New methods and reagents in organic synthesis. 92. A stereoselective synthesis of tilivalline and its analogs

Tetmhedron Vol. 47. No. 27, pp. 5051-5070. 1991

00404O20/91 $3.00+.00

Ritcd in&ear Britain

0 1991 PagamonPressplc

NEW

METHODS

AND REAGENTS

A STEREOSELECTIVE

SYNTHESIS

Shigehiro

Mori,3a

Aoyama,

Ohno,3b and

of Pharmaceutical Tanabe-dori,

SYNTHESIS.

OF TILIVALLINE

Tomoyasu

Toyohiko Faculty

IN ORGANIC

Hiroshi

Takayuki

Sciences,

AND ITS

92.1 ANALOGS2

Harada,3c

Shioiri*

Nagoya City University,

Mizuho-ku, Nagoya

467,

Japan

(Received in UK 26 February 199 1)

Key

: Tilivalline;

Word

cyclization;

Diphenyl

and

its derivatives

diphenyl the

phosphorazidate;

Tilivalline

Abstract:

key

step

is

Diethyl

(la),

a metabolite

have

been

1

the

phosphorazidate,

completely

a

2-oxazoline

Mannich

stereoselective

type

amide

9a

and

various

phosphorocyanidate.

and

stereoselectively

2. the L-proline

intramolecular

introduction

type

from Klebsiefla pneumoniae var

efficiently

of

pyrrolo[2,1-cJ[l,4]benzodiazepin-5-ones acetal

Mannich

Pyrrolo[2,1-c][l,4]benzodiazepin-5-one;

indole. (16)

nucleophiles

by

derivatives

from

5, and indole;

cyclization

accompanied

with

Furthermore,

1 l-substituted

5H -

have the

oxyroca,

synthesized

been use

also of

synthesized

this

new

from

Mannich

the type

cyclization.

(la)

Tilivalline from

Klebsiella

synthesis

is a pyrrolo[2,1-cl[

pneumoniae

of la

has

also

have

had

analogs. convenient cyclization.2 derivatives

a keen We

interest

have synthesis This 1 and

var. onytoca

been

stereoselective nor efficient. the fundamental constituent

of

accomplished

by

Mohr

by the

metabolite and

same

isolated

Budzikiewicz.4

group

though

The

it is neither

Since the pyrrolo[2,1 -cl [1,4]benzodiazepine skeleton of a series of antitumor anthramycin antibiotics.5 in

already

1,4lbenzodiazepine

veiled

biological

accomplished la

activities

a completely

utilizing

a

of

tilivalline

stereoselective,

(la)

is we

and its

efficient,

and

new Man&h type intramolecular Mannich reaction is also applicable to the synthesis of tilivalline 11-substituted SH-pyrrolo[2,1-cl[l,4]benzodiazepin-5-one 5051

S. MORIet al.

(16). The

analogs

details

Nagasaka

and

Synthesis

of

Tilivallines

basic

scheme

Our in

this

co-workers

convergent

accompanied

our

reported

synthesis

the

third

will

be

synthesis

disclosed

here.

Recently,

(la).6

of tilivalline

(1) of 1 is shown

for the synthesis

synthesis

with

of

is construction

simultaneous

and

of the

in Scheme

I.

The key step

seven-membered

stereoselective

introduction

diazepine

ring

of indole.

$OOH HN R’

d:R = H, R’ = OH

(Tilivalline)

a: R = R’ = H

e: R = H, R’ = PhCH20

b:R = CH3, R’ = H c: R = PhCH2, R’ = H

3-Substituted

anthranilic

prepared amination

from the of 2 was

synthon.8

Thus,

DPPA, 67%

and

sequential

sodium

yield.

phosphorus

in

in

The as their (5)

important

intermediates,

of 2 in tetrahydrofuran

bis(2-methoxyethoxy)aluminum of

a sealed

tube

were

easily

3

with

at

55%

acid

(4b)

hydrochloric

hydride

hydriodic

1OO’C gave was acid,

with

acid

gave in

obtained

followed

the

the

3-hydroxyanthranilic also

n-butyllithium, amine

presence acid

(4a)

in quantitative by

50%

3 in of

red

in 86% yield

by

aqueous

sodium

were

prepared

methanol.

second

key

intermediates

hydrochlorides

as shown

(4),

treatment

Hydrolysis

3-Methoxyanthranilic yield. treatment of 3 with 3N hydroxide

acids

2-oxazoline 2,7 as shown in Scheme II. Regioselective achieved using diphenyl phosphorazidate (DPPA) as a +NH2

in Scheme

from Boc-L-proline potassium hydrogen

are

the

amino

acetals

8,

in three steps from N-tert-butoxycarbonyl (Sa) was prepared II. Boc-L-prolinol

according to carbonate

our in

method 9 by treatment dimethylformamide

which

(Boc)-L-prolinols in quantitative yield with

methyl

iodide-

and

then

sodium

5053

New methods and reagents in organic synthesis-XC11

Scheme

Ii CH30

1) n-BlJLi 2) (CrjH50)2P(O)N3

3) NaAIH2(0CH2CH20CH3)2 *q;)

H:;:aO;

3

b;;cH

N’

4 a:R=H b:R=CH3 c: R = Ph2CH2

CH2OH

(CH~)~SO

:

CHO

C5H5N*S03

R’ -cl3

6ocN 3,

9-W3*)2

$WOR212

HC(OR2)3

R’

BocN 3,

SooN%:

H&R, HCI

6

5

7

a: R’ = H

a: R’

b: R’ = TBDMSO

b: R’ = TBDMSO

c: R’ = PhCH20

8

a: R’ = H

=H

a:R’=H

R2 = CH3 b: R’ = TBDMSO

c: R’ = PhCHzO

R2 = C2H5 Boc = tert-butyloxyoarbonyl

c:R’

TBDMSO = tertbutyldimethylsilyloxy

R2 = C,H,

&;zoH + HG2)2

(C,&~)~(O)CN

H’CI

4

= PhCH20

R2=CH3 b:R’=OH ti = C2H5 c: R’ = PhCH20 ti = C,H,

RO

_

R’

8 9 a:R=R’=H,R2=cH3 b:R=CH3,R’=H,R2tcH3 c: R = PhCH2, R’ = H, f?’ = CH3 d:R=H,Rf=OH,R2=C2H5 a: R = H, R’ = PhCH20, R2 = C,H,

S. MOIUer al.

borohydride-lithium

chloride

L-prolinols

(Sb)

and

successive

treatment

butyldimethylsilyl chloride.

complex

aldehydes

6

orthoformate

in

in

obtained

(TBDMS)

ethanol

a chiral

(4)

sodium (5)

in the

presence

was

aldehydes 6b orthoformate. effective

the

and 6c

and

yields.

6a to 8a

iodide,

by

(3) tert-

borohydride-lithium with

sulfur

of triethylamine9

trioxidegave the

corresponding

the

on

hydrochlorides

high

not

smoothly

undergo

the

of triethyl 7b and 7 c

of the Boc and tert-butyldimethylsilyl with 10% hydrogen chloride in methanol

No racemization was since the N-3,5-dinitrobenzoyl

D-isomer

did

However, the use desired diethyl acetals

performance

of

the

amino

found to derivative liquid

acetals

8 in

occur during the of 8a showed no

chromatography

(HPLC)

column. of

4 and 8

was

easily

in the presence

accomplished

by

use

of base to give the acetal

of

diethyl

amides

9 in

yields. The

above

and

methyl

Boc-L-prolinols

yields.

Condensation

(10)

of

(2)

Subsequent treatment of 6a with trimethyl chloride10 in methanol easily afforded the dimethyl

phosphorocyanidate(DEPC)ll 57-85%

bromide,

Deprotection of 7 was easily achieved

of its antipodal

using

dicarbonate,

yield.

The trimethyl

giving of

benzyl oxidation

Trans-4-O-substituted frans-4-hydroxy-L-proline

from

di-tert-butyl

yield.

quantitative

conversion

prepared

dimethylsulfoxide

in good

groups

ethanol)

peak

or

with

orthoformate

nearly

chloride

cerium

in 61%

acetalization

(or

(1)

good

and

7a

were

with

and

tetrahydrofuran-ethanol.

were

Racemization-free

pyridine

acetal

in

(5~)

acetal

amide

and L-proline via

12 - 14,

9b

methyl shown

was

also

ester

(11)

in Scheme

obtained by

from similar

3-methoxy-2-nitrobenzoic sequence

of the

III.

