A mechanistic study of the FK-506 tricarbonyl system rearrangement: Synthesis of C.9 Labeled FK-506

Tetrahedron Letters,Vo1.30,No.45,pp Printed in Great Britain

A MECHANISTIC

STUDY

REARRANGEMENT:

R.A.

D. Askin*,

OF THE

Daisy

Department Merck

Sharp

Joe,

& Dohme

TRICARBONYL

OF C.9 LABELED

R.P.

of Process

Box 2000,

P.O.

FK-506

SYNTHESIS

Reamer,

0040-4039/89 $3.00 + .oo Pergamon Press plc

6121-6124,1989

Volante

and

I. Shinkai

Research

Research

Rahway,

SYSTEM

FK-506

Laboratories

New Jersey

07065

Hydroxide mediated benzilic acid rearrangement of a C.9-13C labeled Abstract: FK-506 derivative gave 97% rearrangement thru a C.8-tC.10 acyl shift mechanism. Recently,

we

rearrangement

reported

of

the

bis-triisopropylsilyl of lithium Lead

(TIPS)

hydroxide

coupled

rearrangement, tricarbonyl 2 of FK-506 , Our accord

system

may

bond

arrays3.

electrophilic

C.9

the hemiketal

linkage,

1,2-acyl

the

shift

for

was

exposing

concerning

thought

of C.8 to C-10 would

gave

the in

to

allow

ketone then

Fiqure

1

R=TiPS

2

R=TIPS

4

R=TES

8*

R=TES.

4’

R=TES,

C.9=13C

afford

nature

that

the

to

the

was

A

(Scheme

the hydroxy-acid

B.

3

R=TIPS

0

R=TES R=H

in

1,2,3highly

tautomerization

to produce

10

6121

reactive

mechanism

1

C.9=13C

of the

reorganization.

LiOH

ring-chain

1).

activity

non-hemiketalized of

at C.10

(Figure

biological

rearrangement naked,

the

nor-C.9-FK-506

facile

of the bond

acid

of

1 equivalent 2

the

remarkable

addition

initial

the

hydroxy-acid

possibility

the

the nature

reorganizations Thus,

ketone

then

intriguing

responsible

speculation

similar

tricarbonyl

with be

rearranged

(1) with

Due to the extremely

yield.

set out to investigate

we

original

with

overall

the

Treatment

of FX-506

decarboxylation

benzilic

mediated

systemI.

derivative

at 0°C afforded

3 in high

hydroxide

tricarbonyl

ether

mediated

tetraacetate

derivative

facile

a

FK-506

of 1). A

6122

a sequence could be envisaged whereby the alkoxide A' generated

Alternatively,

would suffer a 1,2-ketol shift4 of c.11 to c.9, thereby 7-membered lactone, which would presumably be affording an intermediate saponified under the reaction conditions to B'. If the rearrangement proceeds at C.10

by

LiOH

thru the acyl shift mechanism

llall,then decarboxylation

of the

intermediate

hydroxy-acid B would result in the loss of the original C.9 carbonyl group as CO, to afford C. However, if the rearrangement proceeds thru the ketol shift "b" , then decarboxylation would result in the net loss of the 13C labeling Thus, a original C.10 hemiketal carbon as CO2 to afford C'.

mechanism

experiment

of

C.9

either

or

C.10

would

distinguish

between

these

two

possibilities. Scheme 1

C-IL coo I

N

Pb(OAc)4

OH

Me

Me

0

*

% Me0

H

DMe

C

1 or 4

CLcod N

Pb(OAc)4 Me

* =C.Q

*

(foLi

-

wc&k 1

Me0

H

(via

Toward prepared.

this The

C’

B

A’

end,

the

FK-506

bis-triethylsilyl

lo&me)

4f

derivative

(TES) synthetic

13C-labeled intermediate

at

C.9

was

used

was for 5

is this work, since retroaldol decomposition of FK-506 under basic conditions effectively prohibited by a C.24 silyl ether protecting group6. The 99 atom % 13C enriched imide 5 was synthesized as shown in Figure 2. Treatment of the labeled aldehyde

imide 5 with 67

gave

the

triethylamine labeled

and di-n-butylboron

aldol

product

7

(90%).

triflate This

followed by compound

converted to the C-g-labeled FK-506 derivative 4* as previously described7.

