A biomimetic approach to sporidesmins. synthesis of an α,β-epoxytryptophan derivative

Tctr&&oa Vol. 42. No. U, pp. 651I IO6518.1986 Printedin Grnl Britain.

A BILBlIcEIIC

-/sb 55.00+.00 0 WlW~JO~LId.

APPROACH TO SWRIMSMINS. SYNTHESIS OF AN a.8-EPOXYTRYPTOPHANDERIVATIVE

RALF PLATE,

ANNETTE Y.G.

THEWISSE,

RUTGER J.F.

NIVARfl AMI HARRYC.J.

OTTENiELW Department of Organic Toernooiveld,

Chemistry,

University

6525 ED Nijmegen,

(Received in UK 24

Nijmegen,

of

The Netherlands

September 1986)

from 16 Abstract: The reaction of 19 - prepared efficiently with DDQ affords 22. This epoxide may serve as a model compound to investigate the biosynthesis of spridesains, e.g. 1 and 2.

INTRCXIUCTION The sporidesmins turing

a-

causing

make up a group of naturally

0,s ‘-substituted

or

facial

exxema in

which

charterurn liara,s.

occurs A (1)

from the

amino acids

peripheral

changes

that

the N-methyl

delivered

either

the

the

tryptophan must have

groups steps

skeleton

sis

of

place

us with the

introduced

the

tem might

yield

nucleophile This

retention

intriguing

Sammes' , who invoked

2’.

to

would create scheme is

mould qetabolites,

loss

he concluded with

e.g.

of

intermediacy the 5a.b’

groups

1 R’rCI,R2=OMc

series

of the

sulfur

concerning

atoms are

have not been

the

remain obscure.

at C(B) at this

introduction

Kirby’

experiments

pathway

di-epoxide 3;

a-mercapto-B-hydroxy by the following

6511

has

of

tryptophan

considerations.

studied the spo-

involving

C(S)

in the biosythecarbon

atom. This

been

attack

is by

This sys-

by a sulfur

moieties Firstly,

amino acid

group

provided

4 (Scheme I).

subsequent

have an a,B-epoxy

F

of

demonstrated

in the hydroxylation

likely

lx SPORIOESMIN

have

by what mechanism the hydroxyl

R’.OMe SWRIDE!SMIN A

1b.c ,

derivation

an extensive and the

hydroxylation

SCHEMEI

R’.CI,

sporidesmins

to the sporidesmins

details

mono-epoxide

and 6’

Pithomycas and Austra-

a biosynthetic

configuration

question

the

the

fea-

principle

fungus

studies

From labeling that

active

or methionine’.

involved

The most

supported

of

from methionine

two hydroxyl

the

although,

cysteine

metabolites

the

New Zealand

suggests

from tryptophan

hydrogen

fros of

Labeling

In particular,

biosynthetically. react

place.

at the B-position.

derivatives

1 takes

leaves

F (2),

and alaniner, taken

leading

of

areas

structures

are derived

atoms and the

stereochemistry

‘H-labeled

the

and sporidesmin

in any detail.

sulfur

ridesmin

of

pasture

fungsl

They are

and were obtained

certain

by sodium sulfate,

The metabolic investigated of

sheep

in

Consideration

e.g. sporidesmin

ocurring,

dioxopiperaxines.

of

1 or

several

moiety

as a

6512

R. PLME et al,

structural

feature.

well-documented in another oxidative

Secondly,

the conversion

mechanism proposed

synthetic ring

approach

closure

cf.

posed

intermediacy

to

the

4+3 has a close

the biosynthesis sporidesmins,

based on the conversion

Here we wish to report tive,

for

the first

10 (Scheme II). of 3 and

to the Thirdly,

we employed successfully

an

of 4+3i’.

synthesis

of an a,S-epoxy

This

synthesis

4

the biosynthesis

in

resemblance

of gliotoxin’.

provides

further

tryptophan support

to

derivathe pro-

of the sporidesmins’.

4-R koJqpfp 0 l

d

:R= H

b: Rz 044 CYCLOPENOL

STRATEGY

Compound 10 was selected i.e.:

and 4.

3

epoxidation

This

explored

of

the

(Scheme

for

not

the putative

directly

sporidesmin

accessible

o,S-dehydrotryptophan

indole

nucleus.

II).