Scheme

1) (CH3)$30,

the

III

C5H,N-SO3

(GH,),N 2) HC(OCH3)3, CeCI,

14

9b

reactions

acid as

5055

New methods and reagents in organic synthesis-XCIl

We

considered

attained

from

attack

of

Scheme

9

that

by

indole

from In

IV.

final

an the

fact,

construction

intramolecular less

hindered

cyclization

of

the

tilivalline

cyclization top 9b

of

face

of

was

gave

reagent

in

the

Scheme

(lb),

However,

V.

dramatic

acetal

chloride. amides

condensation results

This

are

new

summarized

boron the

also

type easily

(la)

tilivalline in Table Scheme

was

of the final in in

a

condensation underwent and

carried

one-pot

simple

its derivatives

as

shown

was

in with

in

achieved with

indole,

and

(1) (3)

lb in 71% yield.

The

one-pot

type

lc-e,

Mannich

respectively.

H

R’ 0

15 Scheme

out

process (2)

I. IV

be

tetrahydrofuran

(5%),

construction

afforded this

in

poor

acetonitrile,

would nucleophilic

the crude imine 15 b of 15b with indolyl

etherate very

the

15, as shown

imine

to give treatment

trifluoride

yield

improvement

Mannich

9a and 9c-e to furnish

of but

of 9 b treatment iodide-pyridine

the sequential by chlorotrimethylsilane-sodium zinc

presence

0 -methyltilivalline

the

by

successfully

chlorotrimethylsilane and sodium iodide in acetonitrile (R = CH3, ~1 = H) as an unstable oil. Subsequent Grignard

skeleton

followed

V

1

The

5056

S.MORIetal.

Table I

Synthesis

of Tilivallines (1) Reaction Conditions

Compd. No.

R

R’

Temp. (“C)

Time

Yield(%)

a

H

H

r.t. 50

18h 2h

63

b

CH3

H

r.t. 55

overnight 3h

71

C

PhCH*

H

r.t. 45

14.5 h 3.5 h

41

d

H

OH

r.t.

22 h

63

e

H

PhCH,O

r.t.

12.5 h

64

The could

reaction

spectra. with

The

those

Reductive over the

was

be detected

completely

in their

spectral

of natural

400

data

from

was

was

and

proton

magnetic

nuclear

la and lb

synthetic easily

in ethanol lb

stereoselective synthetic

and

of lc

5% palladium-carbon group

of the

tilivalline

debenzylation

methyl

MHz

no

diastereoisomers resonance

were

out under

la

in 80% yield.

to give

unsuccessful

under

a variety

a hydrogen However, of reaction

lithium boron trichloride, tert-butyl boron tribromide, (e.q., or aluminum chloride-ethanethiol). hexamethylphosphoric triamide, The spectra

of

characteristic

tilivalline

(la)

differences,

viz.

and

its

constant

atmosphere removal

of

conditions sulfidelH-NMR

been

reported

. to

for the protons

at C-11

and C-lla

diastereoisomer

a coupling

1

completely identical respectively.4

0 -methyltilivalline,

carried

of

(lH-NMR)

have

show

From these data, the stereochemistry of the indole of 9 Hz and 3 Hz, respectively. group in Id and le was determined to be l3, since the signals of C(ll)-H showed a large coupling The

constant new

(3 = 8-8.3

Mannich

chlorotrimethylsilane-sodium

Hz) in lH-NMR

type

condensation

iodide-pyridine

spectra. developed and

zinc

above chloride

requires in

both

addition

of

Trimethylsilylation of the Hence, the reaction might proceed as follows. indole. amino group in 9 followed by activation with zinc chloride gives A, which furnishes of alkoxytrimethylsildne from B affords the B, as shown in Scheme VI. Elimination imine

which

will

indole

to C from

be activated

with

the less hindered

zinc

chloride

to give

top face produces

C.

Nucleophilic

the tilivallines

(1).

attack

of

5057

New methods and reagents in organic synthesis-XC11

Scheme

VI

Q-

R’

0

1

Synthesis

of

11-Substituted

5H-Pyrrolo[2,1-c][1,4]benzodiazepin-S-ones

(16) Next

we

condensation bearing

investigated

to the

various

the

synthesis

substituents

at the

of the acetal

amide

9a

as described

above

proceeded

Table

in

good

obtained were

with

However,

and

yields,

when used

electron-rich

other as

C-11

various

the

above

new

Mannich

type

-cl [ 1,4]benzodiazepin-5-ones (16) We have found that the reaction position.

nucleophiles

smoothly

under

to give

N-methylpyrrole

16.

similar

reaction

The results

conditions

are summarized

benzene

as

Other

nucleophiles

derivative, derivatives

pentamethylbenzene

condensation

such

with

no

condensation

also

underwent

less

electron-rich

and

the

a large

than

in

to give 16a

as cyclohexanone

and

acetone

with

9a

constant

(J = 9-12

were could

reaction

of

9a

with

sodium

cyanide

furan of

giving

an 16~.

unreactive

to

9a.

also

be used for this Again, this yields.

Hz) in lH-NMR

of the acetonyl it might be

were

and

16d and 16e, though in moderate and the stereochemistry completely stereoselective, in 16a-d was determined to be b, since the signals for

coupling

and

products

1,3,5-trimethoxybenzene,

1,3_dimethoxybenzene,

Although the stereochemistry earlier. determined by 1 H-NMR spectrum, the

9a

reaction

affording

condensation was substituent at C-11

Interestingly,

reacted

imidazole, thiophene, such as pyrazole, 1,3,5-Trimethoxybenzene, representative

heterocycles

benzene

easily

Unfortunately,

respectively.

nucleophiles.

such

showed

of

II. 3-Methylindole

16b

application

of SH-pyrrolo[2,1

spectra

as

of the C(ll)-H described

group on 16e could not be b in analogy with 16a-d. in

the

presence

of

sodium

5058

S. MORIet al.

Table II

Synthesis -bones

of ll-Substituted

SKPyrrolo[P,l-c][l,4]benzodiazepin

(16)

HO

1) (CHs)sSiCI, Nal, C5HsN 2) Nucleophile 0

3) ZrlCl2

0

0

9a

16

Yield(%)

Reaction Conditions

Compd. No.

Nucleophile

Temp.(%)

Time(h)

Wi

I 0

b

R

\ N

C

r.t.

15.5

50

5

r.t.

19

50

6.5

r.t.

15

50

8

cHm 11;

67

0

A-3 I \

79

0

69

0

40

0

50

CH&OCH3

NaCN

4

N

Me

CCH, r.t.

0 =0

f

17

N H

CCHs

e

16

3

a

d

17

14.5 22.5

0

9

6 12

-CH2COCHs

41

0

50 50

21

-CN

60

40

50

4

-CN

26

3

r.t.

a) Mannich reaction with N-methylpyrrole

have been reported to occur at 2 position

pyrrole ring; S. Raines and CA. Kovacs, J. Heferocycl. Chem., 7, 223 (1970).

of

5059

New methods and reagents in organic synthesis-XCII

hydrogen and

2 proceeded

sulfite1

its

introduction molecule. cyanide,

quantitatively,

but

the product

17f (16f/17f= 60:40). The

isomer in

this

reaction

is presumably

due

low

was

to the

less

(16f/17f In

= 89/11)

with

two

conclusion,

particularly

tilivallines

(1) and its analogs

production

and

the

(16)

complete

Furthermore,

of 9.

a decrease

above

racemization,9

interesting

features

are an overall

efficiency

of the

synthesis

the amide

3) racemization-free bond

formation

Biological

using

testing

of

new

includes

acetal

DEPC,l

cyanide

reagent than sodium preference for the /3of

this

synthesis

suitable

generally

formation

from

is

now

scale

type

cyclization

useful

processes

a-amino

underway

of

for large

Mannich

1 and 5) the new Mannich

1 and 16

nitrile

sodium

1) regioselective amination of arenes using by our own group: synthon, 8 2) conversion of a-amino acids to u-amino aldehydes

developed a +NH2

16f

of

the

in yield.

stereoselectivity

the

of

bulky

In fact, the use of DEPC,l3 a bulkier cyanation showed a remarkable increase in the selectivity with

isomer

a mixture

selectivity

DPPA as without

aldehydes,

4)

type cyclization.

and

will

be

was

carried

discussed

elsewhere. Experimental All

melting

Kugelrohr JNM

FX-100,

internal

standard.

