The synthesis of conformationally-restricted diacyl glycerol analogues

Bioorganic dr Medicti ChemistryLetters. Vo1.2, No.2, pp. 131-134.1992 Priited in Great Britain

0960~g94%?‘2 $3.00 + .OCl 0 1992 Pagamon Press plc

THE SYNTHESIS OF CONFORMATIONALLY-RESTRICTED

DIACYL GLYCEROL

ANALOGUES Josie C. Briggsa Alan P. Dawsonb Ian Gibsonb Alan H. Hainesa** Jackie Hookb and Richard J. K. Taylora** School of Chemical Sciencesa and School of Biological Sciences,b University of East Anglia, Norwich NR4 7TJ, UK. (Received 1 Ocrober 1991)

A

Abstract: have been using

In

series

prepared

the

preceding of

potential

proliferation.2 analogues thereby

paper’

form as potential

we

reported

the

diacylglycerols

protein

preparation

(DAG,

the 2-acyl

positions

conferring

unit of diacyl

of the glycerol

e.g.1)

conformational

glycerol

backbone

rigidity

kinase

as starting

analogues C antagonists

materials.

of a series which

kinase C (PKC) antagonists and as As part of the same programme we decided

in which

the 1 or 3

diacylglycerol

and D- and L-2-deoxyribose

intracelluar

protein

conformationally-restricted

in homochiral

D-ribonolactone

analogues

of

were

of acyclic screened

(1) was covalently

[e.g. (A) and (B),

to the extremely

as

inhibitors of cellular to prepare cyclic DAG

flexible

linked

to

respectively], DAG.

(A) X = H or OCOR’ 0

(1) R’=Cf-@‘-kh

R’oco~

R* = C,H,,(CH=CHCH2)4(CH2)2

By using furanose in

homochiral

commencing imidazole chloride

sugars

form.3 with

gave

as starting

Scheme

D-ribonolactone

diol

materials,

1 illustrates (2).

derivative

(4).

the DAG analogues

the

Selective

(3) as a crystalline

to give di-acyl

(B)X=HorOH

solid4

Desilylation 131

preparation

were available

of such

compounds

silylation using tBuPh2SiCI and which was treated with octanoyl of compound

(4) was

achieved

132

J. C. BRIGGS et al.

using

aq. HF in acetonitrile5

acylation

at

the

Rosenthal’s excess

primary

in pyridine

analogue

(7)

along

with

separated

by

analogues

shown

70°C

under

produce using

vacuum,

(10)

acid

acylation

of (9)

analogue

(12).

Several substitution

and

established

activate (11)

PKC.g

compound

has (13)

deoxygenationl

been

Acid-catalysed IR120(H)

freeze-drying

of the

3.”

in the synthesis

of (17)

the

using

Selective

natural

comparison

product

THF,

affording were

key

tri-n-butyltin of

step

DAG

sn-1 ,2-

purposes,

we

hydride (15)

removal

resin

(16).

used

Barton

in boiling

achieved

of the

to those

the

and AIBN was

(17), (16).

the route from

involved

2-deoxy-L-ribose

identical

to

detritylation

(1 1).

to the type (B)

with

at

tritylated

o but we utilised

The

aqueous

filtrate

aqueous

the product

(7) and (12) are sn-1,2-isomers For

previously7*’

deprotection

in refluxing

by the

version of lactone (1 l), i.e. compound sequence we required 2-deoxy-L-ribose

prepared (14)

access

which deoxy-

using

by acidic

analogue

DAGs

Analogues

in Scheme

2 of xanthate

Amberlite

DAG

are sn-2,3-isomers.

shown

toluene.

only

(8)

DAG

(6) (8)

regioselectively

followed

(A)

gave direct

that

the enantiomeric For this in Scheme 3.

L-arabinose

steps

chloride6

derivative

by heating

was

Acylation

using to an

corresponding

2-deoxy-D-ribose

followed

which

solid.

prepared

as shown

and

(9)7

The

of deoxyribose

carbonate,

gave the type

octanoyl

have

Oxidation

lactone

in ether8

pattern (5)

therefore

gave

with

groups

whereas

2.

silica. from

Direct

effected

gave the type (B)

of the diacylated on

prepared

of calcium

as a crystalline

formic

This

in Scheme

in the presence

was

(5).

in dichloromethane

This procedure

amount

were

(2)

of acyl chloride

at O°C.

a small

DAG analogue

D-ribonolactone

chromatography

(1 1) and (12)

procedures

of

the type (A)

the addition

could

bromine

site

procedure,6

of the alcohol be

to produce

using

by filtration

The remaining

in the enantiomeric

series as shown in Scheme 2. Using

the testing

procedures

described

in the preceding

paper,’

we have

that compounds (5), (6), (7) and (11) do not activate PKC. However, data as yet to establish whether or not the compounds are capable PKC in assays where culture

studies

significantly

affect

concentrations observed

it has been activated

(see up

preceding

(either to

with compound

paper’),

stimulate

or

10m4 M whereas (11) at 10s4 M.

by OAG (see preceding compound inhibit)

the

a reduction

(12) growth

in growth

was of

found

we have no of inhibiting

paper’).

In cell

found

not to

HL60

of ca.

cells 20%

at was

Conformationally-restricted diacyl glycerol analogues

peaaen&

133

(TBDPS = tBuPh2Si)

(i)

TBDPSCI, imidazole,

(iii)

aq. HF, CH3CN (65%)

(iv) C7H16COCI.

(v)

Br2, H20. CaC03

(vi)

DMF (66%)

(ii)

C7H16COCI,

py (79%) py, CH2Cl2, O°C

[(7), 53%; (6),12%] P h 3CCI, from (vii)

as ii (59%) then HC02H.

(ix)

BugSnH, toluene, AIBN (66%)

ether (64%)

py,

4-DMAP

[34%

(8)]

(viii) as (iv) [37% from (8)) (x)

Amberlite (l:l),

IR-120(H),

aq.

93% unpurified

yield

THF

134

J. C. BRIGOSet al.

Acknowledaementg We are grateful

to the Medical

for financial

support.

References

and

1.

Research

Council

and the British

Technology

Group

notes

Briggs, J. C.; Dawson, A. P.; Gibson, I.; Haines, A. H.; Hook, J.; Lloyd, A.; Meiners, S.; Taylor, R. J. K. Preceding Paper.

2.

For background

3.

All new compounds spectrometric

4.

information

see references

gave consistent

l-7

spectral

in the preceding

paper.

and analytical/mass

data.

Attwood, S. V.; ; Barrett, A. G. M. J. Chem. Sot. Perkin Trans. I 1984,131s.

5.

Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S. M. Tetrahedron

Lett.

1979,

3981.

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Rosenthal, A. F. Methods in Enzymology; Lowenstein, Academic Press: New York, 35, 436 (1975).

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Deriaz, R. E.; Overend, W. G.; Stacey, M.; Teece, E. G.; Wiggins, L. F.

8.

Bessodes,

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Rando, R. R.

J. M. Ed.

J. Chem. Sot. 1949,1879.

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M.; Komiotis,

G.; Nakagawa, Left.

is a modified

deoxyribose

D.; Antonakis,

1967,

Tetrahedron

Lett.1986,

27,579.

therein.

M.; Shioi, S.; Sugiyama, Y.; Isemura, S.; Shibuya, M.

3983.

version

of the route

from D-arabinose

Sot. 1956, 78, 1399). 12. Barton, D. H. R; McCombie, 1975,1574.

A.

FASEB J. 1988, 2, 2348 and references

(Wolfrom, S.

W.

devised

for the

preparation

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Trans.

I