Approaches to the synthesis of aspidosperma alkaloids

ixMcMo20/86 Pcrgamon

Tetrahedron Vol. 42, No. 21. pa. 6071 lo 6095.1986

Printed inGreat Britain.

APPROACHES

TO THE THE

SYNTHESIS

SYNTHESIS

OF

OF ASPIDOSPERMA

PART

ALKALOIDS,

13.00+ .30

Joumal.s Ltd.

I I I

18,19-DIDEHYDROTABERSONINE.

John W. Blowers, J. Edwin Saxton*, and Alistair G. Swanson. Department of Organic Chemistry, The University, Leeds LS2 9JT.

(Received in UK IO September

1986)

Summary: The total synthesis of 18,19-didehydrotabersonine, via 3-oxo-18,19-didehydrovincadifformine,is described. -

In continuation Aspidosperma

of our synthetic studies' in the vincadifformine

alkaloids we next investigated

(l), a pivotal

sub-group of

routes to 18,19-didehydrotabersonine

intermediate from which a number of other alkaloids could in

principle be obtained. For example, when heated in methanol at 145'C rearrange2 with formation, among other products, of racemic andranginine (2), 3 In addition, the alkaloids (3) an alkaloid of Craspidospermum verticillatum.

ment occurs

and (4), which in a formal sense are the result of hydration of the 18,19-double 4 these two bond in (l), occur in the aerial parts of Catharanthus ovalis:. alkaloids have already been correlated with kitramine

(5) and kitraline

also occur in C. ovalis, 4 with vincoline (7),4 a constituent 7 with melobaline (8),6 an alkaloid of Melodinus balansae.

(6), which 5 and

of C. lanceus,

R

Andranginine

(1) R=H2 (30) R =0

(2)

Me02C Kitramine (5) R = Me; 19R (6) R = Me; 19s Kitraline (7) R = H; 19s Vincoline Melobaline (8) R = H; 19R

6871

J.W. Browsasetal.

6072

As in our earlier work we initially protected Nb by incorporating it in a lactam function, and since it was considered feasible to introduce the 14,15double bond at a very late stage in the synthesis our first objective was the pentacyclic

lactam ester (9), -i.e. 3-oxo-18,19-didehydrovincadifformine. required starting material was thus either the unsaturated aldehydo-ester

or the related phenylthio derivative

(11);

The (10)

the use of this latter would in

principle provide some flexibility in the exact stage at which the 18,19-double bond was introduced. Oxidation of 4-phenylthiobutan-1-o18 succinimide-dimethyl converted

by Swern's method' or by N-chloro-

sulphoxide lo gave the corresponding

into its pyrrolidine

enamine and exhaustively

methyl acrylate to give the desired diester monoalkylated

ester (13).

(ll), together with a small yield of

(11)

Oxidation of

(12), which was

aldehyde

alkylated by means of

by

sodium metaperiodate

in aqueous

methanol gave an almost quantitative yield of the related sulphoxide which, when refluxed in xylene, gave the required unsaturated aldehydo diester

MeO$

Me02C

0

(10).

‘1

‘1

SPh

R

&02Me

(9) R=H (22) R = Me (17) R = H; l&19-dihydro

PhSACHO phsTco2Me CHO

(12) The condensation

(13)

of the intermediate (10) with 2_hydroxytryptamine, prepared 11 was examined under a variety of conditions.

by the method of Savige and Fontana, When 2-hydroxytryptamine

hydrochloride,

the aldehydo ester

(lo), and an aqueous

ethanolic sodium acetate buffer were used, all four products obtained, the proportion of less polar isomers

(A) isomers

(15a and 15b) being approximately

performed with free 2-hydroxytryptamine

(14a and

(14 and 15) were 14b):

more polar

(B)

When the condensation was

2:3.

base in dry benzene, followed by cycliza-

tion with acetic acid, the ratio was 6:1 in favour of the more polar stereoisomers (15a and

15b).

Since cyclization of the (8) stereoisomers

in the desired stereochemistry of the tetracyclic lactams interconversion

(15a and 15b) resulted

at the C/D ring junction, and since equilibration

(14 and 15) was not observed

(contrast the well-known

of the related bases in which the C-3 carbonyl group is replaced

by a methylene group) these latter conditions for the formation of the tetracyclic lactam esters

(14 and 15) were preferred.

In accordance with previous experience in the homologous ally1 series' the methyl iminoethers of the (A) stereoisomers

(14a and

14b)

resisted cyclization

in

the presence of dimsyl sodium in dimethyl sulphoxide, or with sodium hydride in dimethyl formamide, but the (B) stereoisomers

(15a and 15b) cyclized smoothly at

65-70°C to give a mixture of tne cis-fused pentacyclic lactam ester (9) and its At 103OC the yield of (9) and (16) was considerably lower, C-20 epimer (16).

6073

Approachesto thesynthesisof Aspidosperma alkaloids-II

H

(14a) 0

H presumably

owing

However, under observed: 65T

to

2.5

decomposition

none

indeed,

for

H

(15a)

of

the

of

the

conditions

the latter

was

dimsyl

used

totally

(15b)

sodium

was

at

of

interconversion

unaffected

12

temperature.

this

(9)

and

sodium

by dimsyl

in

(16) DMSO at

hours.

0

(16) Of the chemistry contained 227,

and

two epimers

shown

in

important 195 in

with

peaks

the

the

base

at

spectrum

AS in the mass spectra paper)

peak

the

obtained,

(9),

of at

more polar

one was

a -cis C/D ring junction, m/z 350, 227, and 195, of

(19)

its and

the

ally1

due

to

mass

corresponding

to

stereospectrum those

at

3-oxovincadifformine

homologue

the

the

its

dihydroderivative,

m/z 227 is

assigned

since

ion

of

(9)

(see

obtained

(18))

the

352,

(17). preceding

by reverse

Diels-

Alder fission of ring C, followed by cleavage of the Nb to C-5 bond, and is In contrast, the less polar isomer diagnostic of a cis C/D ring junction.