Optical

rotations

HPLC

was

CC-7)

chromatography thickness), used

was

dried

were

recorded

JNM

GSX-400

spectra with

for

(0.5

a

the

was

at 150°C

JASCO

column

for 2h under

PMX-60,

pressure

solution in THF

(1.56 of

high-pressure

hexane,

of DPPA

being

stirred

under

(303

mg,

at

-45’C

hydride (3.58 M in toluene, and the mixture was stirred Ice-water (2: 1). Na2S04.

was The

0.7 1 mL,

added

at

argon,

(Merck

Art.

before

use.

was

added

for

1

mmol)

O’C,

and

for 35 min, the

was stirred

(2 mL)

sodium

1.23 ml, 4.4 mmol) at -5°C

(2)7

in THF h,

mixture

layer

5717

(2 mm

Zinc

chloride

(3).

1 .l

and the mixture

1.1 mmol)

liquid

or Mallinckrodt

thickness)).

2-(3-methoxyphenyl)-4,4-dimethyl-2-oxazoline

(8 mL) at -45°C

A solution After

M in

an

polarimeter.

2-(2-Amino-3-methoxyphenyl)-4,4-dimethyl-2-oxazoline Butyllithium

as

Preparative

mm

then

extracts were washed with saturated Concentration in vucuo gave the residue,

dropwise

(205

mg,

at -45“C then

added

nto

a

1 mmol) for 1.5 h. at -45“C.

bis(2-methoxyethoxy)aluminum

was added was

was

a

MH-

automatic BW-200,

gel plates

reduced

JNM

spectrometer.

Rotar-II

(0.25

by IRA-2

DX-300

chromatography.

or 5715

out

a JASCO

tetramethylsilane

a JEOL

BW-820MH,

out on silica

thickness),

JNM

DIP-140

Tri

7734,

with

with

on

a JASCO

Art.

carried

mm

measured

on a JEOL

obtained

with

gel (Merck

were

spectrometer

were

measured out

(PLC)

5744

spectra

were

used

Distillation

spectra

or

Silica

was

uncorrected. (IR)

MS

carried

chromatograph.

are

Infrared

lH-NMR

spectrometer. 100,

points

apparatus.

to the mixture

at room extracted

temperature with

at -45’C, for

1 h.

AcOEt-benzene

aqueous NaCl, and dried over which was purified by silica gel

5060

S. MORIet al.

column

chromatography

mp 113-114’C (s, 6H), Calcd

with

(EtOH-H20).

3.9 (s, 3H),

CHC13 to give 3 (147 IR (KBr) 3450, 3300,

4.0 (s, 2H),

for C12H16N202

5.3-7.4

: C, 65.43;

mg, 67%)

1627 cm-l.

as colorless

lH-NMR

(m, 5H, 2H disappeared

H, 7.32; N, 12.72.

Found

crystals,

(CDC13) 8 1.4

with

D20).

: C, 65.58;

Anal,

H, 7.23; N,

12.63. 3-Hydroxyanthranilic red phosphorus 100°C for neutralized AcOEt.

Acid

(5 mg,

0.16

(4a).

mmol),

and 55%

A mixture

of 3

(20

mg,

0.091

hydriodic

acid

(0.4

mL)

was heated

14 h in a sealed tube and poured into ice-water. with Na2C 03, salted out by the addition of NaCl, The water layer was again salted out with AcOEt. The combined extracts

extracted concentrated

vacua to give 4a

in

mp

246-252’C,

and

3N

decomp.

Methanol

(1 mL)

(0.6

mg,

Acid was

stirred

mL) and 50%

the mixture

was refluxed

neutralized

with

the

addition

were

86%),

The mixture and extracted

dried

of

over

mp 233-235°C

(4b).

at 100°C

aqueous HCl,

A mixture

of 3

for 20 min.

then

NaOH

for 30 min.

1N aqueous

3-Benzyloxyanthranilic acid

the

(0.4 mL) were

After

salted

acid

according

Precursor

of

hydroxy-L-proline

to the

the

methyl

and imidazole

(0.93

cut

(20

mg,

aqueous AcOEt

NaCl, was

and

purified

literature.1

Amino ester

Alcohol

(1.4

g, 13.7 mmol)

(1:l)

to give

dried by

and (Lit.,14

0.091

mmol)

in

vacua.

concentrated

added

concentration

to the residue,

and

in vacua, the residue

was

by the addition

(4~)

of NaCl,

was

prepared

and extracted

from

(5b).

A solution

over

silica

column

3-hydroxy-2Methyl

TBDMSCl

(6 mL)

was

Concentration

in

chromatography

Ester

of N-B oc-trans-4 (1.72

stirred

(1:l). The mixture aqueous NaHC03,

Na2S 04. gel

dried over mp 169°C

5

g, 5.7 mmol), in DMF

for 12 h, and diluted with benzene-AcOEt aqueous citric acid, water, saturated which

and

Na2SO4,

(decomp.)

N-Boc-trans-4-tert-butyldimethylsilyloxy-L-proline as

was with

NH4Cl

with AcOEt. The extracts were washed with saturated aqueous NaCl, Na2S04, and concentrated in vacua to give 4b (16 mg, quantitative), (MeOH-H20) (Lit.,14 mp 169-17O’C). nitrobenzoic

at

250-252”(Z).

3-Methoxyanthranilic HCl

(12

by

mmol),

-

g, 11.4 mmol),

at room

temperature

was washed with 10% water, and saturated vacua

with

gave

hexane,

the residue, then

hexane-

N-Boc-trans-4-tert-butyldimethylsilyloxy-~-proline

methyl

IR (film) 2920, ester (2.01 g, 98%) as a colorless oil, bp 137-15OYYl.l mmHg. (CDC13) 6 0.05 and 0.07 (2xs, 6H), 0.87 and 1745, 1700, 1250, 830 cm- 1. lH-NMR 0.91 (2xs, 9H), 1.41 (s, 9H), 1.78-2.25 (m, 2H), 3.18-3.62 (m, 2H), 3.69 (s, 3H), 4.104.60 (m, 2H). Anal. Calcd for Cl7H33NO5Si : C, 56.79; H, 9.25; N, 3.90. Found : C, 56.54; H, 9.24; N, 3.96. of

N-Boc-trans-4-benzyloxy-L-proline the Amino Alcohol (SC). Silver

bromide L-proline

(3.75

mL, 31.5 mmol)

methyl

ester

were

Methyl oxide added

(3.1 g, 12.6 mmol)

(5.84

to a solution in DMF

Ester

g, 25.2

as

mmol)

the and

Precursor then

benzyl

of N-Boc-trans-4-hydroxy-

(50 mL) at O’C under

argon.

The

5061

New methods and reagents in organic synthesis-XC11

mixture

was

diluted acid,

over used

at

Et20.

water,

dried was

stirred

with

O’C

After

saturated

5 min,

aqueous

Na2S04. for

for

filtration,

NaHC03,

step

at room was

water,

temperature

washed and

with

saturated

without

further

for

24

h,

10% aqueous aqueous

in vacua gave a pale yellow

Concentration

the next

then

the filtrate

and citric

NaCl,

oil (4.52

and

g), which

purification.

A part Et20-benzene

of the crude oil was purified by silica gel column (1:3) to give pure N-Boc-trans-4-benzyloxy-L-proline

chromatography methyl

as a colorless

oil.

6 1.53 (s, 9H), 1.82-

IR (film)

1740, 1695 cm- 1. lH-NMR

(CDC13)

with ester

2.60 (m, 2H), 3.40-3.92 (m, 2H), 3.74 (s, 3H), 4.02-4.68 (m, 2H), 4.51 (s, 2H), 7.32 (s, 5H). Anal. Calcd for Cl8N25N05 : C, 64.46; H, 7.51; N, 4.18. Found : C, 64.21; H, 7.46; N, 4.15. N -Boc

Amino

methyl

(136

ester

anhydrous mmol)

LiCl

were

and

the

The

mixture

Alcohols mmol)

(11.6

added.

mixture

g,

was

272

EtOH

was

General

mmol)

with

in

and

mL)

at 0°C

was added

dropwise

for

1 h, then adjusted

citric acid (160 mL), and concentrated was extracted with CH2C12. The

aqueous

NaCl,

Compounds purification.

5a

Compound mmol). Colorless 53.9’

and

5b

were

used

mL) below

to pH

for

were

(10.3

5°C during the

acid

argon,

temperature

4 by

in vacua. extracts

amino

under

borohydride

at room

addition

19.5 of

Compound

Sb.

h.

