Studies on the total synthesis of fredericamycin A: Development of an intermolecular alkyne-chromium carbene complex cyclization approach to the ABCDE ring system

Tetrahedron Printed in

Letters,Vol.30,No.l6,pp Great Britain

2037-2040,1989

0040-4039/89 $3.00 Pergamon Press plc

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STUDIES ON THE TOTAL SYNTHESIS OF FREDERICAMYCIN A: DEVELOPMENT OF AN INTERtiOLEC-iJLAR ALKYtiECtiOMIUM CARBENE COMPLEX CYCLIZATION APPROACH TO THE ABCDE RING SYSTEM Dale L. Boger” and Irina C. Jacobson Departmentsof Chemistry and Medicinal Chemistry Purdue University, West Lafayette, Indiana, 47907, USA Abstract: The development of a synthetic approach to the fredericamycin A ABCDE ring system based on a regiospecijic intermolecular alkyne-chromium carbene complex cyclization is detailed. Fredericamycin A (1, NSC-305263),

a quinone antitumor antibiotic2 isolated from Streptomyces

a unique spiro[C4]nonene central to its

has

structure,

been

activity and confirmed in vivo

antitumor

activity

that

synthesis

oxidative

damage

to DNA

through

Consequently,

enzymes.2s srructurc

A

completed

approach

since the unambiguous

determination4

fredericamycin recently

nondiscriminant after

continues total

to

A

intermolecular

and

which

Scheme

I, 5 -+

chromium

carbene

I, 7 --) S/6.

aldol

complex

In

contrast

chromium

to

a useful carbene

related

closure

might

cyclization

failed

and

to

extensive

preliminary

studies

grised

in

on

the

and

a single tautomeric

protein

crystal

efforts6

X-ray

structures,

including

development

applicable

cytotoxic

of DNA processing

through synthetic

bearing

vitro

resolve

on the

ring system

based

assemblage

provide

one

of a general

to the total synthesis

implementation

of the fredericamycin

for introduction

for implementation for introduction

preliminary

of

a

of

regiospecifc

studies

of the

A skeleton

of a regiospecific

of the resulting

fully

~sts

spiro[4.4]nonene inter-

substituted

or intramolecular

B ring

in the preparation

on the facility

CD ring

hydroquinone:

of 2-3 that establish

system; alkyneScheme this as

A.

expectations

predominate

complex

agents

inhibition

of its structure

A ABCDE

potent

carbene complex cyclization.’

we detail

initial and

detail

possess

discriminant

studies’

of biological*

we

of this convergent

a viable approach to fredericamycin provide

Herein

42 and the feasibility

Herein

subject

and/or

establishment

to

from its inhibition of RNA

is derived

spectroscopic

of the fredericamycin

alkyne-chromium a simpIe

the

stmctura.lly

Key to the development with

be

synthesis.

to the construction

fredericamycin

extensive

shown

in

element

cyclization,

which

the

for

control

a study

electronic of

of electronic

2037

the

nature

of

the

regioselectivity

and

steric

features

alkyne of

an of

was

anticipated

intermolecular the

alkyne

that

to

alkynecontrol

2038

Scheme I

the

X-O,R-H

5

x=0

X-0H.H

6

X=OR,H

cyclization

acetylenes

mode’

revealed

alkynes

>

at

alkyne

the

and regioselectivitysJS”

that

the

adjacent

reactions.8*‘G”

the recent

efforts

alkynes). carbons

of Wulff,~

In

carbene

7

complex

t-butyldimethylsilanol that suffers

a subsequent

generally

acylate

attributed

experimentally

do not acylate

phenols

to

modest to

steric

permit

of this

the product

be

20

derived

(entry

9)

optimally

derived

through

to provide

20.

Under

was

supressed

and,

in the

reaction

(entries

6-8) and

19 with generation

that accelerate

+

the rate

%i”

the

Yamashita

X 1

8

intermolecular As

detailed versus

situ

reaction to

elimination conditions

expectations,

under

Thus,

*

conditions

& OCH,

0% Yield

R

Yield

R

&

OSiMe@tt,

H

H

1.4

A%O:J$N (1.5 eq1.5 eq), WC, hepCane. 1 b. 0.3 M

47%

AC

13

-

Bb

OS~u,

H

H

1.5

AqOZt,N (15 cql.5 eq), SOT. heptane, 3 h, 0.1 M

32%

AC

14

-

9n

OSiMe@u.