(16)

exhibits a base peak at m/z 264, probably formed by loss of both the vinyl and ester substituents

spectrum

presence in the proton n.m.r. Hz)

in

the

signals

This conclusion

attached to ring C. at

of

(9)

6 4.03 and 2.72 owing

of

to

H-21

is observed, and none would be expected, between C-17

protons

(6 2.25

15),

the tetraCyCliC

In an attempt Accordingly,

the

to

and

2.975)

develop

in

an improved

systemwasformed

phenylthio

tryptamine hydrochloride

trans

the

(11)

(6

3.77)

(J170,21

= 3

no such coupling and either

of

the

(16).

synthesis

in buffered aqueous

is confirmed by the w-coupling

and H-17o;

H-21

isomer

before

aldehydoester

a small

of vinyl

the

was condensed

ethanol

lactam

double to give

bond

esters

(14 and

was introduced.

with

2-hydroxy-

(19)

as

a mixture

of

J. W. BLOWERS et d.

6874 all

four

possible

increasing

racemates

polarity)

from

were

which

obtained

the

different

isomers

(19a-d)

(in

order

of

by chromatography.

(19) X-SPh (20) X = S02Ph The relative four

isomers

an easily

recognisable,

hydrogens

and all

chemical C-14

stereochemistry

by a detailed

shift

of

(a

to

assignment

remaining units

(-CH2CH2-)

for

all

(and in

of

vice

these

while the

in

(14)

This

the

(15)

and

the

Ii-21

(t9b)

by

is

of

from

the

‘H-‘H

chemical

shift

opposite at

measurements.

the (19c

of

the

face.

these

‘doublet’ and

This

centres

due

19d) is

to

H-9

indicating

pyrrolidine

ring

in

that as

agreement

and polarity

at

C-20

resonances

of

each

could at

be determined

least

one

scale

(25a-d).

This

the

protons

methylene

o to

sulphur

gave

n.0.e.

Irradiating

H-21

(d)

isomers

and enhanced

for

the

(b)

and

(c)

close ring these

to

the

isomers. second

and much further oxidised

all

of

relative entries

it

H-21, with

found

H-9 the

stereochemistry l-8

observation

in of

methylene

of the

and H-21

proton

Table n.0.e.

1.

for

each

as

of

shown.

the

of

for

chain

trans

for of

eight

the

these

C-18

same side of pair

compounds

resonance

shift

n-0-e. it

and

was to

assignments

the of

a

that of

From the

pattern

of

in

hydrogens

on the

sulphide/sulphone all

resulted their

showed

confirmation of

two equivalents

side-chain. the

to

isomer.

models

The chemical

Additional enhancement

with

oxidation

resonances

and by comparing

resonances

each

enhancements

the

away

compounds

necessary

for

and permitted

Consideration from

was

side-chain

on an n.m.r.

on irradiating

came

same face

and

to assign in

The

four-spin

(n.0.e.)

isomer

enhancements their

and a

a straightforward

of

isomers

(a)

relatively

given

on

(lga).

in

sulphones

of

are

those

expected

isolated from

effect

an enhancement

stereochemistry

as

was

two C-S The

and

be made for

was determined

was on the

the

identified. sulphur)

corresponding

COSY spectra

confirm

only

determined

Overhauser

was on the

to

pronounced

the

six-membered

possible

(a

all

H-21

1).

two most polar

oxidising

assignment. for

bond it

the

the

shift

a carbonyl

the

7.8

the

stereochemistry

achieved

unambiguous

for

& 4 and

to different,

Figure

gave

around

for

isomer

above.

mCPBA to give

hydrogens

singlet

as

each

be easily

could

connectivities (see

at

could

was not

stereochemistry

between

unambiguously was

the

by nuclear

H-21

isomers

a downfield

to

assigned

only

Before

of

were

versa) (19a)

and

assign

protons

two

was determined For

hydrogens

C-18

isomers

relationship

C-18

group)

the

experiments

the

rings

the

and C-25 455 MHz.

singlet

a carbonyl

relative

four

Irradiation

on aromatic between

by using

The C-7/C-21

at

broadened

resonances

(COSY)

C-21,

of

aliphatic

correlation

way

those

C-7,

analysis

slightly

difference

and C-16

definite

at

n.m.r.

assignments

H-156

on

6075

Approaches to the synthesis of A~~~~~SJWPPUI alkaloids--II

TABLE 1.

' H Chemical

ehift

All stereochemistry

assignments.

is relative

to H-21a.