10%

Water was added and the washed with saturated

the

next

step

without

further

from N-Boc-L-proline methyl ester (31.19 g, 136 g, 94%). mp 58.5-59.8”C (Et20-hexane), [o]24.5D -

IR (nujol)

Found

272

30 min,

for

3420,

1660, 1440,

1120 cm-l.

lH-NMR

(CDC13) 6

1.50 (s, 9H), 1.55-2.13 (m, 4H), 3.28-3.63 (m, 2H), 3.70 (d, 2H, J = 5Hz), 4.17(m, lH), 4.73 (br, lH, disappeared with D20). Anal. Calcd for ClOHl9N03 59.68; H, 9.51; N, 6.96.

and

g,

in vacua to give 5.

and concentrated

5a. Prepared crystals (25.69

(c = 1.04, MeOH).

(180

sodium

ice-water,

over Na2S04,

THF

then

aqueous mixture

dried

: The N-Boc

Procedure9

dissolved

(360

stirred

cooled

5.

was

3.87: C,

: C, 59.79; H, 9.64; N, 6.83.

Prepared

from

N-Boc-trans-4-tert-butyldimethylsilyloxy-L-

proline methyl ester (1.8 g, 5 mmol). 140°C/1.2 mmHg. IR (film) 3380, 2930,

A colorless oil (1.38 g, 84%), bp 1301670, 1250, 835 cm-l. lH-NMR (CDC13) 6

0.05 (s, 6H), 0.85 (s, 9H), 1.43 (s, 9H), 1.63-2.00 (m, 2H), 3.25-4.35 (m, 7H, 1H disappeared with D20). Anal. Calcd for Cl6H33NOqSi : C, 57.97; H, 10.03; N, 4.22. Found

: C, 58.07; H, 9.91; N, 4.29. Compound SC. Prepared from

methyl proline

ester

(4.52

methyl

g).

ester),

A colorless purified

crude

oil (2.18 by

silica

N-Boc-trans-4-benzyloxy-L-proline g, 56% from N-Boc-trans-4-hydroxy-L-

gel

column

chromatography

with

AcOEt-

hexane (2:3 to 3:2), bp 165-171°C/1 mmHg. IR (film) 3360, 2970, 1690 cm-l. lHNMR (CDC13) 6 1.43 (s, 9H), 1.82-2.38 (m, 2H), 3.10-4.30 (m, 7H, 1H disappeared with D20), N, 4.56.

4.45 (s, 2H), 7.25 (s, 5H).

Found

Anal.

: C, 66.89; H, 8.32; N, 4.71.

Calcd for Cl7H25N04

: C, 66.43; H, 8.20;

5062

S. MORI~~ al.

N -Boc

Amino

trioxide-pyridine

Aldehydes

complex

(47.7

6.

General

: A solution

Procedure9

g, 300 mmol)

in DMSO

(300

mL)

was

of sulfur

added

in one

portion to a solution of 5 (100 mmol) and triethylamine (41.8 mL, 300 mmol) in CH2C12 (300 mL) at -10°C. The mixture was stirred vigorously at lo-20°C for 10 min,

poured

with

10%

aqueous used

into citric

NaCl,

for

ice-water,

the

acid,

and

Compound 95%).

IR (film)

water,

dried

next

and

extracted saturated

over

Na2S04.

step

without

further

6a.

Prepared

from

2980,

1730,

with

1690,

Et20.

aqueous

The

extracts

NaHC03,

Concentration

were

water,

washed

and

saturated

in vacua gave 6, which

was

purification. 5a

(20.1

g, 100 mmol).

A yellow

oil (18.9

g,

1390 cm-l.

Compound 6b. Prepared from 5b (5 g, 15 mmol). Colorless crystals (4.46 g, mp 47-54OC. IR (nujol) 1710, 1670, 1415, 1250, 830 cm-l. lH-NMR (CDC13)

90%),

6 0.07 (s, 6H), 0.88 (s, 9H),

1.46 (s, 9H),

1.84-2.19

(m, 2H), 4.07-4.52

(m, 2H), 9.33-

9.57 (m, 1H). Compound g, 84%).

(17.75

6c. Prepared IR (film) 2970,

1.43 (s, 9H),

1.73-2.37

(m, 2H),

7.25 (s, 5H),

9.27-9.60

(broad

N-Boc

Amino

solution

of

chloride

in alcohol

at 55’C NaHC03,

for

water, gave

and

6

3.27-3.77

mmol),

aqueous which

Compound

trialkyl

7.

orthoformate

NaCl,

was

7a.

and dried

purified

Prepared

(73 mL, 667 mmol),

A colorless

mL,

(film)

oil (14.19

7b.

108 mmol),

2920,

(s, 2H),

General

(667

: A

Procedure10

mmol)

and

0.4M

cerium

over Na2S04.

by column from

6a

and 0.4M

g, 61%),

(18.89

cerium

purified

Concentration

in vacua

chromatography. g,

94.8

chloride

by silica

mmol),

in MeOH

trimethyl

(237 mL, 94.7

gel column

chromatography

IR (film) 2960, 1690, 1400, 1170 (m, 4H), 3.30 (s, 6H), 3.23-3.43 (m,

(m, lH), 4.60 (d, lH, J = 4Hz).

Compound colorless oil hexane-A&Et

4.48

was stirred at 40-45“C for 67 h (for 6a) or The mixture was poured into 5% aqueous The extracts were washed with 10% citric acid,

with hexane-AcOEt (5:1), bp 74-76WO.5 mmHg. cm-l. lH-NMR (CDC13) 6 1.32 (s, 9H), 1.72-2.25

(18

(m, 2H),

(237 mL, 94.7 mmol)

saturated

2H), 3.75-4.03

3.97-4.45

Dialkylacetals

21 h (for 6b and 6~). and extracted with Et20.

orthoformate

(m, 2H),

yellow oil (CDC13) 6

s, 1H).

Aldehyde

(94.8

the residue,

mmol).

from 5c (21.5 g, 70 mmol). A pale 1730, 1690, 1390, 1365 cm-l. lH-NMR

(2.65 (6:1), 1690,

Prepared and

0.4M

from cerium

g, 49%), purified bp 104-120°C/0.38 1390,

1250,

6b

(4.46 chloride

g, 13.5

mmol),

in EtOH

(34

by silica gel column mmHg, [cz]~~D -45.8’

830 cm- 1. lH-NMR

(CDC13)

triethyl mL,

13.5

orthoformate mmol).

A

chromatography with (C = 1.08, MeOH). IR 6 0.05 (s, 6H), 0.85 (s,

9H), 1.15 and 1.18 (2xt, 6H, J = 6,5Hz), 1.48 (s, 9H), 1.70-2.51 (m, 2H), 3.15-4.07 (m, 7H), 4.23-4.78 (m, 2H). Anal. Calcd for C2OH4lNO5Si : C, 59.51; H, 10.24; N, 3.47. : C, 59.42; H, 10.32; N, 3.48. 7c. Prepared from 6c (17.95 g, 58.8 mmol), Compound orthoformate (78 mL, 470 mmol), and 0.4M cerium chloride in EtOH (147

Found

triethyl mL, 58.8

5063

New methods and reagents in organic synthesis-XCII

Colorless mmol). chromatography with 1.02,

crystals

IR (nujol)

MeOH).

(14.42

hexane-AcOEt 1690,

g,

65%),

(6:1), 1400,

purified

mp 58-60°C

1365.

1170,

by

silica

(pentane),

1110 cm-l.

1.13 and 1.18 (2xt, 6H, J = 7Hz), 1.45 (s, 9H), 1.97-2.55 4.43 (s, 2H), 7.22 (s, 5H). Anal. Calcd for C2IH33N05

gel

[a]22D

column

-43.8’

IH-NMR

(c =

(CDC13)

6

(m, 2H), 3.13-4.33 (m, 9H), : C, 66.46; H, 8.77; N, 3.69.

: C, 65.98: H, 8.42; N, 3.67.

Found

Determination Active

of

Optical

N -3,5-Dinitrobenzoyl

mmol)

was

room

dissolved

temperature

dissolved

in

10% HCl

1 h.

THF

dinitrobenzoyl stirred

in

for

(6

of

was

8a.

mg, for

0.78

(3 mL)

mmol) After

7 h.

