Trifluoromethyl group on quarternary carbon; synthesis of 16,16,16-trifluororetinal

Tetrahedron Letters, Vo1.30, Printed in Great Britain

No.5,

TRIFLUOROMETHYL SYNTHESIS

Yuji

Tokyo

College

The

Summary:

Alder

Hanzawa,

synthesis of

GROUP

OF

1989

0040-.4039/89 $3.00 Perqamon Press plc

ON QUARTERNARY

+ .OO

CARBON;

16,16,16-TRIFLUORORETINAL

Makoto

of Pharmacy,

reaction

pp 571-574,

Suzuki

1432-l

of racemic

and Yoshiro

Horinouchi,

Kobayashi*

Hachioji,

Tokyo

16,16,16-trifluororetinal

2-(trifluoromethyl)propenoic

acid

192-03

through

with

Japan

the Diels-

functionalized

diene

is discussed.

In

our

study

rhodopsin

on

the

(bRh),

chemistry

it

was

electronegative

fluorine

chromophore

very

protein's the is

was binding

hydrophobic

atoms

into

with

by

this

retinal

that

the

,

retinal

binding

the

describe

the

of fluorinated

on

give

of

Cl

(L,)

fluorine

to

become

Cl in each

binding

the opsin

rate

shift2)

some

significant

ring

region. 3, In

@ -ionone

study

of

the

about

should

of the

synthetic

the

on chiral on

to study

data

in

carbon group

and

retinal

information

introduction

fluorine-effect

site

the

charges

further

quarternary

be worthwhile

on

bacteriosmall

16,16,16~trifluororetinal

Since

of ,I_.Those

its of

electronic

of obtaining

the

and

position

the trifluoromethyl

also

enantiomer

reaction

the

different

on the protein's we

understand

causes

the

It should

communication,

Diels-Alder

of

retinal

introduction

particular

chromophore.

induce

each

informations

a

the

the purpose

site

it is expected might

apoprotein.

induced

of

fluorinated

that at

to

For

interesting Cl6

asymmetric, enantiomer

useful

binding

considered

atom

site.')

of

found

racemic

_I_through

the

dienophile.

1

3

2

R= H or CH$F3 fluorinated

Retrosynthetically, the

synthesis

cd), which active reaction typical

g.

of retinal

is a useful To

of 2. dienes

our

A,

can

compound

prior

to

for

there

knowledge,

Therefore,

we the

@-cyclocitral

be taken

tried

back

(A), a key

the

forthcoming

has

been

the

preparation 571

intermediate

to trifluoromethylated

no

report

Diels-Alder of 2.

preparetion on

the

reaction Results

of

in

for

compound optically

Diels-Alder

of 2

with

table

1

some show

572 that

the

acid

because

reactivity of

of _ZJas

the

a dienophile

electron

is higher

withdrawing

than

effect

of

that the

of methacrylic

trifluoromethyl

gr0up.l)

Table

1.

The Diels-Alder

Solv.

Diene

Reaction

Temp.

CH2C12

room

of 2

Product

Yield

6/5("

temp.

(%)

81

R=Ba)

74

R=Hb)

48

R=H

79

R=CH2CF3 cl

COOR

CH2C12

120°c

0

J

HO

&

0

3

110°C

Benzene

Me

P TMSO

a)

x

CH2C12

room

endo-COOH/exo-COOH=2,

The

lactonization give type

the

isomer

was

Reaction

of A and

toluenesulfonic 4_ (DIBAL-H,)

For

acid

(2)

was

reduction Formation the

in

obtained handling,

BuO)3A1H/Et20]

to

of 7_ with of the

[2,3]-Wittig

with

ratio

one).

was

of the regio

c)

determined

the endo-COOH

Yield

isomer

isomers

refers

to

was

the

by

iodo-

cyclized 10/l

to

(para

acid-treated

(E)-1-methoxy-2-methyl-3-trimethylsilyl-oxy-1,3treatment

gave

the

subsequent

to methyl

easier

major

subsequent

and

alcohol

product

the

b) The

Only

(TsOH/MeOH).

butadiene5)

converted

stereochemistry

of the stereoisomers.

iodo-lactone.4)

product

the

0

temp.

’

enone

by two

the

nBu3SnH

of

gave

the

methyl

tri-n-butylstannylmethyl

ether

rearrangement7)

THF,

(87%).

alcohol

adduct The

alcohol

high

(

group

volatility

iodide

2

86%,

from

compound (2) -78OC)

with

p-

reduction

of

(Mn02/CH2C12) of 5

[ (Ph0)3P+CH31-

of

(z)6)

(n-BuLi,

yield

the

to the

carbonyl

alcohol

Diels-Alder

allylic

Although

due

enone

iodo

crude

step-procedures

in low yield

give

the

(2) in good

oxidation

55 % yield. group

of

was 5

(&)

and

could

be

nBu3SnHl,

of the

product.

reduced

[Li(t-

). in

Subsequent 83%

(n-Bu3SnCH21/KH, of zgave

gave

yield.

THF)

and

the rearranged

573 alcohol

in 50 % yield.