9-H

10-H

11-H

12-H

14-H

15-H

16-H

17-H

18-H

19-H

21-H

OMe

2.400 1.908

7.09

6.99

7.23

6.87

2.45 2.27

1.65 I.45

1.93 1.93

1.52 0.82

3.00 2.74

1.65 I.42

4.13

3.50

3.946 3.070

2.36. I.866

6.99

6.92

7.17

6.84

2.41 2.27

1.580 1.506

2.46 2.21

1.76 1.45

2.59 2.52

I.53 0.79

4.06

3.61

19c

4.15 3.80

2.17 2.17

7.12

6.99

7.24

6.89

2.39 2.27

I.55 I.55

1.97 1.94

1.61 0.90

2.79 2.61

2.19 1.53

4.05

3.52

19d

4.14 3.81

2.17 2.17

7.13

7.00

7.26

6.93

2.42 2.31

1.680 1.546

2.10 2.08

1.64 1.64

2.58 2.52

1.41 1.03

4.12

3.53

20a

3.960 3.966

2.37 1.91

7.15

7.05

7.29

6.99

2.49 2.33

1.49a I.466

1.99 1.99

1.63 0.80

3.41 2.07

1.88 1.59

4.01

3.52

20b

3.99 3.93

2.30 1.88

7.13

7.12

7.36

7.04

2.36 2.16

1.55 1.39

2.49 2.21

1.55 1.39

2.05 2.79

1.67 0.92

4.12

3.50

2oc

4.08 3.80

2.16 2.16

7.12

7.01

7.26

6.99

2.38 1.66

1.520 1.366

1.93 1.90

1.43 0.88

3.00 2.06

2.12 1.71

4.07

3.50

20d

4.12 3.82

2.15 2.15

7.11

7.05

7.26

6.00

2.40 2.33

1.53 1.53

2.10 2.04

1.62 1.62

2.71 2.54

1.49 1.21

3.93

3.56

24

4.16 3.90

2.23 2.23

7.20

7.07

7.25

6.04

2.54* 2.40

1.92* 1.75

2.37, 2.32

2.11' 2.05

5.42

6.06

4.18

-

5-H

6-H

19a

3.956 3.870

19b

bmpound

*For

(24) the assignments

FIGURE 1.

of (H-14, H-15) and H-16, H-17) may be reversed.

400 MHz 'H spectrum The peak marked

l

and 'H-IH COSY spectrum

is the NH which is folded.

of (19~).

J. W. BLOWERS ei al.

6076

izoj irradiating

H-21.

methylene for

the

of (a)

the and

much higher

It

Preliminary attempted

tion

of

did this

give

seen

cis -

to

the

and C-19

presumably

due

experiments on the

an

approach

be

isomers

acid

improved

was

of

not

that

one

aromatic

for

to

aimed

mixture

phenylsulphinic

not

also

side-chain (cf

field,

were

can

the

of

the

ring

of

(b)

and

a ring-current

at

the

lactams

the

thiophenoxide

of

the

unsaturated

yield

of

the

oxindole

isomers)

first

moiety

[C-17

shifted

to

is

effect.

from

further

the

(d)

introduction

phenylthio

protons

of

the

mixture lactam

vinyl

double the

However,

(19).

(21)

derived

esters

(14)

bond eliminafrom

and

(19)

(15),

and

pursued.

(23) Initial the

aim of

However, not

experiments preparing

the

readily

with

function.

Thus, derivative by sodium

(9)

the

pentacyclic

of

bond,

to most

adjacent which

agents, hydration

by means of

of

methyl

Rodeheaver

Oxidative

periodate

and

ozonolysis

ketone cleavage also

ester

(9)

alkaloids, a fully little

affected the

mercuric

reduction,

corresponding 13 and Hunt. selective

to and

reagents,

oxidising

borohydride

lactam

anilinoacrylate

attempted (22)

followed into

double

accessible

particularly methyl

18,19

on the

a range

carbon achieved,

or as

was

sensitive bond

with failed.

osmium

(9)

by

the

or

its

to

N,-

it

convert

method

tetroxide-sodium

Similarly,

is

trifluoroacetate,

an attempt

(3-oxominovincine)

atom,

anilinoacrylate in

mercuric

did

with

above.

success double

acetate failed,

conducted

outlined

substituted the

18,19

were

as

proved

of para-

impossible

Approacheslo Ihe synthesisof Aspidosperma alkaloids-11 to

functionalise

preferentially

aspidospermidine of

(9).

the

derivative

A possible

(23),

alternative

1,2-dehydroaspidospermidine

series,

tetracyclic

(14)

and

oxindole

(15)

was

obtained and as

to

systems

be a single

and H-21

to be

identified

possible

those

to

on C-16

In a parallel future

18,19

polar

mixture

ozonolysis,

of

with

inseparable desired

then

dimsyl

its

at

of

iminoether

with

the

acid

at

(24)

9 in

direct

the

Table

applied

the

the

the

only

the the

of

(14)

product cyclohexenone and vice

versa,

stereochemistry

different

hydrogens

is

four-spin

in

however,

the

of

mixture

spirocyclic

that

1);

in

cyclization

H-9 and H-21

allowed

unambiguously

and decarboxylation

when the

between

confirmed

again

1,2-dehydro-

been

120-130°C of

‘s

the

has

However,

n.0.e.

entry

experiments

gave

an attempt

an earlier the

sodium

dimethyl

involves (15).

stage

oxindole

furnished

mixture as

of

bond

reagent

cyclized

(23) , which

versa,

of

in

hydrolysis

this

case

on C-14

it

did

and C-15

C-17.

tetracyclic

which

Meerwein’s

function

and vice (see

series

double

of

bond

by acid

diastereoisomer

distinguish

and

double

to

polyphosphoric

The COSY spectrum

prove

route 14 and

The existence

H-19

shown.

from

with

(24).

between

not

heated

proved

derivative

esters

18,19

prepared

6077

in (26)

desired

was also

Meerwein’s

and high

15b)

Thus,

but

this

Protection but

with

could

of

the

not

be

a complex,

instead,

this

more

to

Reaction

ester;

the

the

was subjected

yield.

smoothly,

achieved,

functionalise

synthesis.

pentacyclic

was obtained.

acetal

was made to

the

(15a

(25)

iminoether

the

products

esters

aldehyde

the to

in

aldehyde

failed

to

give

the

reagent,

(26) 0

Yet of

prepared solution to not

another

alkaloids

the

intermediate

containing

lactone

(28). that

An obvious lithium

at

could, C-19

(27). Reaction -via the acid gave the desired iodolactone,

considered

(1).

that

oxygen

Accordingly,

However, this

target

was from

the

a viable the

was of

in

(27)

which

overall route

intermediate

principle,

the

be used

lactone with

was

was

the

(9)

iodine

reduced

yield to

(28),

is

and phenylselenyl

chloride:

and sodium and

it

oxygenated

synthesis be

bicarbonate tin

was

iodide

therefore

alkaloids.