H

CQCK

1.5

WC.

22%

H

15

16

-

I.5

A@Et,N (1.5 q1.5 eq), SOT. heptane. 19 h, 0.1 M

10%

H

15

16

8%

18

6%

AC

THF. 24 h 0.03 M

9b

osPb&Bu,

H

CWH,

1.5

A@St,N (1.5 q1.5 eq), SGT. heprane.19 h. 0.1 M

7%

H

17

10

osiMe@u.

II

ClI,OSiM.@U

1.1

Ac#Et,N (1.0 ql.0 eq) 8D”c. heptane. 4 4 0.3 M

68%

H

1920

-

H

10

0.8

%N (I.0 w, 8m heptane. 16 h. 0.3 M

30%

H

19

17%

H

10

1.0

A@ (1.0 E$. 8(pc he&s-t=, 3 h, 0.3 M

66%

H

1920

9

10

1.0

SGT. kptan.

.

19

10

11

0

CH,oSi?vV@u

1.5

65°C. THF. 9 h, 0.03 M

0%

21

11

12

0

‘=WH,

1.5

65-C. THF. 9 h. 0.2 M

0%

22

17 h, 0.3 M

2n

20

of

which was that

19 or 20 may be

+

c-

in

ether

orthoquinomethane

selected.

eq.

9a

6

in

mixture

R’

with

In addition, 10 with the chromium

contrary

of reaction.

R’

7

II.

of an unstable

obtained cleanly from the reaction of 10 with 7 depending on the reaction conditions

schemeII~~~(co15

the

of alkyne.

presumably

anhydride

pattern

in

of alkyne

elimination acetic

substitution

the

of 1.0-1.5 equivalents

from the reaction

the of

(neutral

in heptane

shift

inclusion

alkynes

conducted

1,Shydrogen to the

complexes

neutral

in Scheme

reaction

6)l’

product

in

carbene

regiocontrol

are detailed

proved

with

differences

complete

study

reactions

chromium

optimal

the primary (entry

the phenol

were

of 0.3 M in the presence

conditions

proved from

addition,

results

of Fischer

conversions

sufficient

the benzannulation

(Et,O, THF) at concentrations reaction

chemical

proved

Representative

under the standard

of the reactions

benzannulation

electron-deficient

cyclization solvents

7

2 4

li 74%

H

2039

a

Scheme III 7 + IO

68% bSit&,t8u

CH,d

QJJL

X-H,OH

28

x-0

29

CH,O

R-H

18

R = CH,Ph

25

X

(Bu),NI (0.1 eq). DMF, 25YZc. IS h. (c) HOAc:THF:H%O (a) 80°C. heptane, Ac+u:Et,N (1.5 1 5 eq). 3 h. (b) PhCHzBr (1.2 eq). K&O, (10 ‘%’ (d) (COCI), (2.2 eq), DMSO (4.8 2. E&N (10 eq). CH,Cl,. -60-Z. 1 h. (e) N&H, ( .I eq), CH,OH. 40°C. 6 h. (f-J FCC (1.5 eq), CH,Cl, 2fC. (1 eq), HCOJW, (5 eq), CH,OIl. 25+, 2 h. 01) &.SH (2.5 eq), NaH (5.0 eq). DMF. 15VC. 3 h.

application

The

of

the

rcgiospecific

fredericamycin

ABCD

carbon

benzannulation

product

19 as its benzyl

proceeded

without

and secondary cleanly that

only

ensure

catalyzed

competitive

benzylic under

activation

elimination

alcohols.

Keto

methoxide

thus

alcohols

the

of

aldehyde providing

to the fredericamycin

ether

afforded

of

both

26.

alcohols

closed

functionalized

A ABCD ring system.

of

7

25 was accomplished

oxidation”

with

to the Oxidation

to

cleanly

under by

the

of

the

spirocyclic

carefully

keto

and

alcohol alcohol

conditions of

salt

that

primary

prior

conditions to

secondary exposure

viability

afforded

the

reaction

and

28 upon

the

of the

27 was accomplished

controlled

the

of

phenol

mild basic

primary

establishing

of the secondary

of a competitive retro aldol reaction and subsequent sequential deprotection

the

free

deprotection

biialkoxysulfonium of

assemblage

of the

of diol 26 to keto aldehyde

oxidation

spiro[4,4]nonene

10

followed

and required

formation formal

with

Protection

III.

r-butyldimethylsilanol

through

sulfide

27 cleanly

reaction in Scheme

Direct oxidation

of Swern

dimethyl the

is detailed

elimination

conditions

of

benzannulation

framework

(3:l:l). 4U’C, 48 h. 5 h. (g) 10% W-C

of

this

base-

benzylic to

sodium approach

29 without detection

of 29 provided 2.