Initially

C

EPOXY -FUMlTREMOROIN

as a model

compound is

of the corresponding

the presence

Me

Me

CYCLOPENIN

Therefore, we

via

precursors,

straightforward

derivative”,

two alternative the

studied

because approaches

S-oxidation

of

of were an

SCHEME II

N-hydroxytryptophan might

yield

approach

the

failed

derivative sion

(vi&

11 (route

9,

B).

which

Oxidation of

A, 7+8).

should

we first

fnfra),

by the intermediacy

Route

(route

derivative” acylimine

Subsequent

yield

prepared

gave indeed

the

elimination

a,[)-epoxide

the a-functionalized 10; we rationalize

of RX-OH

16.

As this

tryptophan this

conver-

12.

A

S-Oxydation

of an N-hydroxytryptophan

derivative

(cf.

7+8)

was studied

using

SCHEME III

NHR’ 3.-

Lj

,- a: R’.R2=R3=H b: R’.R’=Mc;

R’.H

c: R’=R’=H;

R3.CH2CsH~

d: R’ =R2.Mc the

oxime

as an oxidizing thy1 C=N

derivative bond

attempts a

III)

13 (Scheme

13~ - prepared

of

reagent

and the dioxopiperazine 16 (Scheme IV). Treatment of - with DDQ in aqueous tetrahydrofuran”

from 13a by 0-benxylation agent afforded or

14d had

Treatment introduced

of by

2,3-dihydrotryptophan

derivative

soned

of

that

the R-keto

14d was obtained 14c

failed.

; R3=CH2C6H5

reduction

derivative

analogously to

be

14d with us

reduced

14~

from 13d. selectively.

in 89% yield.

The dime-

Subsequently,

the

Unfortunately,

oxime

all

the trimethylamine borohydride complex the gave related reductions” for

15 in 53% yield.

the oxima had to preceed

Having observed

this

the

Accordingly,

B-oxidation.

we rea-

6513

A biomimctic approach to sporidcsmins the next compound we. studied an untractable

ever,

(Scheme IV).

was 16”

reaction

mixture.

Treatment with DDQ gave,

We ascribe

this

failure

bar-

to the high acid-

!? ity

of the a-proton

of

17 facilitating

the elimination

of benzyl

alcohol.

Route B On the basis

of the above findings

out subsequent

we felt

invariably

lead

to elimination

the proper

oxidation

state.

that

reactions

bef,ore

Accordingly,

the

of 16 with sodium methoxide

of

DDQ in aqueous TRP yielded

20

(30%)

reduce

again and

the a-hydroxy

the B-carbonyl

group

order

the B-carbon

a mixture

19

of

a hydroxy

into

(56%).

steps

18 was pre-

(Scheme V).

of

Oxidation

the desired

Unfortunately, group

would

would have reached

derivative

in methanol

derivative Xl

had to be carried

of reaction

a-•ethoxy

pared by treatment 18 using

S-oxidation

the reverse

to a-functionalization

compound

attempts

failed.

Possibly

to the

SCHEME V 0M.O

16 -

presence

&J?

of an a-NH-proton

Having observed rupted

as

soon

this

as the

B-carbon

alcohol.

We reasoned

12+lD)

might be possible

approach was found When the

precludes

failure, that

in

trapping

to

from an a-hydroxy

has to be inter-

state yield

of

a secondary

an epoxide

derivative,

vfz.

(viz.

11. This

indeed.

by

treated

a molar equivalent

to which we assigned

the oxidation

derivative

(83% yield) with

that the oxidation

atom is

star::ng

treatment

conversion.

intramolecular

to be viable

a-hydroxy

this

we realized

19 - prepared

with

aqueous of

structure

from 18 (95% yield)

sodium

hydroxide,

DDQ in tetrahydrofuran

22 on basis

or

from 16

respectively a product

of the following

-

was

was formed

observations

(Scheme

SCHEME VI

VI).

Firstly,

idesr’

-

upon spraying

a positive

pounds reported

(red)

pared

to

spectrum

the spectrum

it

decomposes

derivative hydroxide qetboxide products tion

not

22 is slowly

been

for

an unstable to

the ester

can be rationalized

sodium hydroxider’.

to

loss

feature

26b

22

opening

of

of

(Scheme VII).

by the formation

is

ppm) as impact

26a,

of 5a and 5b’.

formed quantitatively silica

gel.

