12-S -CIS conformationally locked retinoids: Thermal and photochemical interconversions leading to new geometric isomers

Tetrahedron Letters,Vol.25,No.lO,pp Printed in Great Britain

12-S-CIS CONFORMATIONALLY LOCKED RRTINOIDS: -AND PHOTOCHEMICAL INTERCONVRRSIONS LEADING TO NEW GEOMETRIC

ISOMERS

Roshantha A.S. Chandraratna and William H. Okamura* of Chemistry, University of California, Riverside, California

92521,

THRRMAL

Department

0040-4039/84 $3.00 + .oo 01984 Pergamon Press Ltd.

1003-1006,1984

USA

Summary: For 12-s-cis locked retinal analogues, thermal equilibria are established between -and 13-cis-2c and between 9-c&,11-*,13-cis-ld and 9-&,13-cis-2d; a 11-cis,l3-cis-lc phoGsome=ation occurs= transform 2c to -all-trans-2a anzd to 9-cis-2b. That various variety

geometrically

of biological

of synthetic retinoids

efforts.

in vision'

mechanisms

isomeric

Additionally,

to retinoid

we recently

locked retinoid

analogues

reported

role played

has resulted

the synthesis

The occurrence tolysis formed

product

of electrocyclizations

of trans-B-ionone

from the intermediate

5 was in thermal

equilibrium

part of an open chain, retroelectrocyclisation double

-cis-2c

and 9-&,13-cis-2d -

thermal

12-s-cis --

of

of molecular

series of

conformationally

(la-ld).4ctd

In this Letter,

and photochemical

we

isomers of

processes.

i??=Z; d3=E

b,

c, A'=E; b=z

was first demonstrated

of 4.6

that successive

when the pho-

5,5 which was believed demonstrated

electrocyclisation

for geometric

isomerizations

these thermal

processes

from the known

1003

to be that

In cases where the Y double bond is six electron

sense would result in isomerisation

we sought to utilize retinals

isomerizations

(41, and when it was subsequently

in the same disrotatory

Accordingly,

of several

in dienones

with small amounts

it is possible

targets

of the four 7-trans-11-trans --

selective

bond and this has been invoked to account

retinals.4R8

by -cis-trans

(3) was shown to be the a-pyran

-cis-B-ionone

in a

frequent

in many investigations

linkages

and characterization

FsHO

importance

analogues

As a part of a continuing

7-trans-11-cis --

2a-2d, by a series of highly

of central

and their various

transformations.3

possessing

wish to report the preparation this series,

occupy positions

the pivotal

and energy transduction2

pertaining

investigations,4

retinoids

systems make such molecules

11-&,13-cis-lc -

and of the y

of dienones

to prepare

and

the 13-

and 9-G,ll-*,13-cis-ld-

1004

retinals,

respectively,

lyzed lc (refluxing and 53% 2~" changed

was formed

through

hindered" formed lc $ 2c

mixture

To this end, we ther-

mixture

thermolysis

mixture

of this mixture

to the "less hindered"

remained

of ld under identical

sense by thermolysis

retinal.4absS

and id * 2d are presented

of 2d.

In all previously

six electron

1 and 2, respectively.

HPLC (Waters Radial Compression

5% ethyl acetate/Skellysolve

B; 0.5 mL/min)

mixture

reported

electrocyclisations,

exam-

trans-

interconversions

The reactions

Module -100, 5~ Silica

was

the "more

irreversibly

The time course of the thermal

in Figures

un-

conditions

of 38% ld and 62% 2d and this same equilibrium

of retinals by reversible

of 47% lc

of lc and 2c was formed by heating

(i.e., those with more -cis double bonds) was essentially

lowed by analytical tridge,

Similarly,

in the reverse

retinal

of the type 6.

and found that an equilibrium

The same equilibrium

conditions.

ples of transformations

of a-pyrans

(within -1 h) and that the composition

in an equilibrium

also obtainable

argon, darkg)10

8 hs heating.

2c under identical

resulted

via the intermediacy

hexanes,

were fol-

Radial-PAK

and the peak areas adjusted

Car-

for molar

Fig. 2 !!i ===a

d 1

I

20

I1

I

40 TIME

absorptivity

at 300 nm.