Scheme IV

c

e

(a) 8C-Z kptane, A%0(1 =l). 3 h. @) PhCWr (1.5 4. K,CO, (10 eq). (Bu),NI (0.1 en). DMF. WC. 48 h (c) (Bu)+NF (5 eq), THF. 25-Z 72 h (d) (CCCI), (2.2 Y DMSO (4.8 es), &N (10 a. CYCL 67°C. 1 h. (e) NaOCH, (0.1 eq), CH,OH. WC. 3 h (fl PCC (3 es). CH,Cl, 25”. 14 h. (g) BBr, (3.6 eq), CHf& -78 to 25~~. 19

2040

The extension in Scheme

of these observations Regiospecific

IV.

1.0 equiv 31, 80°C benzannulation

heptane,

product

t-butyldimethylsilanol. spirocyclic

keto

(r

95%)

without

36,

detection

of

subsequent fredericamycin

oxidation

previously

products

35, base-catalyzed

provided

developed

32 (85%} as the predominant

37.

derived

from

aldol

closure

(0.3 M 7, or exclusive

elimination

of

of 35 to the

Deprotection

of

37

the

Institutes

provided

3

A ABCDE ring system

Acknowledgments. We gratefully acknowledge the financial (CA42056, NIDDG CA40884) and the Alfred P. Sloan Foundation. References

the conditions

subsequent

of 32 to the keto aIdehyde

and

constituting the partially functionalized

the

A ABCDE ring system is detailed

of the frederlcamycin

of 31” with 7 under

1.0 equiv Ac,O, 3 h) cleanly provided

Conversion alcohol

to the assemblage

cyclization

support

of

National

of

Health

and Notes

1. National

Institutes of Health research career development award recipient, 1983-1988 (CA01136), Alfred P. Sloan research fellow, 1985-1989. 2. In vitro and in vivo activity: Warnick-Pickle, D. J.; Byrne. K. M.; Pandey, R. C.; White, R. J. J. Antibiot. 1981, 34, 1402. Von Hoff, D. D.; Cooper, J.; Bradley, E.: Sandbach, J.; Jones, D.; Makuch, R. Am. J. Med. Derivatives: Yokoi, K.; Hasegawa, H.; Narita, M.; Asaoka, T.; Kukita, K.; Ishizekl, S.; 1981, 70, 1027. Nakajima, T. Jpn. Patent 152468, 198.5: Chem. Abstr, 1986, 204, 33948j. Mechanism of action: Hilton, B. D.: Misra. R.: Zweier. J. L. Biochemistrv 1986. 25. 5533. 3. Prmdey, R, ‘C.; Toussaint, M. W.; S&oshane, R. M.; Kalita, C. C.; Aszalos, A. A.; Garretson, A. L.; Wei, 4. 5. 6.

7. 8.

9.

10.

11. 12. 13.

T. T.; Byrne, K. M.; Geoghegan, R. F., Jr.; White, R. J, J. Antibior. 1981, 34, 1389. Misra. R.: Pandev. R. C.: Silverton. J. V. J. Am. Chem. Sot. 1982. 104. 4478. Misri R.f Pandey; R. C.i Hilton, B. D.; Roller, P. P.; Silverton, J.’ V. i. Antibiot. 1987, 40, 786.

