The total synthesis of (±)-naphthyridinomycin. II. Construction of the pentacyclic carbon skeleton.

0040-4039/85 $3.00 + .OO 01985 Pergamon Press Ltd.

Tetrahedron Letters,Vol.26,No.l6,pp 1911-1914,198s Printed in Great Britain

THE TOTAL SYNTHESIS OF (+NAPHTHYRIDINO~~YCIN. CONSTRUCTION

OF THE PENTACYCLIC

CARBON

David A. Evans* and Scott

II.1

SKELETON.

A. Biller

Department of Chemistry Harvard University Cambridge, Massachusetts 02138 A synthesis

of an advanced pentacyclic intermediate to the quinone antibiotic na hthyridinomycin (1) is described. The stereoselective synthesis of 2b from tricyclic lactam 3 P features a regio- and stereoselective, intermolecular amidoalkylation reaction and a Friedel-Crafts ring closure to annelate the aromatic nucleus.

Abstract:

Studies (1)

have

directed

been

the

Communication,1 an efficient

toward subject

the stereoselective of

considerable

we have described

led to the stereoselective architectural

synthesis

features

required

substitution

independent

variants

It is worth There

noting

of the advanced

CH2CI2) illustrated

afforded

of these

associated

tricyclic

the expected

chlorolactam

naphthyridinomycin

laboratories.l,2

In the

of this challenging

intermediate

preceeding

target,

as well as

the efforts

that have

2 which contains

most of the

lactam

bond constructions outcome

are illustrated

of both of these

with the regioselectivity

lactam

3 involved

a sequential

set of electrophilic

on C(6) and C(5) of 3-methyl,2,4-dimethoxylphenol

amidoalkylation

of the

antibiotic

study we wish to describe

pentacyclic

of the tricyclic

the stereochemical

intramolecular

Treatment

in several

for the total synthesis

3. In the present

consecutively

of the first that

were also concerns

illustrated 43.

reactions

of the antitumor

for naphthyridinomycin.

The basic plan for the elaboration aromatic

interest

a strategy

route to the key intermediate

synthesis

was conveniently

on the following

reactions

hemiaminal

which

variant

set up from the phenyl glyoxylate

was subsequently

of molecular

chlorinated

OMI ;2

!. 1911

a, R=CH20H e. R=COgh

tenuous.

(eq 2).

2

The

hemiacetal sieves

(2YC,

(SOCI2) to provide

5 (eq 1).

LOS

Two

page (eq 1,2).

was considered

of the intermolecular

3 with 4 (4 equiv) in the presence

(6).

the

Cyclization

of 5 with

,Unfortunately afforded

equimolar The

form adduct isolated

quantities

surprising

intramolecular Accordingly

silver

lack

sequence, the tricyclic

of this

associated

C(9) epimer

C(9) diastereomer 3. I

of stereocontrol encouraged

esters

us to examine

the

methyl

(CH2CI2,

of chloride

0°C to 2YC) gave a mixture

by MPLC on silica

gel afforded

10 in 10% yield (naphthyridinomycin

could be obtained Me

overall

corresponding

chloride

-via direct

B

crystallization

lactone

7 in 58% yield. (MeOH,

heat)

9 and 10.

with monomeric

with thionyl

the

Mild methanolysis

1.5:l).

disappointing

In the crucial step, the reaction

mixture

25oC) afforded

(ratio,

methyl

and

3 was condensed

(2.6 equiv, CH2CI2,

Separation

CH2Cl2,

was minimal

of the diastereomeric

lactam

as the free base.

lactam

(4 equiv,

8a, which was then treated

by tin tetrachloride

Scheme

triflate

the C(9) diastereoselection

yield

(33%) observed

intermolecular glyoxylate4,5 25°C) to provide

for

reaction

the

(eq 2).

(CH2CI2, 25°C) to 8b (96% overall)

8b with phenol 6 (1.3 equiv) promoted of several

the desired numbering).

isomer

products.

9 in 56% yield and the

More conveniently,

in a 48% overall

c

amidoalkylation

yield from

the desired the tricyclic

major

(es%)

minor

(IS%)

0

1913

The regiochemical Treatment these formed

assignments

of 9 with base (excess

two substances upon

stereochemistry intermediates

are epimeric

the

cleavage

More significantly, diastereoface &face,

(g or @

features

lactam

apparent

of

upon structural

the

studies

of this amidoalkylation

ion 12 (see Scheme

I). First,

intermediate

which is the more accessible with the basic nitrogen

esters relative

on later is obscured

it is not obvious in the reaction.

prochiral

should further

electrophile encumber

of Z-12 predominately from the a-face. -via amidoalkylation 3 with the aromatic nucleus in a stereoselective manner, our attention

of the C(13a)-C(13b)

at -78°C in the presence

bond.

The hydrochloride

of Sudan 111,6 followed

-78°C to 2X).