(12) as a mixture of diastereomers

The alcohol

(12)

(CrO3.2Py, celite, CH2C12) to aldehyde which was then isomerized -. 8-cyclocitral derivative (z)8)(60 %, from 10) by treatment with base

was oxidized to the

The (DBU, Et20, O"C).') established procedure. 11)

racemic

retinal

(_I_)") was

obtained

by

3*

x=1

1

X=H

_J 8

3

n-Bu3SnH ,9

‘.!?

i) (EtD)*~CHZC(Me)=CHC02Me

CHO 2

ii) DIBAL

I n-BuLi

iii) M “02

-

iv) H.P.L.C. separation

v) repeat

The preparation

the

of optically

i) -

!.

iv)

pure ,l_12) and

the determination

of the

absolute configuration will be reported in the near future. Refernces and Notes 1)

V. J. Rao, F. Derguini, Y. Kobayashi,

2’ 3) 4)

6077 (1986). M. G. Motto,

K. Nakanishi,

T. Taguchi, A. Hosoda, Y. Hanzawa,

C. M. Pande and R. H. Callender, M. Sheves, K. Tsujimoto,

J. Am. Chem. SOC., 108,

V. Balogh-Nair,

K. Nakanishi,

Am. Chem. Sot., 102, 7947 (1980). M. Okabe, N. Shimizu, J. L. Spudich, D. A. McCain, K. Nakanishi, Rodman, B. Honig and R. A. Bogomolni, Biophys. J., 49, 479 (1986). J. S. Meek and W. B. Trapp, J. Am. Chem. SoC., 79, 3909 (1957). should be noted that the ratio (endo-COOH/exo-COOH = 2) of

J. H. It the

cyclopentadiene adduct is inverted from that of the adducts obtained by the reactions of a-alkylated propenoic acids with cylopentadiene. This interesting

effect of the trifluoromethyl

the case of 3-(trifluoromethyl)propenoic Hill, Cem. Rev., 61, 537 (1961).

group has also acid.

been reported in

J. G. Martin and R.

K.

574

5)

S. Danishefsky,

61

C.

N. Fritsch

Jr., Two

separable

former

less

than

The

isomer

gave

than

derived

the

yield

polar/more

polar):

2/l,

L-Selectride

7)

w. c.

Still,

81

'H-NMR

(CC14)

C,0H13F30 9)

The

'H-NMR (s, 6.24 J=l1.5

12)

101,

in

more

a ratio

Wittig

(numbers

7_.

of

isomer

McMcurry,

1:2.6,

2

by

l/1.8,

the

not

nBu3SnH product

following

to

the

was

rearrangement The

refer

K(O-iPr)3BH

M.

(1979).

stereochemistry

polar

isomer

P.

7001

are

some

of

less

ratio

Li(O-tBu)3AlH

l/2.6,

Sot.,

field

of

from

1927

1.53-1.70

allylic),

High

Found

100,

(m, 3H),

10.06

the external

resolution

(1978).

(s,

1.85

IH,

(m, lH),

CHO).

benzotrifluoride

mass

spectrum,

2.13

"F-NMR signal).

Calcd.

for

206.0940.

the

M. Rosenberger

u-cyclocitral

to

and G. Saucy,

the

Ger.

8 -isomer

Offen,

under

2,520,186.

basic

C.A.,

84,

(1976).

5-Me), 14-H),

(d,

lH,

and

spectrum, 11)

2H,

1685.

(CDC13) 6 il.23

3H,

J=8Hz,

l/1.7,

(m,

(higher

isomerization

121303~

[2,31

(s, 3H; 6-Mel,

206.0918,

conditions;

10)

7.3

the polar

Gammill,

relative

the

J. Am. Chem.

2.20

v cm-';

The

from

of less

B.

Sot.,

1.4/l.

A. Mitra,

2-Me),

R.

obtained

examined

NaBH4

(CDC13)&;1.51

(CDCl3)ppm; IR

the

reagents

Singh,

latter.

derived

from

reducing

3H,

K.

J. Am. Chem. were

the

higher

DIBAL

(s,

R.

diastereomers

reduction

of

Yan,

polar

determined.

that

F.

and J. Clardy,

2.05 6.1

(d,

J=16Hz,

15H2,

J=lGHz, 6.37

10.11

A. Hosoda

Separation

of

a

scale

in Japan

1.6

g-Me),

IH,

for C20H25F30

T. Taguchi,

(Received

3H,

7-H),

II-H),

Calcd.

preparative

(s, 3H, l-Me), (s,

of

338.1856,

the

1988)

3H,

6.18

IH,

(d,

J=15Hz,

(d, IH, J=8Hz,

HPLC.

1 December

(s,

8-H), (d,

and Y. Kobayashi,

mixture

(bs, 4H),

2.33

CHO).

Found

(m, 2H),

13-Me),

5.98

IH,

(d,

J=11.5Hz,

12-H), High

7.12

1.76 IH,

IO-H), (dd,

resolution

1H, mass

338.1887.

Tetrahedron

diastereomers

2.0-2.15

Lett.,2& (IL)

was

6209

(1985).

achieved

by