Anthracyclines and related substances. 4. A novel regio- and stereoselective total synthesis of 7-epidaunomycinone and daunomycinone.

Tetrahedron PrInted In

Letters,Vo1.23,No.38,pp

3871-3874,1982

0040-4039/82/383871-04$03.00/o

Great Brltaln

01982 Perqamon Press Ltd.

ANTHRACYCLINES AND STEREOSELECTTVE

S

AND RELATED

SUBSTANCES

TOTAL SYNTHESIS

David Kimball,

K S. Kim, Dllllp

Ermes Vanottl,

Departments

4.

A NOVEL REGIO-

OF 7-EPIDAUNOMYCINONE

and Francls

of Chemistry

AND DAUNOMYCINONE

K. Mohanty,

Johnson*

and Pharmacology

SUNY at Stony Brook Stony Brook, New York

Abstract

Daunomyclnone -Za has been synthesized by a novel reglo- and stereoselectlve route that establishes the tetracvclic framework and the C-7 oxveen m .Y naphthacenol -5c via a double Frledel-Crafts acylatlon

The clinical

Importance

of the anthracycllne

mycln -2b has led to a substantial respectively these systems,

number

antltumor

agents adrzamycm lb and dauno-i of their aglycones, -la and &,

of total syntheses

Several of these have successfully addressed on- of the maJor problems posed by 2 the reglochemistry. A second problem m the synthesis of daunomyclnone

namely

1s the lntroductlon dlfflcult

11794

of the C-7 oxygen3

which

In most cases has been accomplished

by a chemlcally-

last step

@J&p

1:

R=OH

~*R=H a :R’=H b R’= daunosamme

Me04 Previously

2c

=n an efficient, IntermedIate

we reported

that lactone -3b can be converted

reglocontrolled

-3a that establishes

process.

to 7,9-dldeoxydaunomyclnone

We now report a total synthesis

the tetracycllc

3871

ring system m

of daunomyclnone

one step(DB+DCBA)

from

via a novel

3872

4

Meb HO

OEt

5_b

Med

&Et

bEt

F’

Q

9”

PI

Frledel-Crafts

double

It allows control

reactlon

selectrvely

a feature mlsslng

from many prevrous

hydrolyzed(NaOH/MeOH/THF/H2O/reflux/4

reaction

involves

at either of the two free aromatic that dlacld 4 would

first cyclize

could be expected

These expectations 5 mm,

the C-7 oxygen atom 4

to render

Intermediate carbon atoms.

5 whose dlethoxy

to give the anthrone

were fully borne out

Treatment

J&

24 hr) to dlacid 5(83%).

aromatic

Based on our prevrous

the B ring susceptible

In addrtlon. approaches.

days) to give monoacid

In 78% yield, 5 which was then reduced(CF3C02H/Et3SlH/

The critlcal

2

and incorporates

of A ring stereochemistry,

Lactone &was as white needles

cyclrzatlon

lring can be acylated

work 296 we anticipated

5a. Tautomerlzatlon to the anthracenol to acylatron by the other acid moiety

of

4 wrth

CF3C02H/(CF3C0)20

showed,

after

primarily

species -5a(6 4.06, -OCH3). Tautomerrzation of anthrone -5a to anthracenol -5b was half-complete after 1 hr(6 3.97, -OCH3), and some -5d was m evldence(g 6.50, H-5) at the same time After 6 hr the NMH spectrum7 shows only pure x, bicarbonate workup afforded anthracenol -Sc(lOO%)

as a fluorescent

tive is supported In practice

orange 011.

by the chemrcal a one-pot

(CF3C02H/(CF3CO)20/18 5 as orange blades

The structure of -5d as a 5-trifluoroacetyl derrvashift of the proton at C-5, as well as by precedent. 8

sequence

hr) followed

commencing by immediate

with 4 was carried

out by double cyclizatron

oxldation(Cr03/HOAc/acetone/Oo/30

in 46% yield after recrystallizatron.

mm)

to afford

3873

Scheme II

The functlonalization of 5 afforded

of the A ring 1s outllned

the C-7 alcohol e

and lactonlzatlon((CF3CO)20) methyl

as a yellow

Hydrolytic ketone -lOa(78%). hydroxyl

This hydroxy

m

&

78% yield

We believe

that this result

delivers

of -10a

is evident

ketone was shown

ethylatlon(A1C13/PhN02) 12 literature.

a proton

Reduction(BH3/RT/30

mln)

which upon hydrolysls(NaOH/THF/48

in 85% yield.

This was then converted

hr) of j& led stereosalectlvely

hr) to

to trans

1s due to complexatlon

of water by the C-7 10 enol. The relatrve of the Y-equatorial proton at C-7 11

to the u-face of the lntermedlate

from the splitting

;o have the 'natural'

to give z,

II.

from &.

decarboxylatlon(NaOH/H2O/THF/12

group which

stereochemistry

solld(79%),

gave lactone-acid

ketone -9a(SOClZ,CH2N2;YI)'

In Scheme

stereochemistry

whose NMR spectrum

Hydroxylation(t-BuOK/t-BuOH/DMF/02/(EtO)3P/-4Oo/l5

m

was ldentlcal

the A ring by dewith that reported

m

the

mm) 13 of methyl

ketone -10a gave 40% of only trans dlol -lla after chromatography and recrystalllzatlon The selectivity of this step may reflect either steric control or nelghborlng group partlclpatlon by the C-7 hydroxyl group.

