Synthesis of (±) Fredericamycin A

lllwdo39/93 $6.00 + .oo Pcrgamm Press Ltd

Tcmhedmn Lexus. Vol. 34. No. 16. pp. 26652668.1993 Pdcd in Gnat Britain

SYNTHESIS

OF ($

FREDERICAMYCW

A

AVRamaRao+,AshokKSingh,BatchuVenkateswaraRaoandKomandlaMallaReddy Indian Institute of Chemical Technology, Hyderabad 500 007, India

Abstract : The synthesis of Fredericamycin A (1) has been achieved by subjecting the 1,3-dione (II) to an unusual 5-etrigonal radical cyclization followed by reductive elimination of the halogen in 15 and subsequent demethylation.

Fredericamycln been

the

also

target

because

A

of

of

its

(I)

much

CliveSb.

We wish to report

the

of

main

segments, segment

interest

the 3)7

3 were protected

our

earlier

total

leading

model

pentamethoxy were

in the form

Two

good

elegant

were

process

approaches

for

However,

we

condensing of two polyketide Isocoumarine

The two

lized

for

separately

this

purpose Oxidation

methanol, lowed

building

segment

goal.

All

I,

of

afforded

by oxidative

the

ABC

in which

synthesis

of 3 have

a simplified

converted

6

was

compound

7,

to

the

groups at C-3 of’ pentadienyl treated after

with

(2)

the

been

phenolic

in scheme pivotal

and radical

give

exclusively

derivative

(8).

Condensation

of olefinic

group

the

two

isoquinoline

hydroxyls

part

in 2 and

furnished

2665

been but

the

took

6a,b

established overall

advantage

.

yields of

the

1.

of isoqulnoline

side chain to

which

intermediate

and C-6

NBS

developed,

approach

resultant

cleavage

the key step

Spiro system,

has already

the

acetal

by

convenience.

treating

dimethyl

the

1

segment

units as summarized

methyl

but

cyclisation.

2J6 and the

the

ethers for operational

preferred

introduction

compound

for

the

(418 was

set of reactions.

(7).

for

of

radical

1 yielding

10~~~‘~.

trigonal

(ABC the

1 A

to its antitumor properties* approaches 394 have been devised for 5a syntheses, first by Kelly and recently

reactions3

completing

of methyl

has

griseusl

only .due

to the synthesis

benzphthalide

chosen for

by Streptomyces

Various

two

our findings

not

produced

the Spiro system by an unusual 5endo

basis of

(DEF

antibiotic

complexity.

1, including

construction

On

antitumor

synthetic

structural

skeletal

involves building

an

the

aldehyde

(6)

trap

a standard

respectively.

monobromo with

of 8 with

required

through

have to be functiona-

acidic

derivative solution

benzaldehyde

aldehyde

For

(91 which

of folwas

later

transformed

treatment

with

to the styrene

(12) as a mixture form

under

derivative

(IO). Regeneration

crotyltriphenylphosphoniumchloride of geometrical

iodine

catalysed

isomers9. conditions

of aldehyde

and butyllithium

Compound (cis-trans

12 was isomerized

and

at C-3 and further

in THF gave

trans-trans

diene

ester

to a more trans-trans

forms,

16:8+

from

HPLC

and NMR).

Scheme-1

a) NaOH(2N),

24 h (65%), b) DMS, K2C03,

24 h (70%), d) POC13, reflux

aq, 45’C, Benzoyl

MeOH, rt,

peroxide

min (65%),

(cat),

h) MeOH,

6 h, light PPTS,

Mel, 12 h (82%), j) 0s04,

5 h (87%), e) NaOMe,

(95%),

reflux

acetone,

g) Hexamine,

1 h (98%),

Na104, buffer

reflux

Buli,

3.5 days (98%), c) NH3 6 h (80%), f) NBS, CC14,

acid-H20

PhCHO,

V/V),

(I:l,

HMPA,

rt,

pH 7, O°C, 5 h (60%), k) Ph3P+CH3Br-,

THF (20~1, v/v), O°C, 10 min (78%), 1) DDQ, CH3CN-HZ0 CH2-CHXH-MeCI-,

reflux

acetic

i) NaNH2,

reflux

45 min, -45“C,

THF, -78”C,

45 min (93%), o) DIBAL, CH2C12,

80%

30

8 h; K2C03, NaNH2, ether-

(9:l v/v), 1.5 h, rt (95%), m) Ph3P+-

45 min (78%), n) PTS, NaBr, 12, MeOH,

I h, -78“C (92%), p) PDC, CH2C12, molecular

seives,

45 min, rt (70%). Aldol 2). Sodium careful 3 under carried

reaction

experimental Shapiro’s as

(II) acetate

between

methoxide

per

our

2 and 3 in presence

mediated conditions. 10

conditions earlier

and chloroform

rearrangement Model were

approach in acetic

of LDA furnished

to the

experiments

1,3-dione to

the adduct

(13) (Scheme

(14a) was accomplished

synthesize

l4a

directly

from

unsuccessful. Spiro annulation of dione (I4a) was 3c wherein 14a was treated with Mn (III) acetate, , acid

