The circular dichroism of gliotoxin

Tetrahedron Letters No.27, Printed in Great Britain,

pp. 3139-3146,

1966.

l’erw”on

Press Ltd.

TRR CIWULAR DICRROI= OF GLIbJ A. F. Beeoha

and

Ar RcL. Yathieson

Mvizion of Chezieal Physics, Chemical Research Laboratories, Australia. C.S.I.R.O., Box 160 P.O., Clayton, Victoria, (Received On the basis of reference

oozpounds,

Yozoozltz,

a rule relating

azsocleted

dth

dlsz~trlc defined

in a zoleoule

and a selection

of the cimular

The X-my

of considerable

of a clsoid

rigidity.

olmulsr

d.ichrolsm of gliotoxin

oonclude

that,

oaze,

analysis

of these

of gllotorin

(2) has

diene for the first Consideration

with allied

(1)

dichroism

sker dienes to the chirellty

the ohlrality

In thie

treatment

Charneg, Weiss end Wffer

the sig!

ehromophores. absolutely

1966)

of a theoreticsl

enunciated

oisold

22 April

evidence

the rule Is et varlence

time

of the

has led us to with experimental

obzervetione The rule associated (-

states

(1)~

with the lowest

260-280 $)

“A strong pozitlve

frequency

means the presence

in the sense of a rl&t-handed ie Indicative left-handed

This is associated lowest frequency

the dihedral

tzist.” angle

diene

absorption,

3139

band

diene chromophore tzisted

A strong negative In gliotorin,

Cotton effect ze find

L CjC6C7/C6C7C8 being

with a strong positive cieoid

diene ebsorptlon

of e cisoid

helix.

of the left-handed tziet,

cisoid

Cotton effect

a

14’ (2).

C-D. peak in the region

of

FE.1

*

C.D. ourw~w That for

reeordodla (3).

ham uardto du'ivothinxwult are th00.

#liotoxln hu ken ndetendnod on s

BoruulJousnblobrogrph ad aooorbrwlththepublUhedou.rne major feataim ma a lar@ane@in at-PI0 negative

peak nom 233 7

'9"'a #mallZlO~~tivO hfiOOti0~ peak,

~lodlarlymill,at 340 7

at

Ito

a poriflw pati 310

Y-

The peak at 233 9" -

attrlbnto to tr&Atlon~ arrrooiatod with the dlmlphide-bridged p%peraBInodione nyBtemmino0fourothermolooulo~oontaillin#thiB etruotural rlrment&or similar0.9. in thin retion(2,)). ¶%a pa& oooursat nomwhat~lon#er wavelength than wouldbe -0t.d

for

abrorption due to the peptidegoupm In 8 dikotopiporaslna (4). Thle rnw reflectboth tha opaaialdiaporltion of the two pi& dthres~otto

eaoh otherad

mw

the proxiudtyoftha diuulphida brld&a.

Again,the trua baud oentremy ba at &ortrr,wrvelength, the twver W-6

whereit door due to oontigaity with . poaitlvaband

of

higherfrequenoy. The poaitin peak near 270 4" in the C.D. ourvoof gliotoxln lo in the regionwhorethe oontribution from tha lowoatmorg of a ciaoidskewdionewouldbe expeotedto occur (1).

bud

TransforlMtion

of gliotoda,Fig. 3a, to dehydrogliotoxin, Fig. 3b, involveaconversion

No.27

3111

of the oyolohbxadibnb an-try

am

Two obntrbr of

one.

dbrtroybd, a hydroxyl @oup bbing lout in the w-ebb,

FQa 3a mid )b,

but the dibulphidb-@brabin~dionb

rin#

byEtOm ib Mt

8ubtraotion of the C.D. data of dbhydrogliototi

affbotbd.

that of &Lotoxin dib,lb,

ring to UI awn&i0

V,,lb6S

intmdaobd

bhould thbn rbwal

from

thb OontribUtion of thb bkbW

this i# mbnkbd bJ Z-OtatOrjbffbOt#

U’i#iD#

fX’OS

bbndme

uwnatlo

FIG.2

6

Ae ohown in Fig. poblfive ma@itudb

the

2, ewh a diffeI*mcb

pbak at cimr

260 ‘4”)

At - 10,

with that bxpeated from the

bblibf

that thie

That of gliotoxln

absorption

oonteinb

which is albo present 10s E - 3.61 (5). low @twral

oumb contain6

Am_

in dethlogliotoxin,

origin

through the baie

poeitioa

F’lg. 3~s ,%g.

m&on

a&

rbinforcb

in the dienb ay6tbm.