Treatment

of benxoic

acid

of

with

sodium

with sodium

these

This type

So far

amino acid

and reaction

The formation

in Scheme VII.

com-

mass

from the molecular e.g.

using

epoxide.

com-

‘Ii-NMR spectrum

an o,B-difunctionalized the

epox-

(Lk8.56

oxygen it

for other

electron

of epoxides,

gave the acid

as depicted

the

conditions

into

the

C(2)-proton Thirdly,

the

indicative whereas all

Secondly,

compound; whereas

convert ring

test.

indole

under chromarographic

able

- a reagent

was observed,

ppm)“.

is a typical

by nucleophilic

is precedented

the

19 (6~6.87

or sodium methylmercaptide gave

acid

in this

corresponding

fragmentation

The epoxide we have

shift

of

showed an ion

this

ionI’,

picric reaction

here were negative

22 showed a downfield

of

with

colour

degradation of

fragmenm

from 5a upon treatment

with

A biomimctic approach to sporidcsmins

and with brine,

and subsaquently dried (NaeSO.). The residue obtained by evapo-

ration of

the solvent was subjectad

giva

mg

of

W

(N&H)

280

Kw&).

13c

(91%);

to

r..p.

Am,=286,

flash column chromatography (CHsClr) to

120-122

‘C

(CH&lr/n-buana),

255 m.

222 nm; Amin

tic

Rf

0.2

EIMS (70 eV) m/e-S07 ([M]',

25X), 171 (15%). 155 (50%). 130

5%). 216 ([If-CHaC.Hs]*,St), 200 ([M-OCH&.]*,

(IGHeN]+, 55%). exact mass calcd. for C~eHrrNsOs 307.1321, found 307.1325. ~H-NMR (60 MHE, CDCl,), b=8.2 (s(br), lli, indole NH), 7.6-6.9 (m, 5H, indolec(2), C(4)-C(7)H), 7.3 (s. SH, CeHs), 6.5 (s(br), 2H 0X&),

5.15 (s, 2H, CCHs),

4.0 (s, 2H. indole C(3)-WI). 1-[(E)-Benzyloximtno]-2-(HnethylIndol-3-yl)N~thylpropan~lde A solution of benxyl bromide (2.2 -1,

(13d)

380 mg) in dimethoxyethane (10 ml) was

added dropwisc to a stirred solution of 13b"

(2 ssnol, 490 mg) and potassium

terf.-butoxide (2.2 m~ol, 250 mg) in dimethoxyethane (20 ml) at room temperature and in an argon atmosphere. Stirring was continued for 3 hrs.

Then the solvent

was removed in vacua. A solution of the residue in CHrClz was washed with 1N HCl and with brine, and subsequently dried (NasSO.). Evaporation of the solvent and flash column chromatography

(CHrCls) of the residue gave 640 mg of 13d (96%);

m.p. 64-65.5 'C (CHsClr/n-hexane), tic Rf 0.2 (CHsClr).

W

(MeOH) Xmax=286, 228

nm; xmin. 256 nm. EIMS (70 eV) m/e=335 ([Ml', 27X), 228 ([CIIH:.NIO]*, loo%), 47X), 144 171 ([CIIHI~NZ]+, 94%), 170 ([CrrH11Nr]+, 33X), 169 ([C~dWzl+, ([ClrH~rNl*, 80%); exact mass calcd. for C 1,H rrN ,0 r 335.1634, found 335.1628. 'H-NMR (90 MHz, CDCl,), 6=7.71-6.88 (m, SH, indole C(2), C(4)-C(7)H), 7.34 (6, 5H, CIHs). 6.7 (m, lH, CHrNH), 5.21 (6, 2H, OClIr), 4.02 (s, 2H, C(3)-CHs), 3.64 (s, 3H, indole NCHI), 2.76 (d, '5~5 Hz, 3H. CH,NH). l-[(E)-Benzyloximino]-P-(lndol-3-yl)-2-oxo-propanamide TO a solution of 13c (0.2

indole

(14~)

mmol. 63 mg) in THF/HsO (9/l, v/v, 5 ml) was added DDD

(0.4 mmol. 91 mg). After stirring for 2 hrs the solvents were evaporated and CHrCls was added to the residue. The suspension was filtered and the filtrate was washed, dried (NarSO,) and the solvent evaporated.

