipeptide

environments,

surfactant

were prepared

in surfactant

esters.'

The

pnitro-

diastereomers

in CTACl solutlon,2c

of micellar

restrlction

employed

m

PNP esters micellar

included

2 (16-SH),'

m

or vesicular

by

represent

the

nonfunctional

Substrates

esters, s-@

(41,

or A)-Trp-(2

vesicles

are mechanism-dependent, induce

for the cleavages

lower In functlonal

CTACl, dicetyldimethylammonium surfactant

solutions

were

vesicular

from a previous

generated

1 (162),'

Micellar

mono-

solutions

from 162 or 162SH by

2

Cl-

(162SH)

dlpeptide

esters E-carbobenzyloxy

study,2c

and the four diastereo-

or L)-Trp-CL)-Pro-PNP

1985

bromide,

2 (163SH).10

(n-C16H33)2 t eCH$HzSH,

Cl-

the diastereomeric

available

by ves-

x-hexadec(vs. micelles). i'b

systems.

and dicetylthiol

Included

substrates of (s.)

that dlastereoselectlvlties

are substantially

of chi&7

"achlral" vesicles.

systems may not necessarily

2 (16~SH)

methods.'O

in

of Z-Phe-PNP

stereoselectivity

n-C13H33 &M e2CH2CHzSH,

Br-

the greater molec-

the study of reactlons

and for cleavage

vesicular

In fact, we now report

to comparable

(z)-(g or &)--Trp-(&I-Pro-PNP tripeptide

for cleavage

derivatives,7a

obtalnable

coupled with

inevitable

or chiral nucleophlles

are reported

histidine

1 (162)

merxc

or

(CTA) bromide3

of J-Val-Pro-PNP

veslcles,4

make

from CTACl or 16-SH, and vesicular

@-C1$33)&e2,

xqectlon

cetyltrimethylammonlum

to esterolysis

surfactants

and trlpeptlde

relative

The surfactants cetylthlol

upon enantloselec-

armno acid esters)'

and di or trlpeptlde

cleavage

by (A)-cr-E-hexadecanoyl-His

stereoselectivity.

of certain

in micellar

for mlcellar

to mlcelles,5

enantioselectivities

mlcellar)

anoyl-Phe-PNP

surfactants

(e.,

of g or &-methoxycarbonylphenylalanme

relative

with choral vesicular

Indeed, enhanced icular

have centered

in these endeavors.

ular order in vesicles, ral substrates

in micelles

and chiral substrates

(5).

The latter were prepared

1986

by first couPllng Z-(2 or &)-Trp to (2 or L)-Trp-OMe (i-Bu02CC1,~-methylmorpholine,THP, 2h, O", 4h, 25'), followed by saponification (0.18 E NaOH in 2.2:2 2:l dioxane-CHgOH_HzO,25O, tic manitoring), acidification (0.5 5 aq. citric acid, O'), extraction (EtOAc), and crystallization (Etpo/pet.

ether, recryst. from EtOAc-MeOH-pet.ether) to give the four Z-Trp-Trp(COOH) dia-

stereomeric dipeptide acids, 2, which were characterizedby nmr and elemental analysis.11 Mixed anhydride coupling (reagents and conditions above, initial activation of -6 at -15O, 5 min.) then gave the four tripeptide esters, 2, as pale yellow solids after filtration, evaporation of THP, and trituration (3x, dry EtZO) to remove pnitrophenol.

Further purification could not be

effected without significant decomposition of the active esters.12 Kinetic data for pH 8 rmcellar cleavage of tripeptide esters -4 by surfactants CTACl and 16SH appear in Table I, together with analogous results for the previously studied -Z-Phe-Phe-ProPNP dlastereomers.2b All four Trp substrates are cleaved at similar rates by OH-/CTAC~, gesting dlastereomericallyindiscriminatelyate ion esterolysis

sug-

With 16-SH, however, micellar

thiolysis 1s evzdent in the large rate enhancements (-1500-4000). More importantly, the rate constant order --DLL>LLL>LDL or s, previously observed with -Z-Phe-Phe-Pro-PNPsubstrates,2b perslsts with the Z-Trp-Trp-Pro-PNPanalogues, supporting our suggested rationale for 16-SH diastereoselectivity (see refs. 2b, 2c, and below). Key data appear In Table II, which compares diastereoselectivitiesfor cleavages of Z-TrpPro-PNP or -Z-Trp-Trp-Pro-PNPunder micellar or vesicular conditions. Di or trlpeptide esterolyses in nonfunctional micellar CTACl or vesicular 162 are quite comparable (cases 2 vs. l), indicating that altering the aggregate pseudophase does not significantly alter the intermolecular (lyate) esterolysis or (for the dipeptides) the dominant DL-selective intramolecular diketopiperaaine-forrmngesterolysis.2a Significantly,however, functional vesicular 162SH is substantially less diastereoselectivethan mlcellar 16-SH in cleavages of either di or tripeptide ester substrates (cases 3 vs. 4).