18,19-didehydrotabersonine

3-oxo-18,19-didehydrovincadifformine

di-isopropylamide

the could

by tributyl

poor,

C-19

in

which

(9) in

the

was

treated

presence

with of

two

6878

J.W. Browsaset al.

equivalents

This lactam (29) was obtained. 15 who obtained only the biset al.,

of base the monoselenenylated

contrasts with the experience of L&y selenenylated

lactam from 3-oxo-vincadifformine

of reagent and only one

in the presence of a large excess

equivalent of base.

The preparation of (29), rather than the bis-selenenylated

analogue,

afforded a much more elegant method for the introduction of the 14,15 double bond.

Oxidation of (29) by means of m-chloroperbenzoic

elimination

gave an almost quantitative

acid followed by

yield of 3-oxo-18,19-didehydrotabersonine

(30).

$$kePh @! C02Me (31) 2

(2%

There remained only the removal of the oxygen atom at position 3. controlled L&y

reduction of

and his collaborators,

attention

However,

(30) by means of lithium aluminium hydride, as used by was unsuccessful, and we therefore turned our 16 In a model experiment 3-oxo-18,19-didehydro-

to the Borch method.

vincadifformine

(9) was treated with Meerwein's

was reduced with sodium borohydride

reagent, and the salt produced

to give 18,19-didehydrovincadifformine

(31).

In analogous fashion 3-oxo-18,19-didehydrotabersonine tabersonine

(30) gave 18,19_didehydro(l), which exhibited the same RF values as authentic material l7 in

two solvent systems, and the same principal peaks in its mass spectrum. This synthesis of 18,19-didehydrotabersonine synthesis of andranginine rearrangements alkaloids,

(1) constitutes also a formal 2 by thermal (2) which, as noted above, can be obtained

of (1) at 14S°C, and also the biogenetically

scandine

related quinolone

(33), which have recently been obtained 18 by partial synthesis.

(32) and meloscine

from 18,19-didehydrotabersonine

@Ge ($& H (32)

H (33)

Approaches 10the synthesis of Aspidosperma alkaloids-11

6079

EXPERIMENTAL Melting points were determined on a Kofler micro hot-stage apparatus and are uncorrected. Ultraviolet absorption spectra were measured on a Unicam SP 800A spectrometer with ethanol as solvent. Infrared spectra were measured on PerkinElmer 297 spectrometers with chloroform as solvent unless otherwise stated. Proton nuclear magnetic resonance spectra were recorded at 90 MHz on Perkin-Elmer R32 and Jeol FX?OQ_spectrometers and at 400.13 MHz on a Braker AM400 spectrometer. Magnitude mode IH-'H-COSY spectra were obtained on the AM400, using 128 tl Increments and a final data set size of 1K by 512W after sine-bell multiplication in both dimensions, zero-fillinq in the Fl dimension and Fourier transformation. The final digital resolution was approximately 6 Hz/pt. The 90 deg. 1~ pulse length was 13.0 US. Nuclear Qverhauser effect data were recorded on degassed samples with a recycle delay of 8.5 seconds (>>5 Tl). Carbon-13 n.m.r; spectra were recorded at 100.6 MHz on a Brtlker WH400 spectrometer. All n.m.r. Spectra were recorded on solutions in CDC13 and chemical shifts are reported in p.p.m. downfield from tetramethylsilane. Mass spectra were measured on either a Kratos MS25 instrument (low resolution spectra) or an Associated Electrical Industries MS950 double focussing instrument (accurate mass measurement). 4-Phenylthiobutanal

-

(12).

Thiophenol

(22.0 g, 0.20 mol) was added dropwise

to a vigorously stirred, ice-cold ethanolic solution of sodium ethoxide, prepared from sodium

(4.6 g, 0.20 mol) and ethanol

for a further 15 min, then 4-chlorobutyl dropwise over a 30 min period.

(100 ml).

The mixture was then stirred

acetate l9 (30.1 g, 0.20 mol) was added

The resulting solution was then heated under

reflux for 4 h and stirred at room temperature for a further 10 h. hydroxide pellets

(11.2 g, 0.20 mol) were added and the suspension was heated

under reflux for 2 h, then cooled and poured into water was extracted with ether

(MgS04).

(300 ml).

(2 x 250 ml) and water

(2 x 250 ml), then

Removal of the solvents under reduced pressure gave a yellow

liquid which was fractionally distilled 0.16 mol, 81%) as an almost colourless Dimethyl sulphide of N-chlorosuccinimide

to give 4-phenylthiobutan-l-01 oil,

b.p.

152-154°C/0.1

(23.2 g, 0.37 mol) was added dropwise (35.8 g, 0.29 mol) in toluene

atmosphere of dry nitrogen.

toastirred

for a further 2 h and then triethylamine

(800 ml) at O'C, under an

Stirring was continued

(2 x 500 ml), then dried

4-phenylthiobutanal S, 17.07;

at -25OC

(25.8 ml) in a small amount of toluene

The cooling bath was removed after 5 min and ether (500 ml)

reduced pressure gave a yellow/green

H, 6.75;

(32.8 g, 0.18

The organic layer was washed with 1% aqueous hydrochloric

ml) and water

solution

The resulting suspension was then cooled in a dry-

mol) added dropwise to the stirred solution.

was added dropwise.

(29.4 g,

mmHg.

ice/carbon tetrachloride bath to -25OC and 4-phenylthiobutan-l-01

added.