Flash column chromatog-

raphy (MeOH/CHrClr. 4196, v/v) gave 57 mg of 14~ (89%) as an oil which was homogeneous on tic Rf 0.16 (MeOH/CHrClr, 6/94, 236

(sh).

204

(LC,HrNO]*,

nm;

100X),

lmin.

277

ND.

91 (IC,HTI’,

V/V).

EIMS 100%);

W

(70 eV) exact

(MeOH) Imax=305, 260 (sh), m/e=321

mass

([Ml+, 28%),

calcd.

for

144

ClrHlrNaOr

321.1113, found 321.1110. IH-NMR (60 MHz, CDCl~), 6=9.7 (s(br), lH, indole NH), 8.2-7.9 and 7.3-6.9 (m, SH, indole c(~)H, C(4)-C(7)H), 7.10 (6, SH, CeHr), 6.4 and 6.0 (s(br), 2H, NH,), 4.93 (s, 2H, ~cH,). (14d)

l-(Benzyloximino)-2-(N-methylindol-3-yl)-2-oxo-N-~t~lpro~n~ide To a solution of 13d (1.7 -1,

575 mg) in THF/HrO (9/l, v/v, 10 ml) was added

DDQ (3.5 mmol, 779 mg). After stirring for 3 hrs the solvents were evaporated and CHrClr was added to the residue.

The suspension was filtered and the fil-

trate was washed, dried (NarSO,) and the solvent evaporated. Flash column chromatography gave 451 mg of 14d (76%) as an oil which was homogeneous on tic Rf 0.48 (MeOH/CHrClr, 6/94, v/v). 280, 234 nm. EIMS

([CIHTI+,

45%);

W

(MeOH) Xmax=312, 266 (sh), 246, 208 nm; Xmin.

(70 eV) m/e=349

exact mass

calcd.

([Ml', 22%),

158 ([C~IHINO]*, lOO%), 91

for IZ~~HL.N~O, 349.1426,

found 349.1419.

'H-NMR (60 MHz, CDC~X), 6=8.3-8.1 and 7.4-7.1 (m, SH, indole C(2)H. C(4)-C(7)H), 7.3 (s, SH, C&H,), 6.7 (m, lH, NH-CHr), 5.16 (s, 2H, OCHI), 3.69 (s, 3H, indole N-CH,), 2.84 (d, '515 Hz, 3H, NHCH,). l-(Benzyloxaraino)-2-(N-methylIndolin-3-yl)-N-~thylpropllnami~ To a solution of 14d (0.5 mmol, 175 mg) and HerN*BHr"

(15) (1 mol,

80 qg) in etha-

nol (5 ml) a solution of HCI in ethanol (5 ml of a 7N solution) was added dropwise at room temperature in an argon atmosphere.

After stirring the reaction mixture for 24 hrs another 4 equivalent of MerN*BH, (2 -01, 160 qg) were added.

After 4 days the solvent was

evaporated. Then

the residue was dissolved

in

CHsCls and the resulting solution was washed with O.lN NaOH, dried (NasSO.) and

R. PLATSet al.

6516

filtered. Evaporation of the solvent gave a residue which was subjected to flash column chromatography

(CHrClr) to give 90 mg of 15 (53%) as an oil which was

homogeneous on tic Rf 0.25 (MeOH/CHzClr. 4/96,

W

v/v).

(HeOH) Xm6288.

224 (sh), 204 nm; lmin . 276, 237 nm. EIMS (70 eV) m/e=339 (]CirHirN,Ul+, 25x),

144 ([C,,HION]*.

62X),

132

([C,HIDN]*),

133

for CI.H.SNIO, 91 ([C~HIJ+, 46%); exact mass calcd. 339.1947. 'H-NHR (60 MHZ, CDCl,), 6=7.2 (6. 5H, MIS), 7.2-6.2 6.1

(m,

1H. Nl+CHr), 4.6

3.4-2.5 (m, 5H, indoline c(2)H 2, c(3)H. 3H,

indoline

(26x1,

339.1945,

(41%))

c(4)-c(7)H).

248,

([Ii]', 17%). 215

(m,

4H,

131

found

i.ndolioo

(8, 2H, OCM,), 3.7-3.5 (m. lH, C(e)M), and c@)H),

2.7

(d,

3H.

