Enantiospecific synthesis of polyhydroxy amino acids. Synthesis of the C33C38 portion of calyculins.

Tctrahcdron Letters. Vo1.32, No.47,

pp 6977-6980,

1991

Oww4133Y/5)1 $3.00 + .oo Pcrgamon Press plc

Printed in Great Britain

Enantiospecific

Synthesis of Polyhydroxy

Amino A.cids.

Synthesis of the C,, -C,, Portion of Calyculins. Ari M.P.

and Jingshan Chan

Koskinen'*l

Department of Chemistry, University of Surrey Guildford, Surrey GU2 5XH, U.K.

Key

Wards:

Calyculin; enantiospecific synthesis; polyhydroxy amino acids; cis-hydroxylation.

Abstract: A stereocontrolled methylamino-5-methoxypentanoic antibiotic calyculin has been

Calyculins A-H are from the marine sponge

synthesis acid, the achieved.

of

2,3-dihydroxy-4-diportion of

C33-C37

markedly cytotoxic bioactive metabolites isolated cely~.~ Calyculin A .is also a potent

Discodermia

inhibitor

of

promoter.4

Its use as a biochemical tool has been recommended

protein

phosphatases

of cellular phosphorylations.' elucidated

by X-ray

the

1

and

2A,3

and

a

powerful

tumor

in studies

The structures of the calyculins have been

crystallography

and spectroscopic

means,'B3

but the

absolute stereochemistries remain yet to be ascertained. Activity towards the total synthesis of calyculins has been reported: Evans described a synthesis of the spiroketal portion corresponding to the segment C13-C25 of calyculins,6 and Armstrong has devel.oped methodology for the formation of the Cz5-C26 bond.? In a complementary approach, we have also embarked Letter,

we wish

on a synthesis of this intriguing

to report

the synthesis

structure.

of the highly

oxygenated

acid portion, C55-C57 of calyculins in a stereocontrolled manner. OH

0

R

Me

A (R-H) CalyculinC (R-Me) Calyculin

6911

In this amino

6978

The

synthesis

follows.

Reaction

phosphonateg column

of

the

of the

at - 84

serine

'C gave

chromatographic

could

be detected

T

polyhydroxy

amino

derived

the

in the

crude

aldehyde

Z-olefin

product

of

porti0.n

(a8

(2)l"

None

purification.

acid

as

the

Clark

Still

in 90 $ yield

after

flash

the

with

proceeded

corresponding

E-olefin

mixture.ll

CHO a

0

b,c

N 'BOC

1

2

3R-H 4R-Ac

OAc

OAc

NHBOC C02Me

7

6

5

RRAGENTS: (a) (CF,CH,O),POCH,CO,Me,18-c-6, KHMDS; (b) OsO,, NMO, Me,CO:H20; (c) Ac,O, pyr; (d) cat. TsOH, MeOH; (e) CH,N,, silica, CH,Cl,; (f) i: TFA, CH,Cl,; ii: 37 % CH20, NaBH3CN, NaOAc, CH,CN.

The next the

two

hydroxy

mediated more

step

single

isomer

course

of

steric

the

from

absolute

the

of

(2) with

formed

the originating confirmed to

in

50

amino

face

catalytic

% purified bearing

the

six-membered

two

Oz.04 and

new

The

of the

o,o-acetonide

the

a

giving

rise

to the

In the

event,

3 days,

oxide

a single

in a diol

stereochemistry center

acetonider5 &

of

steric

oxygenating

and the new chiral

cleavage

formation

morpho:line

relative

OS04 much

of the

bond,

for

of

is therefore

that

centers.l'

N-methyl

temperature

yield-l4

and

exclusive)

addition

using

experiences

anticipated

of the double

carbon

selective

entail

in the

(7:l) at room

through

(if not

introduction

accomplished

Z-olefin strain12)

furthermore

would

stereochemistry

be

The

allylic

favorable It was

less hindered

of acetone:H20

conversion

a

to

olefin.