This is not a simple function of the structural difference

between 162SH (double chain) and 16-SH (single chain), as IS shown by cases 6 and 7, in which either surfactant, comicellized in CTACl, exhibits similar dlastereoselectivlty. The reduced dlastereoselectivltyis therefore a vesicular effect, quite specific to l67_SHholovesicles; 16SH in vesicular 16, shows comparable diastereoselectivityto micellar 16-SH (cases 5 and 4) and even l62SH covesicallized in 162 shows only partially reduced diastereoselectivity(cases 8 vs 4-7

vs. 3). We suggested2b*c that the CH2 chain of micellar 16-SH approximated well to "clefts" of

XLL tripeptides) defined by the substrates' Pro and PNP moieties, and by the -LL dipeptides (or R group of the amino acid adjacent to Pro, thereby optimally orienting the surfactant's CH#H2Sgroup for ester thiolysls. Approximation was thought to be less productive for E

dipeptides

(or _ XDL trlpeptides),where substrate R groups projected away from the hydrophobic clefts, affording less than optimal thiolate/carbonylinteraction between 16-SH and substrate. We now further suggest that the imposed molecular ordering' of methylene chains in holovesicular 162SH inhibits the flexlbllity necessary for optimal "single chain" approximationbetween surfactant and -LL or XLL substrate molecules which is needed for effective diastereoseproblem is absent With the more flexible chains of micellar 16-SH Or comice11lectivity. TJ.,~~

1987

Table I.

Kinetics of the Micellar Cleavage of Tripeptide Estersa k+, (set-') for tripeptide diastereomers

LLL -

-DLL

LDL -

Tripeptide

Surfactant

Z-Trp-Trp-Pro-PNP

CTAClb

0.0018

0.0024

0.0023

0.0023

16-SHC'd

7.1

9.3

3.2

3.6

CTACle

0.0038

0.0047

0.013

0.0076

16-SHe

9.0

53

4.3

Z-Phe-Phe-Pro-PNP

13.4

DDL

aConditlons: [surfactant]=/4.0~10-~ M; [substrate]= 2.0~16~ PJ;pH 8.0, 0 02 M phosphate buffer, P = 0.05-0.055 (KCl), 25'C. bKinetics for triplicate runs, reproducibility~4%. d -e '-100% free SH. Kinetics for duplicate or triplicate runs, reproduclbillty ~1.8%. Data from reference 2b.

Table II. Diastereoselectivitiesof Micellar and Vesicular Cleavage Reactionsa

Case

Surfactant

M or V

162d

RDLL Ib -JIs-

s

0.00397

0.00475

DDLs_lb $L,$DLb

$s_lc

-+_IC

0.836

0.00239 0.00932

0.256

0.00430

0.900

0.00247 0.00647

0.382

5.71

1.05

10.4

6.69

1.55e

8.20

3.23

2.57

18.7

3.90

4.80

1.12

0.411

L 73

CTACld

0.00307

162~~d

6.00

16-SHd 16&6-SHf

2.23

0.492

4 53

CTAC1/16-SHf

2.53

0.506

5.00

CTACl/16,SHf

1.79

0.402

4.45

16*/16zSHf

2.51

0.786

3.19

"M = micellar, V = vesxular conditions, reproducitllltiesof rate constants were generally b d ~5% for duplicate runs Substrate Z-Trp-Trp-Pro-PNP. 'Substrate Z-Trp-Pro-PNP. Conditions pH 8.05, O.OlPJ tris buffer, u = 0.01, 25", [surfactant]= 5~10~~ M, [substrate] = 2x10s5 M. eThis value reproduced twice by T.T. and G.O.B., each with duplicate runs, error ~5%.

ftnon-

functional surfactant] = 5~10~~ M, [functional surfactant] = 5~10~~ PJ, [substrate]= 2~10~~ bj, other conditions as in _. d

1988

ized 162SH

The lower diastereoselectivity

LL/DL diastereoselectivity -Ing only a reasonable

temperature

with a gel to liquid crystalline as the dominant In which stroys

to a "gel" vesicular

phase, however,

transition

vesicular

discontlnulty

l3

(known to rigidify

dlastereoselectivity

The notion

diastereoselectlvlty

observed

of imposed

is supported

vesicular

with 162/162SH

which might be associated chain ordering by an experiment

structure 14 ) completely

covesicles

(case 8, e.,

deLL/DL --

to 1.0 for the doped covesicles)

It 1s thus clear ably translate speclflc

vesicular

of added cholesterol

the residual

decreases

effect with no obvious

cause of mitigated

50 mol-%

1s not specific

for case 8 of Table II is 3.8 (15'), 3.2 (25'), and 2.6 (35O), show-

that enhanced molecular

into enhanced

to a given reaction

tion mechanism

reaction

mechanism,

which determlnes

ordering

stereoselectivity.

in vesicular

and it is the Interplay

the effect

of Increased

aggregates

The origins

does not inevit-

of stereoselectivity

of molecular

ordering

are

and reac-

order on stereoselectivlty.