Preparation Compound and

of 7a

(0.2

mL,

was

added,

mg,

was

0.65

stirred

and the residue

1.43

concentration

Optically

(160

the mixture

in vacua,

concentrated

Triethylamine

(180

temperature

8a. (1)

of

in MeOH

MeOH

mL).

chloride

at room

Purity Derivative

mmol)

and

the

of the

at was

and

3,5-

mixture

was

in vacua,

solvent

the residue was dissolved in AcOEt, washed with saturated aqueous NaHC03, water, and saturated Concentration in vacua gave the residue, Na2S04.

10% aqueous citric acid, water, aqueous NaCl, and dried over

column

to

chromatography

derivative (2)

of 8a

(158

Preparation

optically MH)

Racemic

aldehyde

at 40°C

in

AcOEt-hexane

mg, 72%)

of

active

trimethyl

with

was

racemized

Acetalization

as described

to N-3,5_dinitrobenzoyl

yellow

derivative

as

7a

by silica

gel

N -3,5 -dinitrobenzoyl

crystals. Derivative

by

of

for

was purified

give

N-3,5-Dinitrobenzoyl

6a

AcOEt.

orthoformate

as pale

which

(1:2)

treatment

the

racemic

gave

racemic

described

with

silica

6a,

thus

7a,

of

8a.

gel

(BW-820

The

obtained,

which

was

with

converted

above.

(3) HPLC Analysis. Each 3,5-dinitrobenzoyl derivative (2.5 mg) was dissolved in 1,2-dichloroethane (0.5 mL), and 0.4 pL of them was subjected to HPLC using chiral Sumipax (flow

OA-1000 rate,

detection peaks

1.5 UV

at R.T.

one

showed

detected. The mmol)

4.6x250

mL/min; 254

= 19.02

Acetal

The

mL),

mmol)

were

hexane racemic

= 20.52

Amides

9. General

in DMF added

min min,

Procedure

(45 mL) (or EtOH

1 h, and concentrated

Sumitomo

Chemicals

: 1,2-dichloroethane

peak

at R.T.

from

: EtOH

3,5-dinitrobenzoyl

and 20.52

and the anthranilic

g, 19 mmol)

purchased

min (D-form)

in 10% HCl in MeOH for

mm,

eluate,

nm).

a single

temperature (150

(i.d.

and

acid 4 (19 mmol)

no

: Method

while peak

A.

was added.

optically

A solution

The residue

was

to the mixture

two active

A solution

at room in DMF

of DEPC

(7.43

at O’C, and the whole

was

of 7 (22.8

stirred

was dissolved

(38 mL) and then N,N-diisopropylethylamine

dropwise

100:6:1;

showed

of D-isomer

for 7b and 7c)

in vacua.

=

derivative

(L-form),

Co. Ltd.)

mL,

was stirred

(3.1 41.8

at O’C

for 1 h, then at room temperature for 2 h. A solution of DEPC (0.93 g, 5.7 mmol) in DMF (19 mL) was further added, and the mixture was stirred at room temperature for

additional

mixture

was

1.5 washed

h,

and

with

concentrated water.

The

in vacua. washings

were

Benzene salted

was out

added,

by the

and

the

addition

of

5064

S. MORIet al.

NaCl, and extracted over Na2SO4, and chromatography

with benzene-AcOEt (1:l). The combined concentrated in vacua. The residue was

to give

Method

temperature

in THF

(9 mL),

for and

acid 4 (1.1 mmol)

were dried by column

9.

B. A solution

at room

extracts purified

of 7 (1.32 mmol)

1 h and

triethylamine

were

in 10% HCl in MeOH in vacua.

concentrated (0.37

added.

mL,

2.64

To the mixture

(2 ml) was stirred

The residue

mmol)

and

was added

was

then

the

a solution

dissolved anthranilic

of DEPC

(215

mg, 1.32 mmol) in THF (1 mL) at O’C, and the whole was stirred at O°C for 1 h, then at room temperature for 40 min. After concentration in vacua, the residue was dissolved in AcOEt-benzene (2:1), washed with saturated aqueous NaHC03, water, and

saturated

aqueous

the residue,

which

Compound mmol) by method silica gel column 1OO’C (Et20),

NaCl,

and

was

purified

9a.

Prepared

[cL]~~D -191.8’

from

IR (nujol)

Prepared

from

2970,

7a

(325

Compound by method

chromatography

(2.91

g, 70%), (15:3:1),

3450,

oil (272 mg, (1:2 to 1:l).

1615 cm- l.

lH-NMR

1.32 mmol)

3350,

g, 19

purified by mp 99.53060,

1620,

and 4b

(184 mg, 1.1

84%), purified by silica gel column [cr]24D -173“ (c = 1.2, MeOH). IR (CDC13)

6 1.5-2.6

(m,

4H),

3.2-3.8

(m, 2H), 4.8 (s, 2H), 6.5-7.1

9c.

Prepared

B.

A yellow

with

Compound

from oil

AcOEt-hexane

9d.

7a

(148

(142

(1: 1).

Prepared

from

mg, 0.6 mmol)

mg,

77%),

IR (film)

7b

(1.33

purified 3450,

1225,

3.00-4.28

1070 cm-l.

(m,

Hz, disappeared Compound

12H,

lH-NMR

and 4c by

3350,

g, 3.3 mmol)

A pale brown amorphous solid (538 mmol) by method A. silica gel column chromatography with CHC13-MeOH (12:l).

mmol) column

4a

(m,

MS m/z : 294 (M+).

mmol)

1605,

9.

and

: C, 59.67; H, 6.85; N, 10.15.

Found

mg,

(m, 2H), 3.48 (s, 3H), 3.53 (s, 3H), 3.9 (s, 3H), 4.2-5.2 3H).

to give mmol)

amorphous solid (3.73 CHC13-benzene-MeOH

: C, 59.99; H, 7.19; N, 9.99.

9b.

3360,

g, 22.8

(c = 1.00, MeOH).

mmol) by method B. A colorless chromatography with AcOEt-hexane 3460,

(5.6

in vacua gave

Concentration

chromatography

7a

brown with

Na2S04.

(CDC13) 6 1.40-2.40 (m, 4H), 3.46 (s, 3H), 3.50 (s, 3H), 3.04(m, 5H, 3H disappeared with D20), 6.24-6.48 (m, 3H). Anal.

Calcd for C14H2ON204

(film)

over

by column

A. A reddish chromatography

1590 cm-l. lH-NMR 3.74 (m, 2H), 4.24-5.44 Compound

dried

(122

silica 2800,

and 4a

1615 cm-l. (480

mg, 57%), IR (nujol)

with

D20),

6.30-6.92

(364

mg, 0.96

mg, 2.92

purified by 3350, 1630,

(CDC13) 6 1.22 (t, 6H, J = 7 Hz), 1.72-2.60

3H disappeared

mg, 0.5

gel column

(m, 2H),

(m, 3H), 7.27 (d, lH, J = 6

with D20). 9e.

by method A. chromatography

Prepared Pale with

from

7c

brown crystals (247 CHC13-MeOH (30:1),

mmol)

and 4a

(123

mg, 0.8

mg, 75%), purified by silica gel mp 134-136°C (Et20), [o]26.5D -

123.3’ (c = 1.00, MeOH). IR (nujol) 3450, 3380, 3230, 1610, 1590 cm-l. lH-NMR (CDC13) 6 1.18 (t, 6H, J = 7Hz), 1.94-2.56 (m, 2H), 3.32-3:?6 (m, 6H), 4.00-4.20 (m, 2H), 4.00 (br s, 3H, disappeared

with D20),

4.40

(s, 2H), 4.96-5.16

(m,

lH),

6.34-6.8

5065

New methods and reagents in organic synthesis-XC11

(m, 3H), 7.25 (s, 5H).

Anal. Calcd for C23H3ON205

: C, 66.65; H, 7.30; N, 6.76.

Found

: C, 66.83; H, 7.30; N, 6.77. N-(3-Methoxy-2-nitrobenzoyl).L-proline mixture

of

methyl

ester

mmol)

in DMF

mL).

The

days.

Methyl

3-methoxy-2-nitrobenzoic (11)

(12.5

g, 97 mmol)

(20 mL)

mixture

After

followed

was stirred

dilution

in DMF (160 mL) was added by triethylamine

(11.4

(12).