(due to

bis-hydroxylation

correct treatment

to

stereospecific

envisaged

the

control

rise

requires

was

of

of the diols.

reagent

it was

This

groups.

to give

expected

(3) was

synthesis

cis-hydroxylation

stringent

mixture

in the

(mp

at

adjacent

to

followed

by

:147-g

'C),

and

6979

examination

of its

lIi NMR

The optical

spectrum.16

also checked at this stage through oxidation NaoAc) to the acid corresponding (S)- and (R,S) -phenethylamine. least 99 % optically pure.

integrity

(L), and derivatisation

to

Based on HPLC analysis,

K

of

(1) was

(RuC13, NaIcI.,,CC14-CHSCNH20, Iof this with

(2) was deemed at

i l-r--Y

0

0

C02Me

BOCNH

OH

8 The

hydroxy

quantitative

groups

were

protected

(Ac20, pyridine)

yield, and the acetonide was cleaved

to give the amino alcohol

(a.

o-Methylation

to

give

(k) in

in (cat. TsOH, MeOH)17

(CHzNs, silica gel, CH2C12,

84 %)I' to give (a). The t-butoxycarbamate was then cleaved

(I'FA,CH2C12),

and without further manipulations the primary amine was subjected to exhaustive methylation (37 % formalin solution, MeCN, NaOAc, NaBH,CN, 48 % from &)I9 to furnish the desired fully protected C 33-C37 fragment

(3

as a

thick colorless oil. We have demonstrated the utility of natural amino acid derivatives the

highly

Although

stereospecific

depicted

assembly

as the enantiomer

segment, we have synthesized which

should

allow

these

natural

the

metabolites.

Acknowledgments.

polyhydroxylated

The

of the

optimized

of the target

amino

calyculin

the more easily accessible

confirmation

synthesis of diastereomers due course.

University

of

of the natural

absolute synthesis,

acids.

amino acid

enantiomer

of 6,

stereochemistry as

in

well

as

structure, will be reported

of the in

The authors wish to acknowledge the support from the

of Surrey

(post-doctoral fellowship to J.C.), and Glaxo Group

Research.

References and Notes: 1.

Present

2.

(a) Calyculin A: Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.;

address: Department Linnanmaa, SF-90570, Finland. Fujita,

S.;

Calyculins

Furuya, B,

C

and

T. D:

J.

of

Am.

Kato,

Chemistry,

Chem.

Y.;

University

of

Oulu,

sot. 1986, 108,. 2780. Fusetani, N.; Matsunaga,

(b) S.;

6980

Hashimoto, K.; Koseki, K. J. Org. Chem. 1988, 53, 3930. (c) Calyculins E-H: Matsunaga, 1991, 3.

47,

Ishihara, Xato,

S.; Fujiki, H.; Sakata, D.; Fusetani, N. Tetrahedron

2999.

H.; Martin,

Y.;

Fusetani,

B.L.; Brautigan, N.;

Hartshorne, D.J. Biochem. 4.

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Watabe, Biophys,

Res.

Commun.

lSB9,

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S.;

Wolecular

Kahn,

S.M.;

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Hoshina,

w.;

2,

S.;

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184.

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5.

Cohen,

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(TIBS)

1900,

6.

Evans, D.A.;

7.

Zhao, Z.; Scarlato, G.R.; Armstrong, R-W. Tetrahedron

a.

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1990,

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1983,

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Mann, A.;

13. Cha, 14. It

is

See also: Jako,

diethylphosphonoacetate.

Taddei, M.; Wermuth, C. Tetrahedron

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with methyl 12.

for isolated, purified products

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1989,

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J.K.;

Christ, W.J.;

interesting

cis-hydroxylation

to

Rev.

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68,

in this

conditions,

the

1984,

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E-olefin

reaction

1990,

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Chem.

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that

upon

corresponding

rise to a nearly 1:l mixture of diols. This dramatically the effects of the allylic strain in directing

of 1

I.; Uiber,

(b) Hoffmann,

Kishi, Y. Tetrahedron note

otherwise

identical to

2 gave

demonstrates

the steric outcome of

such reactions. 15. Beaulieu, P.L.; Schiller, P.W. Tetrahedron

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Gribble, C.W.; Nutatis, C.F. Synthesis

(Received in UK 13 September 1991)

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