was

6123

Treatment (37.5

mg)

of

with

174,

171:

label

at

with

hydroxy minor, the

acid

of

9

at

label

resonance

(97 ppm)

integral of

the

10 showed from

the

original

rearrangement pathway verifying

of

mg,

83%

from

present

60% 9

at

unexpected

rearrangement

The

8 4)

*

appears

unlabeled

4*

overnight)

followed

by

workup

isomer

with

a

Integration of

of

hemiketal

shift

mechanism

to be thru

the

H02CC?Ht120PMB

6

a)

4-methoxybazyl

alcohol.

b)

pivaloyl

TEA,

chorids,

(S)-4-Benzyl-2-ozazolidirrone/n82Lli

Ndf,

THF,

0’

tolumw, C ;

=

“C

enriched

90 ’ C,

4h;

the-n -78

D C to

6,

0’

Et3N,

C

nEk@OTf *

toluene.

7

-50’

(hc

the

of

the

amount the

the

point.

gave

hemiketal

9) vs.

that

hemiketal

"b".

acyl

2

*

this then

of

the

group

8* bearing

at

small

crude

C,

4h

shift

Thus

the

mechanism

of

carbon

that approximately 10 3% carbon , implying

a -

of

the

indicates

our expectation.

HOyX?H,Br

acid

labeled

enhancement

Figure

gave

P~(OAC)~

bearing

This

the

ketol

and

observed

by desilylation

experiment.

is

acid

mg)

carboxylic

be

carbon.

(obtained

O-C,

at the

not

could

hydroxy

(11.3

extractive

respectively).

an approximately

the

4*

THF,

and

labeled

hemiketal

labeled label

by

of the

10

%

eguiv,

carbon

(39.6

atom

acid

(51.7 mg)

crude

the

99

(1.08

rotamers

the

derivative

of

citric 8*

major

original

unlabeled

LiOH

O.lN

guaternary

Decarboxylation nor-C.9

admixture

aqueous

acidification rearranged

an

3% of

major rlalt,

6124

References

1)

Il.:

Askin,

Reamer,

Tetrahedron

2)

(a)

Kino,

Okuhara, (b)

4)

T.; M.:

Kino,

Yajima,

3)

Let&.

T.:

Goto,

Rubin,

Chem.

Rev.

for

See,

example:

Synthesis", 5)

Tanaka,

6)

Attempts

7)

Jones,

LiOH,

R.P.;

THF,

spectrum

The

by

M.;

75,

R.P.;

Shinkai,

I.

the

S.;

H.;

clean

Press,

Hatanaka,

Sot.,

Goto,

T.;

1987,

1249.

Nishiyama,

Aoki,

H.;

M.;

Ochiai,

on

(TESOTf,

Tactics 1984,

109,

FK-506

acid

Askin,

1989,

and Inc. H.:

1987,

benzilic R.A.:

Sot.

triethylsilylation

M.;

N.;

M.:

"Strategies

Academic

Chem.

Chem.

Inamura,

Kohsaka,

in

R.L. ed.,

Reamer,

I. J. Am.

S.:

rearrangement

did not give

Nishiyama,

H. J. Antibiot.

T.

177.

Marusawa,

out

M.;

Imanaka,

Miyata,

T. J. Am.

Mills,

T.;

Goto,

T.;

5031. directly

(1

equiv.

rearrangement.

D.;

111,

Kino,

in Organic p. 54.

Desmond,

R.;

Volante,

1157.

2,6-lutidine,

CH2C12,

25°C)

of

FK-506.

eliminate

delay 3LO)

0°C)

Shinkai,

Prepared

To

carry

T-K.;

natural 9)

to

1975,

A.:

Taga,

H.;

Okuhara,

Lindberg,

Kuroda, M.;

H.;

Danheiser,

Thomas

H.:

Hashimoto,

8)

T.; 1256.

Hashimoto,

Aoki,

Hatanaka,

1987,

M.B.

H.:

M.;

J. Antibot.

Volante,

T.K.;

30, 671.

Hatanaka,

Kohsaka,

T.;

Jones,

R.A.;

1989,

and Notes

was

relaxation obtained

effects using

the

from

nearby

inverse

protons,

gated

a quantitative

technique,

with

a

13C

recycle

of 60 seconds. enriched

(2100%)

enrichment

enhancement original

starting

of

label

(Received-in

the

of

admixture the

natural

hemiketal

carbon

remains.

USA

14 August

is

1989)

23

atom

abundance is 60%,

%

13C

(1.1%). this

at

C.9,

Since

means

that

a

the

21

fold

observed

about

3% of