The solution

(3 x 250 ml) and the combined ether extracts were washed

with dilute potassium hydroxide solution dried

Potassium

(MgS04).

M+, 180.06123.

Removal of the solvents under

oil which was fractionally

(25.03 g, 77%), b.p.

acid (2 x 500

139-141°C/0.3

mmHg

distilled to give

(Found:

C10H120S requires C, 66.67;

C, 66.30;

H, 6.67:

S,

J.W. BLOWBRSefal.

6080 17.8%;

g. 180.060883);

2.15-1.70

"max. (film) 2861, 2720, 1725, 1586 cm -1;

(2H, m, -CH2Ci2-CH2-),

J 7 Hz, -CFi2-SPh), 7.10-7.45 m/z

(%)

180

(95),

152

(30),

(CDC13)

2.60 (2H, dt, J 1, 7 HZ, -Cg2-CHO), 2.95 (2H, t, (lH,

(5H, m, aromatic C-H), 9.73 136

6

135

(30),

(20),

123

t,

J

1 HZ,

-CiO):

110 (loo), 109 (271,

(70),

71

(30), 45 (30). Pyrrolidine Enamine of 4-Phenylthiobutanal. 0.13 mol) in toluene potassium carbonate ml) at O°C.

-

4-Phenylthiobutanal

(100 ml) was added to a stirred suspension of anhydrous (12 g) in pyrrolidine

(18.2 g,

0.26 mol) and dry ether

The suspension was filtered through a sintered glass funnel

and the solid residue washed well with dry ether. reduced pressure gave the crude pyrrolidine

(2H, m, -CH2-CF12-CH=), 2.60-3.06

-N-CH=CE-CH2),

Removal of the solvents under

enamine of 4-phenylthiobutanal

vmax. (film) 1650, 1585 cm-'; 6

g, 0.12 mol, 97%):

(CDC13) 1.42-2.00

6.23 (lH, d, J 14 Hz, -N-CH=CH-),

of the pyrrolidine

6.90-7.41

enamine of I-phenylthiobutanal

added dropwise over 0.5 h.

and then at room temperature for 15 h. cooled, acetic acid

(20 ml) and water

refluxed for a further 8 h.

(11).

-

A solution

(23.0 g, 98.8 mmol) in dry

The solution was then refluxed for 48 h, (40 ml) were added, and the mixture was

Removal of the solvents under reduced pressure gave

layer was separated and washed with dilute hydrochloric solution

(40.0 g,

The mixture was stirred at O°C for 4 h

a brown oil which was partitioned between dichloromethane

sodium carbonate

(4H, m),

(SH, m, aromatic C-H).

(60 ml) was stirred at O°C under nitrogen and methyl acrylate

0.46 mol)

(28.9

(6H, m), 4.07 (lH, dt, J 7, 14 Hz,

Dimethyl 4-Formyl-4-(2-phenylthioethyl)-heptan-1,7-dioate

methanol

(50

The mixture was stirred at O°C for 1 h and then at room temperature

for a further 3 h.

2.01-2.26

(23.1 g,

(2 x 100 ml) and water

and water.

The organic

acid (2 x 100 ml), dilute

(100 ml), then dried

(MgS04).

Removal of the solvent under reduced pressure gave a yellow/brown oil.

The

majority of the crude mixture was carried straight through to the next stage, but a small amount

(1.05 g) was chromatographed

on Kieselgel G (50 g), with 15% ethyl

acetate in benzene as the eluting agent, to give two main fractions. The first fraction contained methyl 4-formyl-6-phenylthiohexanoate mg) as a colourless 'max.

oil

(Found: M+,

266.09813.

(film) 2850, 2720, 1735 br, 1585 cm-';

C14H,802S requires M, 266.097659); 6 (CDC13) 1.6-2.7 (7H, m), 2.98

(2H, t, J 7 Hz, PhS-C$2-), 3.67 (3H, s, -C02Me),

(JH, s, CHO); 83

(37),

69

m/z

(34),

7.10-7.45

(%) 266 (28), 136 (60), 123 (52), 45

(40),

41

(13) (95

110

(SH, m, aromatic), 9.40

(loo),

109

(20),

(42).

The second fraction contained dimethyl 4-formyl-4-(2_phenylthioethyl)-

97

(29),

Approachcstothe synthesis ofAspidospema heptan-1,7-dioate

(805 mg) as a pale yellow oil vmax

C18H2405S requires M, 352.134435); 6 (CDC13) 1.60-2.40 -C02Me),

7.10-7.40

alkaloids-11

(Found:

6081

hJ+, 352.134436.

(film) 2850, 2710, 1740 br, 1585 cm";

(lOH, m), 2.88 (2H, t, J 7 Hz, PhS-(X2), 3.65 (6H, sr 2 x

(5H, m, aromatic), 9.40 (lH, s, -CEO);

m/z (%) 352 (29), 324

(60), 321 (22), 216 (28), 183 (62), 151 (39), 141 (19), 136 (39), 123 (IOO), 110

(861,

109 (30), 55 (39), 45 (27).

Dimethyl 4-Formyl-4-vinylheptan-1,7-dioate and dialkylated thioetheraldehydes (240 ml) and water

(10).

The crude mixture of mono-

-

(19.2 g, 0.55 mol) was dissolved in methanol

(48) ml), and sodium metaperiodate

(11.66 g, 0.055 mol) was The

added in small portions to the stirred solution over a period of 1 h.

solution was then stirred for a further 2 h (i.e. until t.1.c. analysis showed the complete absence of starting material).

The solution was then filtered

through sintered glass and the solid washed several times with methanol.

The

solvent was then removed under reduced pressure to give an orange oil which was partitioned between chloroform and water.