NHCH,),

2.6

(s.

(dry,

150

ml)

N-CH,).

l-Methyl-3-methoxy-3-[(N-raethylindol-3-yl)methyl]-6-methylenepiperazine-2.5dione To

(18) a stirred

was added

solution

potassium

of

16l’

tart-butoxyde

(1.14 (320

g,

2.9

sxuol)

qg, 2.9 ml)

in

methanol

at room temperature. After

stirring for 4 days at room temperature the mixture was neutralized by adding ammonium chloride (0.160 g). Stirring was continued for 17 hrs, where after the solvent was evaporated in vacua. Dichloromethane was added to the residue and the suspended salts were filtered off. The filtrate was concentrated to dryness to yield an oil which consisted of 20 and benzyl alcohol. Column chromatography (CHrCl,/MeOH, 98/2, v/v) gave 735 mg of 20 (81%), which was crystallised CHrClr/n-hexane:

m.p.

172-173

'C;

tic

Rf

0.35

(solvent

system

(methanol) Xmax=218, 255 (sh). 284, 296 (sh) nm; lmin=281 nm. m/e=313

from

II).

EIMS

([Ml+, l%), 281 ([CLCHI~N~O~]+, lo%), 144 ([CioHI~N]+, 100%).

UV

(70 eV) exact

mass calcd. for Ci,HirNrO, m/e 313.1426, found 313.1423. 'H-NMR (90 MHz, CDCl,), 67.65-7.0 (m, 4H, indole C(4)-C(7)H), 6.91 (s, lH, indole C(2)H), 6.26 (m, lH, NH), 5.57 (B part of AB spectrum, lH, 'JAB=1.5 Hz, C=CHBHA), 4.59 (A part of AB spectrum, lH, *JAB=1.5 Hz, C=CHAHB), 3.74 (s, 3H, indole N-CHr), (B part of AB spectrum, lH, 'JAB=14.5 Hz, indole C(3)-CHAHB), 3.35 (A part of AB spectrum, lH, 'JAB=14.5 Hz. indole C(3)-CHAHB), 3.27 (s, 3H, C(3)CCHr), 2.98 (s, 3H, piperazinc N-CH,). l~thyl-3-hydroxy-3-[(N-methylindol-3-yl)methyl]-6-rsethylenepiperazlne-2.5-

dlone

(19)

From 16: To a stirred 0.5N

solution

of

16l’

(3.2

rmuol,

1.24

g)

in dimethoxyethane

(60

ml)

NaOH (40 ml) was added at room temperature in an argon atmosphere. After 4

days the reaction mixture was treated with NH.Cl. Then the solvent was evaporated, the residue was partitioned between water and CHrClr. The organic layer was dried and the solvent evaporated. Recrystallization (CHrCl,/n-hexane) gave 0.79 g of 19 (83%), m.p. 163-165 'C. Rf 0.24 (MeOH/CHrClr, 7/93, v/v). UV (MeOH) 1,,=296 3X), 281

(sh), 284, 252 (sh), 221 nm; Xmin

280 nm. EIMS (70 eV) m/e=299 ([Ml+,

(ICIC~ISN~~ZI+, 6%). 144 ([C~DH;,N]+, 100%); exact mass calcd. for

C1~H1,N,OI 299.1270, found 299.1263. iH-NMR (90 MHz, CDClr), 6=7.50-6.90 (m, 4H, indole C(4)-C(7)H), 6.87 (s. lH, indole C(2)H), 6.80 (s(br), lH, piperazine NH), 5.37 (B part of AB spectrum, 'JAB=2 Hz. lH, =CHAHB), 4.44 (A part of AB spectrum, 'JAB=2 Hz, lH, =CHAHB), 4.30 (s(br), lH, OH), 3.71 (s, 3H, indol N-CHI), 3.50 (B part of AB spectrum, 'JAB=14 Hz, lH, CHAHB), 3.30 (A part of AB spectrum, 'JAB=14 Hz, lH, CHAHB, 2.78 (s, 3H, piperazine N-CHI). To a solution of 18 (0.5 mmol, 150

From 18:

qg) in THF/HrO (9/l, v/v, 10 ml) was added

1N NaOH (1 ml) at room temperature in an argon atmosphere. After stirring the reaction mixture for 24 hrs the room temperatrue it was neutralized (NHbCl) and the solvent was evaporated. Usual work-up gave 135 mg (95%) of 19, vhich vas identical with the compound described above. l-Methyl-3-Rethoxy-3-[(Nmethylindol-3-yl)carbonyl]-6-methylenepiperazine-2.5dione

(20)

6511

A biomimetic approach to sporidesmins TO a stirred

solution

was added DDQ (0.5 ture

of 18 (0.25

in an argon atmosphere

the

The

residue.