AcOEt-benzene

(2:1,

DEPC

at room

750

To a

and L-proline (18.4 g, 113

g, 113 mmol)

at 0°C for 0.5 h, and then

with

Ester

(10)(15.9 g, 80.6 mmol)

acid

in DMF

temperature

mL),

the

(20 for 2

mixture

was

successively NaHC03,

washed with 10% aqueous citric acid, water, saturated aqueous water, and saturated aqueous NaCl, and dried over Na2S04. Concentration

in

gave

vucuo

(18.4 cm-l.

crystals,

which

were

recrystallized

from

g, 74%) as pale yellow crystals, mp lOO-1Ol’C. lH-NMR (CDC13) 6 1.83-2.50 (m. 4H), 3.37-3.75

3H), 4.23-4.85

(m, lH),

H, 5.23; N, 9.09.

6.97-7.97

Found

(m, 3H).

Anal.

AcOEt-hexane

Calcd

for Cl4Hl6N206

g, 6.7 mmol)

alcohols

5.

(13).

as in the general

The

crude

product

procedure

was

purified

with AcOEt-benzene (1O:l) to give 13 (1.67 (film) 3350, 2930, 1620, 1525 cm- 1. lH-NMR 3.58 (m, 2H), 3.58-3.93 oxidation

procedure

for

the

of

: C, 54.54;

silica

gel

13

(13.25

2-nitrobenzoyl)-L-prolinal

(9.9

of N-Boc

column

g, 47

g, 77%).

mmol)

was

amino The

12

amino

chromatography

(m, 2H), 6.92-7.77 Dimethyl

of N-Boc

from

g, 89%) as a yellow viscous oil. IR (CDC13) 6 1.65-2.42 (br m, 4H), 3.25-

(m, 2H), 3.97 (s, 3H), 4.08-4.63

preparation

Prepared

for the preparation by

N-(3-Methoxy-2-nitrobenzoyl)-L-prolinal DMSO

12

: C, 54.82; H, 5.39; N, 9.12.

N-(3-Methoxy-2-nitrobenzoyl)-L-prolinol (2.06

to give

IR (KBr) 2950, 1725, 1640 (m, 2H), 3.80 (s, 3H), 3.97 (s,

carried

aldehydes aldehyde

(m, 3H).

Acetal

out

as in

(14).

the

general

6 to give N-(3-methoxy(9.9

g) was converted

to its

dimethyl acetal 14 (9.18 g, 79%) as in the general procedure for the preparation of N -Boc amino aldehyde dialkylacetals 7. A pale brown oil, [cz]~~D -206’ (c = 0.5, MeOH).

IR (film)

2920,

2820,

3.08-3.83

(m, 2H), 3.58 (s, 3H), 3.62 (s, 3H), 4.07 (s, 3H), 4.28-4.67

(d, lH, J = 3 Hz), 6.73-7.65

1630 cm- 1. lH-NMR

(CDC13) 6 1.93-2.45

nitro

(200

acetal

mg)

hydrogen 9b (939

in

14

(1.05

g,

ethanol

(20

mL)

atmosphere. mg, 98.5%),

7a and 4b,

described

Tilivallines mmol) 8.4

was added

mmol),

and

under

argon,

and

mmol)

was

added

(br m, lH),

4.91

(m, 3H).

N-(3-Methoxy-2-aminobenzoyl)-L-prolinal The

(br m, 4H),

3.1

which

mmol)

at

Filtration was

Dimethyl

room

was

hydrogenated

temperature

followed

by

identical

with

for

over 18

concentration the

sample

Acetal

(9b).

palladium

black

h under

of the prepared

stirring

filtrate

and

afforded

by coupling

of

earlier. 1.

General

dropwise pyridine

to a suspension (0.85

the mixture to the

Procedure mL,

was

mixture.

10.5

stirred After

: Chlorotrimethylsilane of 9 (2.1 mmol) at -15°C being

in

mmol),

sodium

acetonitrile

for 30 min. stirred

(1.07

at room

iodide

mL, (1.26

8.4 g,

(21 mL) at -15°C Indole (0.49 g, 4.2 temperature

for 30

5066

min,

S. MORIeral.

zinc

chloride

temperature NaHC03,

(1.15

g, 8.4 mmol)

for 12.5-22 h, then then AcOEt were added

filtered off. The filtrate Na2S04. Concentration chromatography The

(la).

amorphous solid (130 CHC13-benzene-MeOH concentrated amorphous [IX]~~D yellow 2900,

and solid,

-1-126.8’ prisms,

1610

times

Prepared

at room

aqueous NaCI, and dried over which was purified by column

from

was

169-171°C,

(MeOH)),

9a

in Table

(131

solidified

[IxI~~D

which

lH-NMR

are shown

mg,

1.

0.47

mmol).

A

yellow

purified by silica gel column chromatography A solution of the synthetic la in MeOH

residue

mp 242-245“C.

cm-l.

stirred

at 45-55°C for 2-3.5 h. Saturated aqueous to the mixture, and the insoluble materials were

and

mg, 83%), (15:3:1).

the mp

was

1.

temperature

Tilivalline

and the whole

was washed with saturated in vacua gave the residue,

to give

reaction

was added

was

[ol27D (CDC13)

with

+197’

Et20

(c = 0.98,

recrystallized

to

give

MeOH)

from

a

(lit.,4

aqueous

with was

colorless

mp

MeOH

168’C. to give

+243’ (c = 0.57, MeOH).

IR (KBr)

3380, 3200,

8 1.4-2.1

(m, 2H),

4.2-4.6

(m, 4H), 3.6-4.2

(m,

lH), 4.9 (d, lH, J = 9 Hz), 6.7-8.4 (m, 10H). 12.2 (s, 1H). MS m/z : 333 (M+), 264, 247, 216, 130, 117, 90, 89. HRMS calcd for C2OHlgN302 333.1477, found 333.1481. The with

those

UV (MeOH)

hmax

spectral

(IR,

data

of natural solid

(246

(lb). mg,

71%),

AcOEt-hexane (3:l to 5:1), mp [a]l9D +241° (c = 0.56, MeOH). 6 1.58-2.03

: 220, 240, 257, 281, 289, 334. MS,

and UV)

of synthetic

(m, 4H), 3.59-4.57

Prepared purified

from

by silica

9b

(294

gel column

spectral

data

were

identical

(IR,

mg,

1 mmol).

chromatography

135’C (moistend) (AcOEt-hexane) IR (nujol) 3380, 3200, 1610 cm-l.

An with

(Lit4 mp 130°C), lH-NMR (CDC13)

(m, 3H), 3.72 (s, 3H), 4.83 (d, lH, J = 9 Hz), 5.4 (br s,

lH), 6.67-7.97 (m, 8H), 9.5 (br s, 1H). MS m/z : 347 (M+), HRMS calcd for C2lH2lN302 347.1634, found 347.1631. The

la

tilivalline.4

0 -Methyltilivalline amorphous

(nm)

lH-NMR,

1H-NMR,

and

MS)

of synthetic

278, 230, 215,

130, 117.

lb

were

identical

with

mg,

0.38

mmol).

Pale

those of 0 -methyltilivalline.4 0-Benzyltilivalline

(1~).

Prepared

from

9c

(142

yellow prisms (66 mg, 41%), purified by PLC (AcOEt : hexane = 5:1), mp 125-126’C, [a]2OD +132.5’ (c = 0.52, MeOH). IR (KBr) 3350, 2850, 1615 cm-l. lH-NMR (CDC13) 6 1.5-2.2 (m, 4H), 3.7-4.2 (m, 2H), 4.2-4.7 (m, lH), 4.8 (d, lH, J=lO Hz), 4.9 (s, 2H), 5.3 (br s, lH), 6.8-7.9 (m, 13H), 9.6 (s, 1H). HRMS calcd for C27H25N302 423.1947, found

423.1946. 2-b-Hydroxytilivalline

(Id).

Prepared

from

9d

(680

mg,

2.1

mmol).

A

63%), purified by silica gel column colorless amorphous solid (461 mg, chromatography with AcOEt to AcOEt-MeOH (lO:l), mp 181-19O’C (decomp.), IR (nujol) 3200, 1610, 1560, 1250 cm-l. lH[a]22.5D +213.7’ (C = 0.51, DMSO). NMR (CDC13 + DMSO-d6) 6 1.59-1.66 (m, lH), 1.69-1.78 (m, lH), 3.60-3.66 (m, lH), 3.95 (d, lH, J = 12.6 Hz), 4.23 (br, lH),

4.46-4.54

(m, lH),

4.66 (d, lH, J = 8.3 Hz),

5067

New methods and reagents in organic synthesis-XC11

4.75

(br s, lH,

disappeared

with

D20),

5.28

(br s, lH,

disappeared

(t. lH, J = 7.8 Hz), 6.83 (dd, lH, J = 1.5, 7.5 Hz), 6.95-6.99 7.26 with

(s, lH), 7.36-7.42 (m, 2H), 7.49 D20), 10.82 (s, lH, disappeared

3/5CH3C02C2H5 pale yellow chromatography (nujol)

(le).