The organic layer was separated, dried

and the solvent removed under reduced pressure

WgS04),

to give a yellow

i.r. spectrum of this material showed a band at 1040 cm

-1

corresponding

gum.

The

to the

sulphoxide group of dimethyl 2-formyl-(phenylsulphinylethyl)-heptan-l,7-dioate. The

gum

was dissolved

carbonate

in dry xylene

(= 0.5 g) added:

(150 ml) and a small quantity of calcium

the mixture was then heated under reflux for 18 h

under an atmosphere of dry nitrogen.

The mixture

was then cooled, filtered

through sintered glass, washed with dilute sodium bicarbonate solution and water

(150 ml), and dried

(MgS04).

(150 ml)

The xylene was removed by distillation

under reduced pressure, the resulting yellow/orange

oil was transferred to a

smaller vessel and subjected to short-path distillation

to yield two major

fractions. The first fraction contained methyl 4-formylhex-4-enoate yellow oil, b.p. 78-82OC/O.5 mmHg; cm

-1

;

vmax

(film) 2830, 2720, 1740, 1685, 1645

6 (CDC13) 2.06 (3H, d, J 7 Hz, Ii3C.CH=C), 2.3-2.7

(4H, m), 3.67 (3H, s,

C02Me), 6.69 (lH, q, _J 7 Hz, MeCEJ=C), 9.39 (lH, s, CtJO). characterised

as its 2,4_dinitrophenylhydrazone,

from glacial acetic acid requires C, 50.0;

H, 4.8:

(Found:

(1.8 g) as a pale

c, 50.1;

m-p.

H, 5.05;

The aldehyde was

157-159OC, recrystallised N, 16.4.

C14H16N406

N, 16.7%).

The second fraction contained dimethyl 4-formyl-4-vinylheptan-1,7-dioate (0.5 g, 43.4 mmol) as a colourless oil, b.p. 127-129 “C/O.3 mmHg 59.50;

H, 7.45;

242.115414);

M+, 242.11518.

'max.

C21H1805 requires C, 59.49;

(film) 2850, 2720, 1730 br, 1640 cm-'1

(Found:

C,

H, 7.49t;

M.

6 (CDC13) 1.88-2.40

6082

J. W. Browras er al. 3.65

(8H, m), m/z

(6H, 6,

(%) 242

(3),

211

2 x C02Me), (16),

(3H, m, Cg=CH2),

5.1-5.92

182 (100))

154

(64),

150 (82))

9.40

(lH,

6,

122 (65))

CHO) ;

109

(35),

98

(15). 3-Oxo-1-demethyl-18,19_didehydrovincatine 4-vinylheptan-1,7-dioate (2.49

acetate

atmosphere and the

(3.33

of

with

residue

3% methanol

a white

fraction

requires

(Found: C, 68.46;

279 infl.

nm;

(lOH,

3.61

m),

exchanges

with

108

94

contained

H, 6.57:

N, 7.60%;

(lH,

D20,

3150,

C02Me),

(%)

fraction

The fourth

as a yellow m.p.

contained

fraction

solid

nm;

2.7.(10H,

m),

150

(34), (b)

pressure G (200 g)

368

(4),

the

and

by its

polar

(1.1

7 g,

white

(lo),

254,

1.20-2.90 (2H, m,

9.50

(16),

m.p.

271 infl.,

N-Ck12), 4.40-4.95

159

29%)

C21H24N204

6 (CDC13)

cm-‘;

(A)

needles,

225,

(4H, m, aromatic), 187

less

14b)

imax.

(3H, m, -N-CH,

6.85-7.40

of

M+, 368.17410.

1630 br,

(0.3

g,

of

136

(lH,

(25),

6, 130

(ll),

all

the stereoisomers

H, 6.57:

vmax 3.55

a stereoisomeric

mixture

(3H, s,

144 (27),

with 136

(15a

3360, -C02Me), (lH,

N, 7.50;

1695,

1645,

3.70-4.30

m/z

130 (37))

3-0x0-1-

and

(%) 368 117

4-formyl-4-vinylheptan-1,7-dioate

(67))

(19),

15b)

gave

Amax 1620 cm

-;

(3H, m, -N-C!, 6.85-7.45

the more polar (1.74

heavy

224,

254,

(65),

108 (221, (3.91

g,

160 (23),

rods,

272 infl., 1.25-

9.85

159 (971,

94 (26). 16.4

43%)

4.40-5.15

(4H, m, aromatic). 187

(H)

C21H24N204

; 6 (CDC13) -N-CH2),

g,

white

M+, 368.17369.

M, 368.17359);

m, -CE=CH2),

D20, N-H) ; (93),

1720,

of

from methanol

H, 6.65;

N, 7.60%;

. (Nujol)

5.60-6.05

exchanges

Dimethyl

C, 68.45;

of

7%).

on recrystallisation

(Found:

(2H, m, CH=Cg2), s,

layer

as verified

gave

M, 368.17359);

a mixture

contained

which

C, 68.46;

278 infl.

(lH,

(14a

3-oxo-1-demethyl-18,19_didehydrovincatine

186-198OC

requires

pressure

(11).

demethyl-18,19-didehydrovincatine

of

reduced

mixture

N, 7.85:

3.75-4.40

m/z

;

reduced

main fractions.

from methanol

1725 br,

m, -CH=CH2),

N-H)

and

in an

The organic

(300 mg),

a stereoisomeric

H, 6.70;

(Nujol)

(23 ml)

on Kieselgel

four

aldehyde

on recrystallisation

(3H, 6,

The third

isomers

to give

11

behaviour.

C, 68.35;

‘max.

CH=CJ12), 5.05-5.70

(ll),

was chromatographed

unreacted

under

removed under

l-formyl-

hydrochloride

reflux

and water.