(NatSO.) 2/98,

v/v)

(HeOH) Lmex=316,

homogeneous on tic,

268

(sh),

159 (29%).

4X),

207

nm; l,,,in.

found

327.1226.

8.30-8.20

and 7.40-7.20

‘JAB=5 Hz, C=CHAtiB) , 5.00

lH, 3.89

(s.

3H, indole

N-CM,),

282,

(s,

was washed,

nm. EIHS (70 mass calcd.

6=8.47

C(4)-C(7)H), of

dried

(MeOWCHaCl1,

(MaOH/CH,Clr, 6/94. 237

100%); exact

(A part

3.55

and CHrClr was added to

filtrate

0.39

‘H-NMR (90 MHz, CDCI,), (m, 4H, indole

10 ml)

19 (58%).

Rf

158 ([C1,H,NO]+,

327.1219,

v/v,

at room tempera-

column chromatography

gave 25 qg of 20 (30%) and 44 mg of oil,

24 hours

and the

Flash

evaporated.

for

were evaporated

was filtered

solvent

Compound 20: (WI+,

stirring

the solvents

suspension

and the

mmol. 78 mg) in THE/H.0 (9/l,

After

114 qg).

maol,

(6,

5.93

AB spectrum,

3H, OCH,), 3.21

for

lH,

lH,

W

ClrHrrNrCb

indole

(B part

(s,

v/v).

eV) m/e=327 C(2)H),

of AB spectrum,

‘JAB=5 Hr., C’CHAHB,

3H, piperazine

N-CH,).

l-Methyl-2,5-dfoxo-6-methylen-plperazine-3-spiro-3’-(N-methylIndol-3-yl)-2’(22)

oxirane

To a stirred argon

solution

atmosphere

residue

of

2/98,

was washed with v/v)

246,

brine.

gave a small

found 297.1115;

ClrHIIN,O,

6=9.30

lH, piperazine

7.70-7.10 5.11

(m, GH, indole

(A part

6=3.5-3.3,

was filtered

was concentrated

column chromatography v/v).

to dryness

281.1164, NH),

found 8.56

C(4)-C(7)H).

281.1163. (s,

5.64

lH,

C(3’)H

probably

266 (sh),

([Ml+,

4%).

281

C1‘HirN,O~ 297.1113,

‘H-NMR (90 MHz, d’-DMSO),

indole

(B part

lH, C=CHAHB, 3.91

N-CHr), proton

for

to give

which was homo-

236 nm. EIMS (70 eV) m/e=297 mass calcd.

an

(M~OH/CHIC~Z,

(MeOH) &x=314,

W

in

and the

C(2)H),

8.30-8.00

of AB spectrum,

(s,

3H, indole

superimposed

and

lH, C’CHAHB),

N-CHr),

by solvent

3.14

picks

(s, (Hz0

d’-DMSO 2.5-2.7).

N-Methyl-indole-3-carboxylic of

A solution

crude

above

was treated

acid

(26a)

22 (0 .OB mmol , 23 mg) in THF (5 ml) prepared with

1N aqueous

After

24 hrs the reaction

vents

were

layer

was washed with water,

evaporated

mixture

and the

NaOH solution

was treated

residue

brine,

and dried

in ethyl (NarSO.).

(lit.”

(MeOH/CH,Clr,

243

(sh),

Rf 0.28

215 run; Amin=

run.

ml)

at

as described

room temperature.

with NH&Cl. Subsequently,

which was crystallized

205-206’C);

(2

dissolved

vent gave 13 mg of 26a (93X), 286,

room temperature

DDQHr. Flash

100%); exact

of AB spectrum),

3H, piperaxine

at

mixture

The filtrate

281,

158 ([Ci,H,NO];,

(s(br),

72 hrs

(MeOH/CH,Clr, 7/93,

203 NO; Xmin

4X),

([n-01+,

with

for

The reaction

amount of pure 22 as an amorphous solid

Rf 0.20

208 (sh),

nrmol, 185 mg) in dry THF (10 ml) was added

stirring

NarCO, was added.