at room

temperature

for 30 min, resulting

under 2 and first Cu in the

2667

formation

of

chloro

Bu3SnH gave

ether

derivative

a mixture

of the

bromo

in 60% which

and acetic

Reductive

10% yield.

at room

acid

yield.

separation

However,

temperature

for

(14b) in 80% yield’ ‘. Radical

derivative

elimination

on chromatographic

A (16) in less than

of fredericamycin

Mn (III) acetate

(15a)

of products,

of

treatment

with

of l4a with CuBr2,

15 min resulted

cyclitation

chlorine

gave the hexamethyl in the

of 14b with

formation

slow addition

Scheme-2

c

I@

c

llo

X=tl

Ub

X=CIorBr

x =Cl

l>b X - Br a) LDA, 3, THF, HMPA, (58%),

c) CuBr2,

benzene,

-78OC, 3 h (54%), b) NaOMe,

Mn(lII)acetate,

slow addition

AcOH,

12 h, 50°C,

I5 min,

e) Ph3SnH

ethylpropionate,

MeOH,

reflux

1.5 h

rt (SO%), d) Ph3SnH (1 eq), AIBN (0.03 eq), (1.1 eq), benzene,

reflux

2 h (55%), f) BBr3,

CH2C12, -78“C, 30 min, OOC, 10 min. of Ph3SnH (I eq), AIBN (0.03 eq) in benzene of

bromine

additional

in 15b (not

isolated)

graphic

2 h gave the hexamethyl ether I1 separation . The NMR spectrum

ture12.

Subjecting

ricamycin

16 with

at 50°C for

by adding

Ph3SnH

12 h followed

(1.1 eq) and

of fredericamycin

of 16 is fully in agreement and bringing 13 sample .

with the natural

the

elimination mixture

A (16) in 55% yield after

BBr3 in CH2C12, -78“C,

A (1) which is identical

by reductive

refluxing with

it slowly

for

chromato-

the assigned

struc-

to 0°C gave

Frede-

Referencess 1.

Isolation

- Pandey,

R.C.;

Toussaint,

Garretson,

A.L.;

1981,

34,

1389; Structure

sot.,

1982,

104,

Wei, T.T.; Byrne,

4478;

-

Misra,

M.W.; Stroshane, K.M.;

Misra,

R.;

R.;

Pandey,

J.V. .I. Anlibiot,

1987, 44

Misra, R.; Pandey,

R.C. Biochemistry,

R.M.; Kalita,

Geoghegan, Pandey,

786; Biosynthesis

R.C.;

R.C.;

B.D.;

KM.;

C.C.;

White,

Silverton,

Hilton,

- Byrne,

1985, 24, 478.

R.F.;

Jr.

XV. Roller,

Hilton,

Aszalos,

A.A.;

R.J. .I. Antibiot., J.

Am.

P.P.;

Chem.

Silverton,

B.D.; White,

R.J.;

2668

2.

Warnick-Pickle, Latham,

Byrne,

a) Rama

K.M.; Pandey,

R.C.;

1988, 41, 976; Dalal,

King,

M.D.;

Pharmacol., 3.

D.J.;

R. J. Antibiot.,

Misra,

C.K.;

Gorycki,

R.J. J. Antibiot.

1981, 34, 1402;

N.S.8 Shi, X. Biochemistry,

White,

1989, 28, 748;

P.; Macdonald,

T.L.;

Ross,

(Bemother.

W.E. Cancer

1989, 24, 167. Rao,

Reddy,

D.R.;

1119; b) Rama

Rao,

A.V.;

Reddy,

1065; c)

Rama

Rao,

A.V.;

Rao,

Comrtun,

1989, 400; d) Rama

A.V.;

Deshpande, D.R.;

D.R.;

Rao,

A.V.;

J.

B.V. Indian

Reddy,

B.V.;

Rao,

J. Chem. Sot.

V.H.