Acknowledgments. We are grateful to the National Science Foundation for financial support. T T acknowledges with pleasure an International Student Exchange Fellowship from the Ministry of Education, Japan. G.O.B. thanks the Graduate School of Rutgers University for a fellowship. 1

2.

3. 4

5.

6

7.

8. 9. 10. 11

References and Notes Y. Ihara, N. Kunikiyo, T Kunimasa, M Nango, and N. Kurokl, Chem Lett., 667 (1981), S Ono, H Shoshenji, and K. Yamada, Tetrahedron Lett., 2391 (1981); K. Ohkubo, K. Sugahara, H.Ohta, K. Tokuda, and R. Ueoka, Bull. Chem. Sot. Japan, 2, 576 (1981), K Ohkubo, K. Sugahara, K. Yoshlnaga, and R. Ueoka, Chem. Commun., 637 (1980), Y. Ihara, M. Nango, and N. Kuroki, 2, Org. Chem., 45, 5011 (1980), H Ihara, S Ono, H. ShoshenJi, and K Yamada, m., _, 45 1623 (1980); Y. Ihara, J.C.S. Perkin Trans II, 1483 (1980). (a)R.A. Moss and Y-S Lee, Tetrahedron Lett., 2353 (1981), (b)R.A. Moss, Y-S. Lee, and K W. Alwls, u., 283 (1981), (c)R A. Moss, Y-S. Lee, and K.W. Alwls, J. Am Chem. Sot., 102, 6646 (1980). Reference (l), first entry Reviews J H. Fendler, "Membrane Mimetlc Chemistry," Wiley, In press. (We thank Professor Fendler for a prepublicatlon copy of his book), T. Kunltake and S Shinkal, Adv. Phys. Org. Chem , 17, 435 (1980); J H. Fendler, Act. Chem. Res , 2, 7 (1980). T. Kunitake, Y. Okahata, R, Ando, S. Shinkai, and S-I. Hirakawa, J. Am. Chem. Soc.,z,7877 (1980), T. Kunitake, N Nakashima, M. Shlnmomura, Y. Okahata, K. Kane, and T. Ogawa, $x& , 102 2467 (1980). 102, 6642 (1980), E.J.R Sudholter, J.B F.N. Engberts, and D. Hoekstra, s.,, T. Kunitake, N. Nakashima, S. Hayashida, K. Yonemori, Chem. Choral vesicular surfactants: 1413 (1979), Y Murakaml, A. Nakano, and K. Fukuya, J. Am. Chem. Sot., 102, 4253 g, (1980), T Kunitake, N Nakashlma, M Shimomura, Y Okahata, K Kano, and T. Ogawa, g., 102, 6642 (1980) (a)Y. Murakami, A. Nakano, A. Yoshlmatsu, and K. Fukuya, J. Am. Chem. Enantloselectivity. x., 103, 728 (1981), (b)R. Ueoka, Y. Matsumoto, Y. Ninomlya, Y. Nakagawa, K. Inoue, and K Ohkubo, Chem. Lett., 785 (1981) We thank Professor T. Kunltake for a gift of 162. R.A Moss, G.0 Blzzigotti, and C.-W. Huang, J. Am. Chem. Sot., 102, 754 (1980) R.A. Moss and G.O. Bizzigottl, J Am. Chem Sot , 103, 6512 (1981). LD-6 mp 184-186" (dec), [a]~'-20 2' s-5, mp 202-205' (dec), [c~]~~-lO.2" (c=O 95, MeOH), -_*

(c=O.92, MeOH), g-2, mp 183-185", [alp+20 0" (c=O 97, MeOH), DD_a, mp 203-204' (dec), [a]~0+10.9" (c=l.O * MeOH). A satisor recrystallization conditions. 12. Esters 2 were unstable to various chromatographlc Apparent chemfactory analysis was obtalned for -DLL-5aH20, but not for its diastereomers lcal purity was demonstrated by tic (silica gel 60 (EM), 20% MeOH/80% CHC13) and by nmr, mp 106-109", [al6'-6 6' LLL-5, mp 112-116", [c~]~~-14.8" (c=O 98, dioxane), Rf=O.72; g-5 -(c=l.O, dloxane), Rf=0.68, -LDL-5, mp 88-94', [a]62-38.1" (2=0.95, dioxane), Rf=O.73, E-2, rni 72-78', [a]i"-25.4" (c-0.98, dloxane), Rf=0.76 xc for 162 1s -28', reference 5, first citation. 14. B.R. Lentz, D A Barrow, and M. Hoechli, Biochem., 13

(Received

In

USA

17

November

1981)

19, 1943

(1980)