I

I

I1

60

(mid

80

I

I

I,

100

-

12-s-cis --

c&,13-&-retinals,

conformations.4b lc

I

60

TIME

(mid

have been suggested

and Id, should be relatively

parent

retinals

and 9c&,l3-cis-retinals, 13-cis-

of the same geometry.

retinals,

1

40

interconversions,

Thus, the 12-s-cis-locked --

parent

9-*,13-cis-

II

(69 OC) of 1.1 and 1.7 were calculated

Keq values

and 9-&,11-&,13-e $ 9-&,13-c& -cis t 13-cis retinals which Possess the 11-*,13-cis-geometry ponding

I

20

120

However,

II

I

100

120

for the 11-&,13Parent

to exist in the corresand g-*,11-

energetically

compared

is disfavored

the 12-z-e-locked higher

I

respectively.

the 12-s-cis conformation --

2c and 2d, would be of a relatively

I

80

ll-cis,l3-+-

unperturbed

and, accordingly,

I

13-e-

to the in the and

energy than the correspond-

1005

ing parent

Thus, while

retinals.

in the parent

series retinals

considerably

less stable than those of 11-trans,l3-cis --

tive thermal

conversion

of the two geometries The presence course

are of comparable

of light

(fluorescent

of the above thermolysis The isomer derived

each case. 2a

of the former to the latter,

clearly

2d under

similar conditions

resulted

retinoids.

This proposal

largely

dependent

excited

singlet

such rotation. spatial the

13-double

bond exhibited

locked

retinals

spatial

demand

We have utilized -cis-retinals lability

series

further

12-s-cis --

Photolysis

of

In both cases, photolyabout

in terms of the elegant

ap-

photoisomerization

substituted

photo-products double bonds

on the volume of displacement

favored.

of is

in the

accompanying

The bias towards photoisomerization is further

of the 12,20-tetramethylene

six electron

reinforced

of

in the 12-s-cis--

bridge which

increases

the

bonds.

electrocyclizations

isomerization

illustrate

and, in the following

solu-

for photoisomerization

amounts of primary

retinals13

characteristic

of 11-&,13-

about the 11-double bond and the photochemical

of the 13-double bond in 13-cis-retinals -

These reactions

affinity

explicable

about the 9- and 11-double

reversible

When a hexane

about the 13-double bond is by far the mode of least

by the parent

to effect thermal

If light is completely

light source at -10 OC, it

of only 2d and 2b.

about equivalently

heavily

by the introduction for twisting

isomer in

as the -all-trans-retinal

2b.

model to the regioselective

in turn is dependent

and is consequently

bulb) during the

isomer being detectable.

that the relative

In 2c and Zd, rotation

demand

tungsten

The remarkable

on the ease of rotation

state, which

no other

by 2c and 2d is readily

contends

compounds

situation.

of an additional

of the thermal manifold.g

in a mixture

by Liu12 of the Dellinger-Kasha

are

no trace of these isomers could be detected,

to a loo-watt

of 2c and 2a,

out to >15% conversion.

13-double bond exhibited

plication

in the formation

from the lc -t-2c system was identified

2c was exposed

to give a mixture

sis was carried the

results

series,

equilibrium

room lights or a loo-watt tungsten

reactions

that they are not products

tion of the 13-cis-isomer isomerized

in a thermal

geometry

in the quantita-

in the 12-s-cis-locked --

energy resulting

during the course of the thermolyses, indicating

resulting

from the Id t 2d system as the 9-cis-retinal -

and that derived

excluded

geometry,

of ll-cis,l3-cis -

to effect isomerisation

the multifarious

communication,

transformations

we discuss

about this bond.

accessible

the novel absorption

in the retinoid

spectra

of the new

locked retinoids.

Acknowledgments. The National Institutes of Health (USPHS Grant BY-02452 and NC1 Contract CP-05715) provided financial support for this project. We also acknowledge the National Science Foundation Midwest Center for Mass Spectrometry for mass spectra and BASF (Ludwigshafen) for chemicals. References and Notes (1)

Wald, G.

(2)

Stoeckenius,

(3)

Science

For general

W.

reviews,

ing articles. (4)

(Washington, see:

1968, 162,

(a) Menger,

(b) Dttolenghi,

(al Knudsen,

C.G.; Carey,

(b) Knudsen,

C.G.; Chandraratna,

Cooper,

D.C.)

Sci. Am. 1975 (Nov.),

T.M.; Birge,

M.

230.

38. E.L.

Act. Chem Res. 1975, 2, 81, and accompany-

Adv. Photochem.

S.C.; Okamura,

W.H.

R.A.S.; Walkeapaa,

R.R.; Okamura,

W.H.

_Ibid.

1980, 12, 97.

J. Am. Cbem. Sot. 1980, 102, L.P.; Chauhan,

1983,

105,

1626.

6355.

Y.S.; Carey,

S.C.;

(cl Chandraratna,

1006

R.A.S.;

Okamura,

A.L.; Okamura,

W.H.

Ibid.

BGchi,

Marvell,

G.; Yang, N.C.

(7)

(a) Kluge,

A.F.; Lillya,

Org. Chem.

1971,

E.N.; Caple, G.; Gosnik,

(9)

36,

1968, 5747.

(d) Schiess, R.; Suter, C.

G.; Brown,

41,

438.

MS.

(cl Kini, A.; Matsumoto,

During

studies

retinals

earlier

efforts

discussed

W.

c.P.

Tetrahedron 485.

-J.

Lett.