3-oxo-1-demethyl-18,19_didehydrovincatine which

Dimethyl

water

under

were removed

chloroform

as eluent,

and t.1.c.

fraction

was heated

and the solvent

contained

(a)

(175 ml) containing

solvents

between

in chloroform

solid

197-229OC

the

The residue

and n.m.r.spectra,

of

18 h,

-

and 2-hydroxytryptamine

The mixture

(MgS04),

oil.

The second

as

added. for

dried

a yellow

isomers

13 mmol) in ethanol

was partitioned

The first i.r.

g)

nitrogen

was separated, leaving

g,

11 mmol) were dissolved

g,

sodium

(3.19

(14 and 15).

mmol) and

6083

Approaches to thesynthesis of Aspidospermaalkaloids-II

2-hydroxytryptamine

(2.32 g, 13.16 mmol) were dissolved

in dry benzene and the

resulting solution was heated under reflux for 4 h in a Dean-Stark apparatus with removal of the azeotropic

The solution was allowed to cool before

benzene/water.

Glacial acetic acid (30 ml) was

removal of the solvents under reduced pressure. then added and the mixture

The solvent was

heated under reflux for 1.5 h.

removed under reduced pressure and water (100 ml) added before extraction with chloroform

The combined organic extracts were dried

(3 x 50 ml).

(MgSO4) and

the solvent was removed to yield a yellow oil which was chromatographed Kieselgel G (300 g) with 3% methanol in chloroform

on

as eluent, to give four main

fractions. The first fraction contained unreacted aldehyde and n.m.r. spectra, and chromatographic

(403 mg) as verified by i.r.

behaviour.

The second fraction contained a stereoisomeric mixture of the less polar isomers of 3-oxo-1-demethyl-18,19_didehydrovincatine a white solid which on recrystallisation 195-222OC

(Found:

Pj+, 368.1739.

(14a and

14b)

(0.49

g,

(A) as

10%)

from methanol gave white pillars, m.p.

C21H24N204 requires ,M, 368.17359).

The third fraction contained a mixture of all the stereoisomers of 3-0x0-1demethyl-18,19-didehydrovincatine

(0.25 g. 5.2%).

The fourth fraction contained a stereoisomeric

mixture of the more polar

isomers of 3-oxo-1-demethyl-18,19-didehydrovincatine as a white solid which on recrystallisation (Found:

182-199°C

E', 368.1742.

hydrochloride water

(15a and 15b) (3.05 g, 63%)

from methanol gave white needles, m.p.

C21H24N204 requires E, 368.17359).

3-Oxo-1-demethyl-18-phenylthiovincatine phenylthioethyl)-heptan-1,7-dioate

(19).

-

Dimethyl 4-formyl-4-(Z-

(3.95 g, 11 mmol) and 2-hydroxytraptamine

(2.13 g, 10 mmol) were dissolved in ethanol

(20 ml), and sodium acetate

(B)

(2.84 g) was added.

(150 ml) containing

The resulting mixture was

then heated under reflux for 18 h, cooled and the solvent removed under reduced pressure.

The residue was partitioned between chloroform and water and the

organic layer separated and dried

(MgS04).

Removal of the solvents under reduced

pressure gave a yellow foam which was chromatographed 2% methanol in chloroform The first'fraction

on Kieselgel G (500 g) with

as eluent to give five main fractions.

contained unreacted aldehyde

i.r. and n.m.r. spectra, and chromatographic

(205 mg), as verified by

behaviour.

The second fraction contained 3-oxo-1-demethyl-18-phenylthiovincatine-I (19a) (0.73 g, 15%) as a white solid which on recrystallisation colourless needles, m.p.

133-135OC

478.19224.

requires C, 67.75;

C27H30N204S

(Found:

C, 67.25: H, 6.32;

H, 6.35: N, 5.85%;

from methanol N, 5.81;

gave

M+,

fi, 47E.192616)

;

J. W. Browrro er al.

6084 max

”

(Nujol)

.

14.5

(lH,

m),

7,

12.5

Hz),

1.93

10,

11.5,

12.5

12 Hz),

3.00

(lH,

11.5

Hz),

4.13

br.

(t),

28.1

(t),

28.20

(t),

51.6

(q),

55.9

128.6

(d), 177.9

(s);

m/z

144

(20), third

14 Hz),

(1H,

m),

(lH,

ddd,

(lH,

m),

1.76

7.5

Hz),

(3H,

(lH,

30.8

69.0

(d),

110.7

(d),

130.3 (27),

267

109

(20),

94

The

fourth

(1.23

methanol

fi,

478.192617)

5,

(lH,

d,

35.1

(t),

(d),

11.5,

135.7 (13),

244

125.4

(s),

136.0

(17),

(s),

244

(51))

on

109

210

6c (t),

139.8

(ll),

(lH,

dt,

J 4.5,

(lH,

dt,

J

_J 1,

7.5

Hz),

(CDC13) 38.7

(d),

(s),

126.3

(s),

187

44.0 (d),

169.1

(lo),

27.9

(s),

172.9

(16),

160

(30).

67.75;

H,

6.32;

cm-‘;

6H

15 Hz),

H,

0.79 m),

ddd,

J

m),

2.36

(lH,

ddd,

J 9,

17 Hz),

2.52

(lH,

dt,

m),

3.94

6.92

(lH,

s,

NH);

125.1

38.6

27.9 43.8

126.4

169.0

(15),

6c (s),

(d),

(s),

J

(d),

(s),

160

1,

7.5

137

ddd,

7, 11,

1.58

m),

12 Hz), 12

2.21

Hz),

2.41

12 Hz),

2.59

(lH,

J

Hz),

4.06

7,

12

6.99

(lH,

br.