This procedure

13a and 13b were isolated

a minor component

was found to be regioisomeric the major product

based course

to the two methyl

assignment

(1) that

the

as proceeding

(H2, 5% Pd-C,

In addition,

was

ions, E-12 or Z-12, is the putative

Since Lewis acid complexation

from which the major isomers = 1:l).

adduct

of the acylimmonium

acylimmonium

to the construction

intermediates

major

The

evidence:

of 9 and 10, indicating

9 and 10 are identical methanol.

the

we view this reaction

to ozone in methanol

refluxing

for the stereochemical

it is also not immediately

Having coupled turned

7 in

A rationale

structural

which of the illustrated

lactone

as in 9 to

(vide supra).

by two ambiguous

9 and 10 are based upon solid chemical

MeOH, O’C) gave a 1:1.6 mixture

at C(9), and; (2), adducts

of

indicated

for structures

NaOMe,

(approx.

with regards

diastereomer

resulted

to substitution secured

11 was subjected

workup of the peroxidic

in a mixture

of tetrahydropyranols

in 70% yield by silica gel chromatography

18%) could be isolated

was conveniently

salt of benzoate

by reductive

as a mixture

at C(3a) and C(13b). by lactonization

Structural

Me

OMe

OMe

Me

Me

6Me

I,3

a

X=H,

OMe

Y=OH

b X=OH, Y=H

I P(NW,), c Cl,

Me

Me

OMe

Me OMe

Me6

(13a:l3b

of stereoisomers,

to 14.

Me

then

assignment

and of

1914

Typically, mixture

this crude of pyranols

25“C) to afford

ozonolysis

product

was treated

chloride

was used for the subsequent

with (Me2N)3P

159 as the major component,

with SnC14 (2.5 equiv, -78’C to O’C) to provide the benzoate

ester

In order enhancement

determine

study

II,12

of the C(9) proton

establishes

a syn relationship

and its precursors.

the

between

Related

2b. A subsequent

X-ray analysis

the

course

for dealing

of naphthyridinomycin. important

interaction”

of

the

synthesis

For example,

in the synthesis

target

points

in the establishment that

structure

the potential

reagents.

prior

associated

should not be underestimated.

4. 5. 6. ;: 9.

10. 11. 12. 13.

this

oxygen functions

technique

proton

Overhauser

at 500 MHz.12

and vice

versa.

This

assignment

of 2b

of the incorporated

as illustrated

in structures

16 and

2b, reasonable

advanced

intermediate

One of our first lactam

precedent

2b.

has been

in a projected

synthesis

to evaluate

observations

Due to the “double

at C(7) and C(lO), this function

hand, this reduction

construction.

We have

is readily also

two

pertained peri-

has been

accomplished

encountered

similar

ring -via the oxidation of either 2a or 2b. We have thus with the advanced redox transformations leading to the A successful

This research

was supported References

1.

of

solution

to this final set of problems

will be

shortly.

Acknowledgments.

2. 3.

directly

assignments.13

lactam

On the other

a nuclear

the stereochemistry

numbering)

in pentacyclic

to pentacycle

of the quinone pitfalls

C(3a),

and redox issues inherent

employed

was treated

from 11. Hydrolysis

the C(9) stereochemical

in the synthesis.

moiety

with the resident

at earlier

C(9) and

of the C(13c)

secured

of pentacyclic

we have

of the C(9) carbomethoxyl

of this substituent

at

all stereochemical

with many of the stereochemical

The

(-78’C to

(NaOH, H20, THF, MeOH, 84%).

and secures

experiments

of 16 confirmed

to a host of hydride

reported

protons

at C(3a) (naphthyridinomycin

found to be inert

concluded

these

purification.

in CH2Cl2

This solution

16 in 42% yield, overall

manner

stereochemistry

redox issues to be faced at later stages

to the reduction

problems

pentacycle

in an enhancement

enhancement

stereocenter

without

on phenol 2b using the NOE difference

resulted

methoxyl-bearing

During

relative

was performed

Irradiation

established

along with HMPA.

gave phenol 2b in a straightforward

to

reactions

(1.3 equiv) and CC14 (33 equiv)7,8

by the National

institutes

of Health

(GM33328-02).

and Notes.

Part I: Evans, D.A.; Biller, S.A. Tetrahedron Lett. 1985, preceeding communication. See references 1,2, and 5 in Part I.1 Adduct 4 was prepared y& ozonolysis of the E crotonate ester of phenol 6 (03, CH30H, -78“C; CH3SCH3, -78°C to 25“C). Polymeric methyl glyoxylate was prepared by the method of Kelly,5 and was converted to the monomer by redistilling from P20 and collecting the distillate at -78°C. Material thus obtained was VO-95% monomer as estimated by I5H NMR. Kelly, T.R.; Schmidt, T-E.; Haggerty, J.G. Synthesis 1972, 544-545. Veysoglu, T.; Mitscher, L.A.; Swayzee, J.K. Synthesis 1980, 807-810. Downie, 1.M.; Lee, J.B.; Matough, M.F.S. J. Chem. Sot., Chem. Commun. 1968, 1350-1351. Ireland, R.E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C.S. J. Org. Chem. 1980,45, 48-61. The stereochemistry depicted in 15 is based upon the large anomeric effect ( approx. 2.7 kcal/mol) that the chloride which is characteristic of pyranosyl chlorides. 10 The 1H NMR spectrum indicated derived from 13a and 13b was greater than 90% a single isomer. Stoddart, J.F. “Stereochemistry of Carbohydrates”; Wiley: New York, 1971; Chapter 3, pp. 67-87; and references cited therein. a) Anet, F.A.L.; Bourn, A.J.R. J. Am. Chem. Sot. 1965,87, 5250-5251. b) Noggel, J.H.; Schirmer, R.E. “The Nuclear Overhauser Effect”; Academic Press: New York, 1971. Hall, L.D.; Sanders, J.K.M. J. Am. Chem. Sot. 1980, 102, 5703-5711. J. Org. Chem. 1981, 46, 11321138. The X-ray study was carried out by N.S. Mandel and G.S. Mandel at the Medical College of Wisconsin. (Received

in

USA 15 January

1985)