(e) Schiess,

Proc. Natl. Acad. Sci. U.S.A. Ibid. 1956, 42,

R.; Wald, G.

J. Am. Chem. Sot. 1979, 101,

Liu, R.S.H.

of lc and ld

in Reference

to convert

All new compounds

lc

and

grade hexanes

and magnetic

Ibid.

1983, 105,

5078.

2923.

carried out under ordinary

Id

4b) led to some confusion

to

laboratory

was freshly

which might

distilled

induce geometric by IH-NMR, W

were characterized

and complicated

our

2c and Zd, respectively.

from LiA1H4 under

stir bars used in the reactions

to remove any impurities (11)

A.F.; Lillya,

resulted

Spectrophotometric glassware

619.

1966, s,

(b) Kluge,

in Al3 _cis to trans isomerization as well. This unusual light (an unexpected complexity not observed for the analogous isomers of the

sensitivity parent

M.;

Ibid.

P.K.; Hubbard,

H.; Liu, R.S.H.

, thermolyses

Bayerque,

1713.

R.; Oroshnik,

W.; Brown,

A.E.; Kini, A.: Denny,

initial

G. 4458.

Helv. Chim. Acta 1970, 53,

1970, 3,

P.K.; Hubbard,

(b) Oroshnik,

93,

P.; Chia, H.L.; Suter, C.

P.; Chia, H.L.

(a) Wald,

R.A.S.;

2318. 1971,

Ibid.

Ibid.

(d) Chandraratna,

T.A.; Zimmer,

Cc) Schiess,

1955,

light conditions

(10)

C.P.

1988.

P.; Seeger,

(d) Asato,

6114.

3588.

Ibid. 1957, 2,

(5) (6)

(8)

1982, 104,

Ibid. 1983, 105,

W.H.

argon.

All

were washed with Na28203

solution

isomerisation.

and high resolution

mass

spectroscopy. ab 'H-NMR Data for Za-d and la-d-'H7 la:

1

6.19

1

6.05

1

(16.4)

2a:

1 1

6.30 (15.8)

1 1 1

1

6.21

1

(16.0)

lb:

2b: lc: zc:

Id:

Zd:

*11

HlO

%

(16.4)

1 1

6.46

1

(11.7)

1 1

6.17

1

(11.7)

6.29

1

6.80

(12.0)

1

(12.0)

1 1 1

(15.8)

1

1

6.64

1

(16.0)

1

6.08

1

6.55

1

1

(11.9)

1

(11.9)

1

6.18

5.96

2(CH3)16,17

S15

S14

1

1

10.11

(8.0)

1

(8.0) 1

6.18

I 1

10.04 (8.2)

I 1

I

10.12

I

1

(8.1)

l

(8.2) 5.97 (8.1)

1

6.23

1

6.66

I

6.20

1

6.87

1

6.15

1

10.04

1

1

(16.2)

1

(16.2)

1

(11.8)

(

(11.8)

1

(8.2)

1

(8.2)

1

I

6.17

1

5.95

I

6.57

1

5.99

I

9.51

1

(16.1)

1 1

6.00

1

(16.1)

1

(11.7)

1

(11.7)

1

I

6.31

1

6.17

)

6.29

1

6.47

1

5.98

I

9.64

1

1

(16.4)

1

(16.4)

1

(11.7)

1

(11.7)

1

(8.2)

1

(8.2)

1

)

6.19

1

6.62

(

5.86

1

6.65

)

6.00

)

9.51

I

1

(15.8)

1

(15.8)

1

(12.0)

1

(12.0)

1

(8.2)

1

(8.2)

1

(8.2)

1

1 6.28 ) 6.58 1 6.20 1 6.54 1 5.95 ( 9.60 1 1 (15.8) 1 (15.8) 1 (12.3) 1 (12.3) 1 (7.6) 1 (7.6) 1

%hemical

1.02

I

1.70

1.04

I

1.74

2.00

1.05

I

I I

1.76

1

1.93

1.74

I

2.04

\

1.95

I

I 1.04

I

I 1.01

I

1.68

1

(8.2)

(CS3)19

(CH3)1S

1

1.94

I 1.04

1.74

1

1.95

I 1.04

I

1.75

I

1.89

I 1.02

I I

1.71

I I

2.04

shift data in 6.

ðyl groups appear as singlets and all other protons constants in Hs are in parentheses. (12)

Liu, R.S.H.;

Asato,

(13)

(a)

W.H.; Crouch,

Waddell,

(b) Waddell, Ibid.

W.H.; Hopkins,

J. Am. Chem. Sot. 1983, 105,

R.; Nakanishi, D.L.

Ibid.

in USA 8 December

1983)

1977, 2,

(Received

A.E.; Denny, M.

listed appear as doublets;

4865.

K.; Turro, N.J. 1977, 2,

6457.

_Ibid.

coupling

4829. 1976, 98,

4189.

(c) Denny, M.: Liu, R.S.H.