Fredericamycln A ABCD(E) ring construction: (a) Ramo Rao, A. V.; Reddeppa Reddy, D.; Deshpande, V. H. .I. Chem. Sot., Chem. Commun. 1984, 1119. (b) Parker, K. A.; Koziski, K. A.; Breault, G. Tetrahedron Len. 1985, 26, 2181. (c) Kende, A. S.; Ebetino, F. H.; Ohta T. Tetrahedron Lett. 1985, 26, 3063. (d) Eck, G.; (e) Eck, G.; Julia, M.; Pfeiffer, Julia, M.; Pfeiffer, B.; Rolsndo, C. Tetrahedron Left. 1985, 26, 4723. B.; Rolando, C. Tetrahedron Lerr. 1985, 26, 4725. Q Bach, R. D.; Klix, R. C. J. Org. Chem. 1986, 51, 749; 1985, 50, 5438. (g) Braun, M.: Veith, R. Tetrahedron Lett. 1986, 27, 179. (h) Bennett, S. M.; Clive, D. L. J. J. Chem. SM., Chem. Commwt. 1986, 878. (i) Bach, R. D.; Klix, R. C. Terrohedron Len. 1986. 27, 1983. (j) Mehta, G.; Subrahmanyam, D. Tetrahedron Leta. 1987, 28, 479. (k) Clive, D. L. J.; Angoh, A. G.; Bennett, S. M. J. Org. Chem. 1987, 52, 1339. (1) Ciufolini, M. A.; Browne, M. E. Tetrahedron Lerr. 1987, 28, 171. Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J. Org. Chem. 1988, 53, 4149. (m) Parker, K. A.; Spero, D. M.; Koziski, K. A. J. Org. Chem. 1987, 52, 183. (n) Ramo Rao, A. V.; Rcddeppa Reddy, D.; Annapuma, G. S.; Deshpande, V. H. Tetrahedron Lert. 1987, 28, 451. (0) Ramo Rao, A. V.; Sreenivasan, N.; Reddeppa Reddy, D.; Deshpande, V. H. Tetrahedron Lerr. 1987, 28, 455. [p) Naik, S. N.; Pandey, B.; Ayyangar, N. R. Syn. Commun. 1988, 18, 633. (9) Evans, J. C.; Klix, R. C.; Bach, R. D. J. Org. Chem. 1988, 53, 5519. Fredericamycin (C)DEF ring construction: (r) Parker, K. A.; Breault, G. A. Tetrahedron Lerr. 1986, 27, 3835. (s) Clive, D. L. J.: Sedgeworth, J. J. Heterocycl. Chem. 1987, 24, 509. (t) Ramo Rao, A. V.; Reddeppa Reddy, D. J. Chem.

Sot., Chem. Commun.

1987, 574.

Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J. Am. Chem. Sot. 1988, 110, 6471. Kelly, T. R.; Ohashi, N.; Armstrong-Chong, R. J.; Bell, S. H. J. Am. Chem. Sot. 1986, 108, 7100. (a) D&z, K. H. Pure Appl. Chem. 1983, 55, 1689. (b) D&z, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. (c) Wulff, W. D.: Tang, P.-C.; Ghan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S. R. Tetrahedron 1985, 41, 5813. (d) Semmelhack, M. F.; Bozell, J. J.; Keller, L.; Sate. T.; Spiess, E. J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803. (e) Wulff, W. D.; Chart, K. S.; Peterson, G. A.; Brandvold, T. A.: Faron, K. L. Challener, C. A.; Hyldahl, C. J. Orgunomet. Chem. 1987, 334, 9. Krapcho, A. P. Synthesis, 1974, 383, 1976, 425. To date only the efforts of Kelly and coworkers’ descnbe me use of an aldol closure for introduction of the spire center employing a Dibal-H reduction of an cnol lactone and in situ aldol condensation; d Holland, H. L.; MacLean, D. B.; Rodrigo, R. G. A.; Manske, R. F. H. Tetrahedron Len. 1975, 4323. D&z, K. H.; Fiigen-Kbster, B.. Chem. Ber. 1980, 123, 1449. Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Sot. 1981, 103, 7677. Yamashita. A.: Scahill, T. A.; TOY. A. Tetrahedron Lerr. 1985. 26. 2969. Yamashita. A. J. Am. Chem. Sot. 1985, 107, 5823. Yamashita, A.:-Timko, J. M.: Watt, W. Terkzhedron Letr. 1988, 29. 2513. Yamashita, A.; Toy, A. Tetrahedron Lett. 1986, 27, 3471. Mancuso, A. J.; Swem, D. Synthesis 1981, 165. Prepared from 7-hydroxyindanone by the following sequence: (a) PhCH,Br, K&O,, (Bu),NI, DMF. 2s”C, 10 h, 94%; (b) Ph,PCHOCH, dioxane, 100°C 3 h, 75%; p-TsOH, dioxane-H,O (1:3), 100°C 16 h, 75%; (c) CC,H,CH(OSiMqrBu)CCLi, THF, 0°C 2 h, 79%; (d) rBuMe$iCl, imldazole, DMF, 25°C 72 h, 87%. (Received

in

USA 13

January

1989)