3200,

1615,

1590,

Found

Prepared

amorphous solid (85 mg, with CHC13 -MeOH (3O:l).

3400,

(m, lH),

D20),

7.09-7.13

6.56

(m. lH),

(d, lH, J = 7.9 Hz), 9.39 (s, lH, disappeared with D20). Anal. Calcd for C2OHl9N303

: C, 66.88; H, 5.96; N, 10.44.

2-P-Benzyloxytilivalline

with

l

: C. 66.61; H, 5.57; N, 10.63.

from

9e

(95 mg,

0.23

mmol).

A

84%), purified by silica gel column [c~]~2.5D +220.6’ (c = 0.51, DMSO). JR

1550 cm- 1. lH-NMR

(CDC13

+ DMSO-d6)

6 1.62-

1.96 (m, 2H), 3.12-3.86 (m, 2H), 3.90-4.56 (m, 2H), 4.39 (s, 2H), 4.70 (d, lH, J = 8 Hz), 5.18 (s, lH, disappeared with D20), 6.36-7.72 (m, 8H), 7.24 (s, 5H), 8.17 (s, lH, disappeared

with

C27H25N303

l

Catalytic 5% Pd-C

D20),

H20

9.62

Debenzylation

(17 mg) in EtOH

mg,

0.045

gas

was

(s,

mmol)

bubled

filtration

and

the filtrate

spectral

data

of

of

le.

(1 mL)

at room was

identical

Preparation mL, 0.7 mmol)

and

saturated

was

the mixture

by

the

was

Concentration

in vacua

without

purification.

further

and to give

the

(0.056 of

a solution

of the

mL, 0.47 mmol)

the

indolyl

above

reagent,

which

showed

the

bromide

(3M

ethylmagnesium

in THF,

0.31

added at once at -7l’C, and the mixture temperature for 1 h. Saturated aqueous extracted with AcOEt. dried over Na2S04. by silica hexane

gel column

= 5:l) The

sample

The extracts Concentration chromatography

to give lb

spectral

prepared

data as

at -18°C

by

whose (0.089

under

aqueous

used

argon,

NaHC03

(10

mL)

0.93

for

ion was

the

next

at mlz

peak added

and and was

mmol)

mg,

0.94

in THF

step 230

BF3*Et20

at 0°C for 1 h. (110

A solution mmol)

and

(2 mL),

was

was stirred at -7l’C for 1 h, then at room NaHC03 was added, and the mixture was

were washed with saturated in vacua gave the residue, with

80%),

mg, 0.47 mmol)

molecular

indole

mL,

hydrogen

removed

as above.

(138

was

was stirred

from

(19

The extracts were washed with NaCl, and dried over Na2SO4.

residue,

prepared

of

of lc

and

was

(12mg,

prepared

Saturated

aqueous

at 0°C and the mixture

Grignard

for

a mixture

mixture,

catalyst

(5 mL)

in THF

into

Chlorotrimethylsilane

AcOEt.

residue

above

of 9b

in acetonitrile for 20 min. with

Calcd

A solution

to give la

Reaction.

saturated

Anal.

bubled

The

sample

to a suspension

extracted

was

for 1 h.

1 h.

authentic

The MS spectrum of the residue corresponding to the imine 15b. To

gas

in vucuo

D20).

: C, 70.42; H, 5.57; H, 8.95.

to the

for

Grignard

dropwise

NaHC03

added

concentrated with

lb

was added

aqueous

with

Found

Hydrogen

temperature

sodium iodide (105 mg, 0.7 mmol) the mixture was stirred at -18’C added,

disappeared

(3 mL) at room temperature

in EtOH

again

were

lH,

: C, 70.88; H, 5.95; N, 9.18.

aqueous NaCI, and which was purified

AcOEt-hexane

(5:1),

then

were

with

those

by PLC (AcOEt-

(9 mg, 5%). of the compound

above.

identical

of the

authentic

5068

S. MORIet al.

11-Substituted Compounds

SH-pyrroio[2,1-c][l,4lbenzodiazepin-5-ones

16a-e

the preparation The

were

reaction

mg,

from

9a

according

to the

general

temperature 16a.

1 mmol).

and

Prepared

Colorless

times

from

are shown

9a

crystals

(140

(116

in Table

mg,

mg,

0.5

(16). for

67%),

2.

mmol)

purified

(CDC13

+ DMSO-d6)

6 1.38-1.44

(m, lH),

1.69-1.91

and

3-methylindole

by silica

chromatography with AcOEt-hexane (3:1), mp 248-251’C Lol22.5~ +67“ (c = 0.50, DMSO). IR (nujol) 3400, 3350, 3250, NMR

procedure

of 1.

Compound (131

prepared

gel column

(deomp.) (MeOH), 1620, 1590 cm-l. lo-

(m, 3H), 2.27 (s, 3H), 3.57-

3.62 (m, lH), 3.66-3.73 (m, lH), 4.22-4.28 (m, lH), 4.78 (d, lH, J = 9 Hz), 4.99 (s, lH, disappeared with D20), 6.57 (t, lH, J = 8 Hz), 6.83 (d, lH, J = 8.1 Hz), 6.99 (t, lH, J = 8 Hz), 7.08 (t, lH, J = 7.7 Hz), 7.22 (d, lH, J = 8.1 Hz), 7.29 (d, lH, J = 8.1 Hz), 7.48 (d, lH, J = 8.1 Hz), 9.86 (s, lH, disappeared with D20), 10.91 (s, lH, disappeared with D20).

HRMS calcd for C2lH2lN302

Compound methylpyrrole

16b. (81 mg,

1490

cm-l.

3.70-3.87

Prepared

1 mmol).

gel column chromatography benzene), lo122.5 D +117.8’ lH-NMR

347.1619, from

Colorless

9a

found (140

crystals

347.1635. mg,

with AcOEt-hexane (3:1), (c = 0.5, DMSO). IR (nujol)

(CDC13)

6 1.71-1.76

0.5

(117 mg, 79%),

(m, lH),

mp

6.51-6.54

(m, 2H),

6.70

(br,

lH,

by silica

3180,

(m, 3H),

(m, 3H), 4.29 (d, lH, J = 9.7 Hz), 4.45 (s, lH, disappeared

(t, lH, J = 2.2 Hz),

and

145-147’C

3380,

1.83-1.97

mmol) purified

disappeared

(MeOH1620,

D20),

Compound

16~.

by silica (decomp.) 1590,

(168

Prepared

mg,

from

1 mmol).

9a

(140

gel column chromatography (MeOH), [o]22.5 D +43.7’ (c = 0.50, DMSO).

1370

cm-l.

lH-NMR

(CDC13

mg,

Colorless crystals with AcOEt-hexane

+ DMSO-d6)

0.5

mmol)

6.00

6.79 (t,

IH, J = 7.9 Hz), 6.88 (dd, lH, J = 2.2, 7.9 Hz), 7.40 (dd, lH, J = 2.2, 7.9 Hz). calcd for Cl7HlgN302 297.1477, found 297.1479. trimethoxybenzene

1590,

3.61 (s, 3H),

with D20),

with

N -

and

HRMS 1,3,5-

(132 mg, 69%), purified (3:1), mp 229-234’C

IR (nujol)

6 1.39-2.00

3370, 3100,

1620,

(m, 4H), 3.60 (s, 3H),

3.82 (s, 6H), 3.40-3.98 (m, 2H), 4.26-4.56 (m, lH), 4.82 (br s, lH, disappeared with D20), 5.12 (d, lH, J = 9 Hz), 6.14 (s, 2H), 6.57 (t. lH, J = 7 Hz), 6.86 (dd, lH, J = 2, 7 Hz), 7.38 (dd,

lH, J = 2, 7 Hz), 8.76 (s, IH, disappeared

C2lH24N205

: C, 65.61; H, 6.29; N, 7.29.

Found

Compound 16d. Prepared from 9a Colorless crystals (63 (98 mg, 1 mmol). chromatography with CHC13-benzene-MeOH (CHC13), cm-l.

lo~l8.5

lH-NMR

D +6.9” (c = 0.11, DMSO). (CDC13

+ DMSO-d6)

with D20).