Rao,

Singh,

Chem. Comrmn.,

CRem. Sec.

A.K.

B.V.; Reddy,

J.

Chem.

D.R. lrriian

1982,

B, 1988, 27, Sot.

Chem.

J. Chem.

Sec.

Khodabocus,

A.;

B, 1991, 30, 723. 4.

Other

approaches

Vernon, D. J.

P.G.;

for

constructing

Angoh,

Chem.

Sot.

Spiro system,

Bordeleau,

A&.;

Trans. 1, 1991,

Perkin

see

L.; (in part)

a) Clive,

D.L.J.;

Middleton,

1443; b) Boger,

D.S.;

D.L.;

Lowe,

C.; Kellner, I.C. J. Org.

Jacobson,

Chem., 1991, 56, 2115. 5.

a) Kelly,

T.R.;

Bell,

S.H.; Ohashi,

110, 6471; b) Clive, S.M.; 6.

Boddy,

C.J.;

Richardson,

ABC

Segment

Tetrahedron J.

- a) Rama 1987,

Chem.,

DEF Segment 574; b) Pulla

ault,

G.A.

Rao, 28,

1987, 52,

Reddy,

Rao,

A.; Wu, Y.-J.; Kleiner,

D.R.; Rao,

Thesis,

Chem., 1987, 24, 509. S.H. Synthesis, 1980, 708.

9.

a) Bohlmann, Schmid,

H. HeIv. Chim. Acta.,

10.

Shapiro,

S.L.; Geiger,

11.

Details

12.

Spectroscopic

F.; Mannhardt,

Reddy,

D.R. J. Chem.

Pune University,

H.-J.

of this methodology

will be published

India,

Deshpande, N.;

V.H.

Reddy,

D.R.;

K.A.; Spero,

D.M.; Koziski,

A.; Tsuboi,

T.; Hayashida,

Sot.

Chem.

1m

D.L.J.;

Comrmn,

c) Parker,

Sedgeworth,

1987,

K.A.; Bre-

J. J. Hetero-

H.-J.:

L. J. Org. Chem.

l%l,

26, 3580.

separa-tely.

of 16: ‘H NMR (200 MHz, CDC13):

data

6 1.87, 1.95 (3H, d, J = 7.0 Hz,

2.55 (2H, t, J = 7.5 Hz), 3.40 (2H, t, J = 7.5 Hz), 3.49, 3.52 (3H, s, CH3, 3.96 (3H, s, CH3,

two

sets),

4.05-4.15

(ISH,

s, 5CH3),

5.95 (IH,

6.95, 6.98 (IH, s, two sets),

7.35 (IH, dd, J = 15.0, 10.0 Hz), 7.60, 7.65 (IH, s, two sets),

at 2.55 ppm resulted

singlet

at 3.40 ppm and vice

versa;

IR vmax

(CHC13):

MS m/z : 625 (M+).

We thank Dr Ven L Narayanan,

IICT Communication

G.S.;

1972, 55, 1828.

6.30 (IH, m), 6.50, 6.55 (IH, d, J = 15.0 Hz, two sets),

1700 cm-‘;

Bennett, Nicholas,

Ber. 1956, 89, 1307; b) Hug, R.; Hansen,

Chem.

K.; Youlus, 3.; Freedman,

7.15 (IH, s, two sets),

13.

A&.; D.S.;

1992, 1489.

Sreenivasan,

Y.; Terada,

183; d) Tanoue,

Angoh,

Middleton,

Annapurnq,

A.V.;

1986, 27, 3835; d) Clive,

Lett.,

Bertz,

diation

C.;

1987, 28, 455; c) Parker,

A.V.;

S. Ph.D.

Tetrahedron

3.95,

Reddy,

b) Rama

Lett.,

cyclic.

sets),

A.V.;

451;

8.

two

D.;

1988,

Chem. Sot. Jpn, 1987, 60, 2927.

- a) Rama

CH3, two sets),

Kellner,

J. Am. Chem. Sot.,

R.J.

P.G. J. Chem. Sot. Chem. Comnun.

V.H. Tetrahedron Org.

Y.; Khodabocus,

L.;

S.R.; Vernon,

T.; Tsuge, 0. &II. 7.

Tao,

Bardeleau,

Lett.,

Deshpande, K.A.

D.L.J.;

C.N.;

N.; Armstrong-Chong,

No. 3153

(Received in UK 7 December

1992)

NCI, USA, for providing

natural

Fredericamycin-A.

m), 7.10, irra1730,