- 270 7’

~btd@ZOdsfbiO~iOtO~~,

absorption

in

U-V. epeotra

dibnb.

h.ee lte

L band

eonel~tbnt

bn IEOlatbd

(6).

log G - 3.64 (5) Am, 3,

= 29 hOWE

Od,

Ps

No.27

It abaorptloa

16

not to

diffloult

~oribe

the pm&tire of Rg.

2 to the lrft-

h6nded 6ker dieB0.

Thin, however, would constitute

au iniringemcmt

of the rule

In certain

aeewd brin#

revealed by the diffOIWBCe o~rw

dlohrola

(1).

to violate

the mla

them IBto like.

theOmtiCi%lly

dieno

(7),

the rule dth

regazd to ri(g.

(8) and the

CI6jOrity Of 6rperiIWBtti ObEem6tiOnE On the other hsnd, the

666unption6 Underlying the mle

It i6,convenient Imd ln6trwtive 6hip PtWen

BOwever,

at leacrt, it appear6 to be Ebundlg biued

the pC66ibl6 existence of other anomdo~6

the fmdamntal

C.D. re6Ultr hav6

Because of these examples, we at fir6t explored

t0 6UppCr.t it6 OOlTeCtEle66. d

caaee

end 6peclal effect6 have been invoked to

the porrd'bility of inverting for the oiroid

other

rCtatiOBd

Ettrmgfh

di66y6lMtlriC ChrO6lCphCre by meen

CR]

uempb6

appear

resultfrom

gllotoxlB

do aUgg66t that

rarrrnt examination.

to illrutrate the relation-

and dihedral Pgle

0 in 6

Of a pOlar dia@aEl, a6 in ng.

4a.

No.27

3143

(ii)

(i)

h

sa@rlentarepresenting

The lobe

intended as descriptive be a line et al. --

only,

of anti-egmetry,

the looun of but the null

an shorn,, g

TM* vierpoint

between the rotatory the oisoid the oarbony

diane,

properties

impliee,

the optical

sywnetric

in ketones.

Althou&

with the second-order activity

strengths

seem8 reasonable

alragr,

too clear

a distinotlon

ohlorvphorea,

chromophorea

suoh u

repmoente&by

it hss been stated

(9) that

of such a ohromophora ia to be

dia8ymrmtry of a oarbonyl

is merely induced by its

the ranges of rotational therefore,

perhaps,

of disrrmtric

11, - - the high degree of dlsamtry contrasted

at 0 = 0’ till

m

one aa8um8n with Hoeomits

and perturbed

poup

line

in the figulv

di~egnwwtry of the ~hromaphon,need

(1) that only the inherent

be oonaidered.

CR]

au~otmdin~”

of the two classes

to suggest

stituenta a, b, o end d, F’ig. 4(b)(i),

for rhlah in faot,

overlap.

that the preeenoe of subwill

modify the dichroio

It,

No.27

3144

lb~~orptlo:~~of the diene syetem, not 60 drastically

ll(p of ttie lobee in the polar dlagrmn, but nuffiolentlg diaporiti,n

of the lobes

relative

to 8 - O’,*

be at @ - 8’ aud no longer these circumstances, a p0miti.w observad

a line

of era&

a left-handed

ohirditg

Cotton effect

as llluntrated

rifeoting

the rotatory

wested

then the dlene rule from X-ray structure

We

of o( -phe:Llaudrene

feel *

losea

l

(cc

4(b)(ll)

with

aud aa

asywnetry lr capable

for

has been deduoad by cir&lar

end lrvopimaric

absolute

The pauoity

of

geometry of

diohroiao

ir

of the anomalous behaviour

acid (7) 10 warranted and we of the latter.

structure

oompounda would prove moat valxeble In thle

value.

the absolute

inepectlon

of

dlene in the way

much of ite

analysis

that oloaer

C-D. data with detailed

oertalntle~

could be aaaociated

of a clsold

intend to oarr~ out an X-ray analgala

#elected

UndOT

antl-ametry.

in Fig.

peripheral

propertiea

oompounds In which this rmiortUMb.