Anal.

Calcd for

: C, 65.55; H, 6.24; N, 7.31.

(140 mg, 0.5 mmol) and cyclohexanone mg, 40%), purified by silica gel column (15:3:1), mp 188-191.5OC (decomp.) IR (nujol)

6 1.57-2.59

3350, 3050,

1700,

(m, 13H), 3.59 (ddd,

1610, 1550

lH, J = 6, 7.5,

11.5 Hz), 3.81 (ddd, lH, J= 4, 7.5, 11.5 Hz), 3.93 (dt, lH, J= 7, 11.5 Hz), 4.13 (d, lH, J = 12 Hz), 4.73 (br s, lH, disappeared with D20), 6.67 (t, lH, J = 7.5 Hz), 6.86 (dd, lH, J= HRMS

1.3, 7.5 Hz), 7.22 (dd, IH, J = 1.3, 7.5 Hz), 8.79 (s, lH, disappeared calcd for Cl8H22N203

314.1632,

found

314.1646.

with D20).

5069

New methods and reagents in organic synthesis-XC11

16e. Prepared

Compound

from

9a

(140

1 mmol). Colorless crystals (56 mg, chromatography with CHC13-benzene-MeOH [01]24D

+230.6’

(c = 0.13,

DMSO).

lH-NMR

(CDC13 + DMSO-d6)

3.34-4.16

(m, 4H,

9.10 (s, lH,

6 1.62-2.42 with

with D20).

and

acetone

(58 mg,

41%). purified by silica gel column (12:2:1), mp 171-172T (MeOH-H20).

IR (nujol)

1H disappeared

disappeared

mg, 0.5 mmol)

3340,

3080,

1715,

1610,

1595 cm-l.

(m, 4H), 2.21 (s, 3H), 2.57 (d, 2H, J = 8 Hz),

D20),

HRMS

4.52-4.76

(m,

lH),

6.64-7.34

calcd for Cl5Hl8N203

(m, 3H),

274.1381,

found

274.1321. ll-Cyano-SH-pyrrolo[2,l-c][l,4]benzodiazepin-5-ones 17f).

1)

mL,

Reaction

3 mmol)

sodium Sodium mmol)

2:l)

with dropwise

under

argon,

hydrogen

sulfite

(104

added.

(237

After

mg,

usual

chromatography

the

mg,

1 mmol) stirred

added

of

(0.283

mixture

work-up,

the

then

room

crude (2:l

sodium and

product

to 4:1),

IR (nujol)

6 1.96-2.10

3350, 3100,

(m, 3H),

2.21-2.92

(d, lH, J = 11 Hz), 4.80-5.60

(m,

lH),

3.54-3.69

(br, IH, disappeared

for

(m, 2H),

purified

DMSO).

IR (nujol)

6 1.81-1.91

(m,

3.89 (m, lH),

(decomp.)

(MeOH-AcOEt).

lH),

1.92-2.09

3.97-4.05

(m, 2H),

(m, lH),

2.39-2.46

4.99 (s, lH),

silica

lH),

gel

: hexane

+332.9

=

(c = 0.50,

(m,

lH),

6.86 (t, lH, J=

IH-NMR

(m,

at

(CDC13 + DMSO-d6)

[cz]~~.~D

3350, 3100, 1610, 1590, 1560 cm-l.

1

zinc

stirred

by

6.97 (d, lH, J = 7.8 Hz), 7.06 (d, lH, J = 7.8 Hz), 9.74 (s, 1H. disappeared MS m/z : 216 (M+-HCN). 17f : mp 198-200.5”C

mg,

min,

was

3.87-3.92

with D20),

30 min.

(49 30

then PLC (AcOEt

IH-NMR

mmol),

for

cyanide

[a]22.5D

1620, 1570, 1430 cm-l.

0.5

in acetonitrile

the whole was

(0.38

mg,

at -20°C

temperature

to give 16f (73 mg, 60%) and 17f (49 mg, 40%). 16f : mp 208-210°C (decomp.) (MeOH-AcOEt).

DMSO).

(140

3.5 mmol)

stirred

to the mixture

with AcOEt-hexane

9a

mL,

was

and

at

and

Chlorotrimethylsilane

to a suspension

and

was

(16f

Cyanide.

and pyridine

being

2 mmol) After

21 h.

Sodium

mg, 3 mmol),

at -20°C

for

column

9a

added

(450

was

chloride 50°C

was

iodide

(5 mL)

of

4.38

7.8 Hz),

with D20).

+555.3”

(c = 0.50,

(CDC13 + DMSO-d6)

3.56-3.64

(m,

6.40 (br s, lH, disappeared

lH),

3.82-

with D20),

6.57 (t, lH, J = 8 Hz), 6.85 (d, lH, J = 8 Hz), 7.38 (d, lH, J = 8 Hz), 9.80 (br s, lH, disappeared with D20). MS m/z : 216 (M+-HCN). 2) Reaction as described (0.152 product

of 9a with

for

mL,

the

1 mmol)

was

purified

DEPC.

general was by

Reaction

procedure used

silica

for

instead

was carried

the preparation

of indole.

gel column

After

chromatography

out in 0.5 mmole of 1 except usual with

that

work-up,

the

AcOEt-hexane

scale DEPC crude (2:l)

to give 16f (31 mg, 26%) and 17f (4 mg, 3%). Acknowledgment Scientific 60470151

Partial

Research and

No.

from

financial

the Ministry

02250230)

and

supports

of this

of Education, the

Japan

research

Science, Research

and

by Grant-in-Aids Culture,

Foundation

Japan for

for (No.

Optically

S. MORI~~al.

Active

Compounds

Budzikiewicz

are

gratefully

of University

acknowledged.

of Kiiln for sending

REFERENCES 1. 2. 3.

For Part 91, see Aoyama, A part

of this

T.; Shioiri,

Present

address

Industry

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Research 564,

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6111.

Research

Laboratory,

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Kanagawa Ltd.,

228,

Hanno,

Pharmaceutical

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7.

Meyers,

8.

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(c) Osaka

T.; Koseki, A.I.;

Avila,

John Wiley Y.; Hamaguchi,

S.; Aoyama,

F. Tetrahedron

Left., 1989,30,

T. Tetrahedron

T.; Shioiri,

Lett., 1984,25,

T. Chem. Pharm. Bull., 1982,30,

Shibata,

M.; Sugiura,

10.

Gemal,

A.L.; Luche,

11.

Shioiri,

T.; Yokoyama,

T.; Kato, S.; Shioiri, Y.; Kasai,

J.A.V. Org.Synth.,

Tetrahedron

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1524. 1921.

(b) Hamada,

Y.;

T. J. Org. Chem., 1987,52,1252.

Y.; Yamada,

C.F.H.;

S.;

1871.

Hamada,

Lett., 1979,20,

14.

Warnell,

J.L. Biochem.

15.

Cleaver,

L.; Nimgirawath,

S. Tetrahedron,

1976,32,2211,

T. J. Synth. Org. Chem. Japan, 1979,37, 856.

see Shioiri,

Allan,

L.H.;

J.-L. J. Org. Chem., 1979,44.4187.

For a review, Harusawa,

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W.B. J. Org. Chem., 1981, 46, 3881. T. Chem. Pharm. Bull., 1986,34,

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Enoki,

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(c) Remers, W.A. In The Chemistry of 8z Sons : New York, 1988; Vol. 2, pp 28-92.

T.; Shioiri,

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13.

Morinaga

Saitama

Co. Ltd.,

Mori,

1980.

see (a) Hurley,

D.E.

6.

H. Tetrahedron,

N.; Budzikiewicz,

(University

For reviews,

12.

H.

5507.

communication;

Left., 1986,27,

Zama,

Dainippon

Left., 1990,3Z,

as a preliminary

Pharmaceutical

to Professor

AND NOTES

Biochemical

Higashihara,

Taiho

grateful

Japan.

Thurston,

9.

:

Laboratories,

(a) Mohr, thesis

5.

was

are

T. Tetrahedron

T; Shioiri,

T. Tetrahedron

Ltd.,

Laboratories,

4.

work

Aoyama,

We

us Dr. N. Mohr’s Ph. D. thesis.

Y.;

1970, Col. Vol. 3, 223. Shioiri,

T.

Synthesis,

1979, 716;

Idem,

4663.

Preparations, S.; Ritchie,

1958,6, 20. E.; Taylor,

W.C. Aust. J. Chem., 1976,29,