22 which was contaminated geneous on tic;

19 (0.6

After

mmol, 110 qg).

DDQ (0.5

Evaporation

v/v).

the sol-

The organic of

from MeOH, m.p.

6/94,

EIMS (70

acetate.

the sol-

199-203

oc

(MeOH) Xmax298 (sh),

W

eV) m/e=175

([Ml’,

loo%),

158

mass calcd. for CIDHINO~ 175.0633, found 175.0635. 79%), exact ‘H-NMR (60 MHz, CDCl,), 6=8.3-0.1 and 7.5-7.2 (m, 4H, indole C(4)-C(7)H), 7.84

([CI,HINC]+, (s,

lH, indole

Methyl

c(~)H),

(s,

3H, indole

(N-methylindole)-3-carboxylate

A solution

of

crude

above was treated ture.

3.86

After

the solvents matography

22 (0.11

with

24 hrs the (CH,Cl,)

(26b)

mmol, 33 mg)

a 1N solution reaction

were evaporated

N-CHr).

of

in THF (5 ml) prepared

mixture

was treated

and the residue

with

was subjected

NHbCl. Subsequently, to flash

26b (91%) as a foam which was homogeneous on tic;

189.0790,

found

189.0790.

C(4)-C(7)H),

N-CH, and CQCCH,).

column chro-

gave 20 qg of Rf 0.71

(MeOH/CHrClr, 6/94.

W (MeOH) Xmax287 (sh), 226 (sh), 214 nm; Xmin=258 nm. v/v). m/e=189 ([Ml’, 90%), 158 ([CI,H,NO]*. 100%). exact mass calcd.

4H, indole

as described

NaOMe in MeOH (1 ml) at room tempera-

‘H-NMR (90 MHx, CDClr), 7.69

(s,

lH, indole

c(z)H),

6r8.10-7.90 3.78

EIMS (70 eV) for CllHr~0rN

and 7.40-7.00

and 3.76

(2s,

(m,

6H, indol

R. PLAIT et al.

6518

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Nakatsuka,

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Nakatsuka,

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hydroxylation

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B-hydroxylation

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Press,

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the

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Nivard,

R.J.F.;

Tijhuis,

M.U.;

Scholten,

1980, 45, 1885 and references

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Akkerman, M.A.J.,

Smits,

J.M.H.;

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Otten-

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H.J.C.

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synthesis

sluggish

hedron 1963, 26,

terreus,

natural

N-hydroxytryptophan Shimizu,

S.;

Moreover,

J.D.;

may play

tryptophan;

a

Haeflinger,

an important

product K.; Yammoto,

the

relevant

acid,

a very

H.J.

Tetra-

Dimsdale.

has

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1981, p.

proposed

Conn,

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Mohri,

isolated

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Y.;

E.E.;

1981, 29,

an intermediate

Knowles, 0.

contains

K.; Sate.

Arai.

G.J.;

197 and references Yonemitsu,

pathways Aspergillus

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N-hydroxytryptophan

13. Yoshioka,

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perbenzoic

Astechrome, a metabolite from

with

as part

Nitta,

biosynthesis

treatment

with metachloro

233.

12. N-Hydroxytryptophan with

involves

derivative

see White,

reaction,

starting

5a

for

reported

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cited

B.L.

S.; 1510.

in

the

in Cyen-

Westley,

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1981,

194. 14. Tijhuis,

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Ottenheijm,

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H.C.J.

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[M-16]+.

15X, exact

18. Mohammed, Y.S.; 19. Arx,

E. von;

Faupel,

20. “Anfaerbereagantien Merck, 21. Plate,

R.;

22. Ottenheijm, Chem. 23. Millich,

Bruggen,

F.R.G.,

Hermkens, 51,

[CisHisN~Os]*

die

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1953. 1976, 120. 224.

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Fa.

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P.H.H.;

Smits,

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J.D.M.

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301.

H.C.J.;

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M..Tetrahedron Lett.

fuer

Darmstadt,

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mass calcd.

Luckner,

Plate,

R.;

Noordik,

J.H.;

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19%.

Herscheid,

2147.

Becker,

E.I.

23,

1096.