1100 would then

in @lotoxin. We are aware that if

evidence

to rotate the

the amount of rotation The null

depending on the nature of a, b, c and d.

the

go to Invert

analyses

Correlation

of

of other carefully

In resolving

the un-

Irltuation.

Footnote: A hint aa to the poselbilltg of Invoking such an explanation resulted from plotting the values of (4, vereun dihedral engle for 1,2-iiohloropropane, listed by Kirkwood Gal. (IO) end considering the lnfluewe of molecular symmetry on the resulting polar diagrem. Aaymaettic perturbation of a dissgrmnetrlo ohromophore will, in anoral, alter uhequa’lly the ahepes as well as the an&adisposition of the lobes of Fig. 4a. Footnote: A recent rtudy of the C.D. of d-phellandrene down to -15O’C has revealed no change in si@ (11). Such n&&t have been expects&if, as suggested (12), the obserkd results at 2040% depend on a thermal balance betveen equatorial and axial oonformatlons.

316

No.27

The Msulllde

ChrOmODhOre

In the gliotoxin a dlssymmetrlo

the group Cl-&&c3

chronophore with a left-handed

skewness being indicated dominant influence disulphide

molecule,

by the dihedral

of dihedral

frequency

the trsnsltion

is observed

At

= 0.4 at 340

a8 an inflexion,

At = 0.3,

disulphide

absorption

cieoid

feature

on this

here

the molecule

determined

the

frequency

chirality

but whether Adjacent

mey well have a perturbing

chromophore as suggested Absolutely

“r’

appears

In gliotoxin,

of the lowest

with left-handed

at 340

to the negative

Is dominated by the skew sense remains unclear+

diene.

valuable

at 310 "r" (14).

band is associated

(13),

In gliotoxin,

shoulder

corresponding

C.D. in the region

asymmetric elements within influence

towards O”.

A second negative

‘3”’

of the

of Calvin &t.

perceptible

curve,

The

band of the chronophore

~100’

as a barely

c - 200 on the U.V. abeorptlon C.D. peak,

LCSS/SSC = 14O.

in magnitude as the angle is

end decreases

reduced from the open chain value of

the elm

angle

the degree of

angle on the U.V. absorption

where It is shown that the lowest

negative

chirality,

group is demonstrated by the results

moves to longer wavelengths

constitutes

in the case of the

model

compounds

would

be

also.

References 1.

A. Moscowits, E. Charney, U. Weiss end H. Ziffer, Q, 4661 (19611.

2.

10 F. Beechsm, Jo Fridrichsons Letters - accompanying paper.

3.

8. Herrmann,

4.

L. J. Saidel,

5.

J. D. Dutcher, J. R. Johnson and W. F. Bruoe, J.A.C.S., (1945).

and A. LicL.

R. Hodees and A. Taylor, Arch.

Blochem.

Biophys.,

J.A.C.S.,

Yathleson,

Tetrahedron

J. Chem. Sot., 4315 (1964). 2,

45 (1955). 3,

f-l36

No.27

3146

6.

J. R. Johnson and R. Buohauau, J.A.C.S.,

7.

i;g~;~Burgstshler, 0

8.

A.

9.

10.

C.

Burley

fi. Ziffer

-

private

P. &abbe, O&ioal Bgnlo Chemistrs,

ad

5

2103 (1953).

U. Weiss, J.I.c.s.9

g

4660

oo~ioationo

Rotatory Disuersion end Circular Mohroism Holden-Dw, Sau Frauoisoo (19651, p.180.

1. 1. Wood, 1. Flckett

end J. 0. -hod,

in

JO C&em. PRY0.) $g.,

561 (1952)e 0.

Roremau

snd C. A. &ela,

Tetrahedron

Letters,

lo.,

3037

“’

(1965).

12.

S. Ziffer,

13.

J. A. Barltrop,

14*

C. Ejerassi, H. Wolf and E. Bunnenberg, J.A.C.S., &, 4552 (1962) 6,S-thiootio acid will have a dihedral angle ora26O (se X-qy data on 1,2-dithiolane-4-carboxylio acid, 0. Foss and 0. Tjmslaud, Acta Ohem. Soand., 12, 1810 (1958)) end therefore oonutltutes the nearest availane oomparison dth gllotoxin in this respect.

-

E. Charney and U. Weiss,

J.LC.S*,

P. Y. Hayes aud 1. Caldn,

2,

J.A.C.S.,

2961 (1962). &

4348 (1954).