In either case, the net result

1s the transfer

of re_atlve

stereochemistry

from C-7 to

c-9 l4 Selective in 64% yield. llterature16 eplmerzzed synthesis

de-ethylation15(dry The physical

A1C13/PhN02/2

characteristics

hr) of J&afforded

of a synthetic

and also the spectra of an authentic sample. 3b to daunomyclnone in high yield, the synthesis

of the latter

substance

7-epldaunomyclnone

sample matched Because

3c

those recorded

7-epldaunomycmone

of -llb constitutes

j.l& in the

has been

a formal total

3874

Acknowledgement

We thank Dr

of 7-epIdaunomyclnone partial generous

C.R

aid of this rr;earch(CA financial

References

Iden for mass spectra,

We are indebted

to the National

and Professor

Institutes

20197) and to Farmltalia/Carlo

A.S. Kende for spectra

of Health

for a grant In

Erba Spa.(Milano,

Italy) for

support

and Notes

1.

For recent comprehensive reviews see Kelly, T.R. Ann. I&&. Med (1979), 14, 288 and Kametani, T , Fukumoto, K _ Med. _. Res Rev.(1981), L,??-72. For detailed monograph Arcamone, F. "Doxorublcin", Med Chemxonographs(1981), II, Academic Press, N Y., N Y.

2

(a) Swenton, J S.,Raynolds, D.W. J Am. -Chem. Sot (1978), 100, 6188-95 (b) Suzuki, F., Trenbeath, S., Gleam, T.D., Slh, C.J.J. Am. Chem Soc.(1978), 100, 2272-3 (c) Kim, K.S , Vanottl, E , Suarato, A , Johnson, F 3 Am. Chem =.(1979), (d) Kende, A , l.&, 2483-4 Rlzzi, J , Rlemer, J Tetrahedron Lett-(1=9), 12OlT (e) Kelly, T.R , Vaya, J , Ananthcsubramanian, L. 2. Am. -Chem Soc.(1980), 102, 5983-4. (fj Parker, K A., Fallmerten, J J. Am Chem. Sot 1980), 102, 5881-6. (e) Dolson, M.G , Chenard, B L., Swenton, J S. J. & Che: Sot (1981), 103, 5263-4. --

3

(a) Wong, C.W., Schwenk, R., Poplen, D , Ho, T -L --Can. J Chem (1973), 51_, 466-J. (b) Kende, A., Tsay, Y , Mills, J.E ---J Am Chem Sot (1976), 98, 1967-9 (c) Smith, T.H., (d) Kende, A Fullwara, A.N., Henry, D W , Lee, W W. J. --Am Chem. Sot (1976). 98, 1969-71 (e) Arcamone, F., Curran, D.P., Tsay, Y., Mills, 3 E. Tetrahedron Lett.(1977), 3537-40. Bemardl, L., Patelli, , Glardmo, P., DQlarco, A , Casazza, A M., Soranzo, C , Pratesl, G Experientia(l978), 3&, 1255-57

4

For routes to J-keto compounds that were unsuccessful, Gleam, R.D , Slh, C.J. J. 9. Chem (1978), 43, 4154-69

see Suzuki, F , Trenbeath, and reference 2a

5.

All compo_Ids

data

gave satisfactory

spectral

and analytical

6.

Kim, K.S. Doctoral

7.

From the NMR evidence there 1s no build-up of either -5b or SC appears to be the rate-llmltlng step m the reaction sequence Whltlock, Wolfram,

Dlssertatlon,

B.J., Whitlock, R.K., Brown,

H.W. -J

R.L

SUNY at Stony Brook, 1978

a.

J. Am. Chem -_--

Chem.(1980), Soc.(lo43),

For a slmllar case of Internal protonatlon hydroxymethylcyclohex-2-enone. Nagata, W 1650 -Soc.(1968), 90 Brockmann,

J

H.; Nremeyer,

12. Kende, A.S., Belletire, 4425-27.

to -5b

thus

45, 12-15 65, 1516-21

see the Wolff-Kishner

reduction

of 3-ethyl-5& Chem

, Hlral, S., Okumura, T., Kawata, K 2

Chem. Ber.(1967), --

100,

3578-87

, Bentley, T.J , Hume, E , Alrey, 3. J

(19J5),%,

Introduction of chlrallty at C-7 via asymmetrlc reduction would thus allow establishment of This posslblllty 1s being an optically pure stereocenter at C-7 and subsequently, at C-9 explorrd III an attempt to develop a direct synthesis of optically active daunomyclnone.

K., Tolklehn,

(Received

In

USA

Sci. Hung

(1957), 12, 83.

K

Chem. Ber (1979), 112, --

22

June

1982)

Chem.(1968),

2~:

Gardner,

C. ---Acta. Chum. Acad

a

&I. Chem

13

16. Krohn,

F E , Gnol, D. J

Tautomerlzatlon

14

15. Szantay,

J.N., Carlon,

J

S.,

3453-71.

33, 3294-97.

,