(t),

28.1

(t),

28.5

(t),

(t),

51.7

(q),

55.8

(s),

(d),

128.8

(s), (40),

;

2 4.5,

Hz),

128.7

173.6

(19),

dt,

fi+,

478.192616)

(lH,

1.5,

J 5,

(lH,

dt,

M,

1.53

(lH,

gave

5.75;

(lH,

1.86

(lH,

N,

5.82%;

(CDC13)

(lH,

methanol

6.05;

N,

1.50

(19b)

from

15 Hz),

(t),

210

recrystallisation 67.75:

br.

139.8

(18),

(d),

br

36.0 (d),

(s),

122.5

C,

Hz),

(lH,

122.7

35.9

3.87

7.5

8.0

(t),

(lH,

s),

m),

34.8

(d),

s,

ddd,

(lH,

dt,

NH);

(t),

11.5,

11.5,

J

(lH,

11,

178.0 130

(26),

130.1

(d),

(s);

m/z 123

d,

(%) (21),

(24).

gave

5.85;

J

(t),

fraction 23%)

g,

N,

carbonyls),

(6H,

(s),

478

br.

3.95

28.4

(Found:

1618

2.27

3.61

(t),

(19c)

J 5,

12 Hz),

m),

br.

123

C,

ddd,

17 Hz),

(lH,

6.92

J 6,

2.40

2.74

(lH,

Hz),

1.90

18 Hz),

(lH,

which

(lH,

J 5,

11.5,

3.87

J 7.5

m),

18 Hz),

s),

ddd,

3-oxo-1-demethyl-18-phenylthiovincatine-II -

br,

_J. 5,

28.7

(27))

6,

(2H,

7.90

167

requires

ddd,

7.18

(23))

J 6,

0.82(lH,

m),

130.3

238-240°C

ddd,

d,

110.8

solid

(lH,

6.84

s),

(d),

1720

11.5,

2.46

(t),

br,

(lH,

_J 5,

J 4.5,

(lH,

J

1.45

br.

(6H,

contained

m.p.

3030

(lH,

130

C27H30N204S

(Nujol)

(3H,

(d),

a white

needles,

478.19278. ‘max.

as

3.50

478

(62),

fraction

15.4%)

g,

colourless

dt,

137

12 Hz),

69.5

(%)

ddd,

(lH,

1.65

m),

_J 3.5,

7.25

130.0

(lH,

1.52,

ddd,

28.22

(s),

(d),

The

12,

(t),

6H (CDC13)

(lH,

6.84

Hz),

cm-‘;

2.27

2.45

s),

br

m)

m),

J 4.5,

J 7.5

128.9

(25),

(0.81

d,

1615

(lH,

(2H,

(lH,

(lH,

br,

1.45

Hz),

dt,

7.09

(s),

1720

1.42

J

7,

br,

Hz),

_J 1.5, ddd,

3050

as

contained a cream/white

colourless

E+,

pillars,

‘max.

1620

10,

15 Hz),

ddd,

J 5,

br

10,

(Nujol)

(lactam

1.53

solid m.p.

(lH,

16 Hz),

3030

and m), 1.97

(lH,

on

requires

br

C,

(N-H),

aromatic 1.55

which

143-144OC

C27H30N204S

478.19217.

;

3-oxo-1-demethyl-18-phenylthiovincatine-III -

(2H, ddd,

1710

bonds) m),

cm

1.61

J 7,

10,

recrystallisation

from

(Found:

C,

67.75;

67.75;

H,

6.32;

br -1

;

(lH,

(ester

and

6H (CDC13) ddd,

16 Hz),

H, M,

6.03; 5.85%;

oxindolyl 0.90

J 7,

10,

2.17

(2H,

(lH,

ddd,

15 Hz), m),

1.94

2.19

Approaches

(IH,

m),

2.27

(lH,

(lH,

dt,

J

12 Hz),

(lH,

br.

d,

7.21 (t)

I

4,

7.5

3

(6H,

m),

30.3

(t),

2.39

(lH,

3.52

(3H,

m),

6.99

Hz),

8.05

(lH,

34.9

s,

(d)

, 122.1

(d),

130.2

(s),

136

. 3 (s),

141.0

(381,

167 (22),

224

(40),

123 (72),

109 (55),

The fifth (1.19

fraction

colourless

needles,

478.19231.

14 Hz),

1.41

m) , 1.68

(lH,

12,

18 Hz),

dt,

J 5,

solid

which

197-198OC

m),

2.08

(lH,

m),

2.10

(lH,

ddd,

2, 2.5,

12 Hz),

3.53

(3H, s),

Hz),

7.15

(6~,

28.2

(t),

28.3

(t),

28.7

(t),

29.2

51.8

(q),

54.6

(s),

70.8

(d),

110.5

(d),

128.9

(24),

Small

137

scale

(20a-d).

(d),

(lH,

dt,

J

(t).

129.5 (Sl),

130

(s),

267

(33),

of

m/z

510

(z+);

m) -

1.59

(lH,

(2H,

m),

3.41

(lH,

dt,

J

3.5,

6.99

(lH,

br.

d,

J

7.29

(lH,

dt,

J

(lH,

1,

oxidation

(lH,

m),

(d),

128.9

(s),

28.6

54.7

180.0

(s);

144

(24),

6.89

Hz), (t),

(s),

(d),

29.3

70.1

130.1

m/z

(d),

(%) 478

137 (63))

130

(lH,

m),

Hz),

3.52

7.5

Hz),

7.5

Hz),

7.05 7.4-7.7 (19b-d)

H, 6.11;

dt,

7.5,

7.00

Hz),

8.35

(lH,

br.

35.31

109

14 Hz),

1.64

(2H,

12

s,

140.6

(s),

210

(20),

i

6c 26.1

126.3

(t),

44.0 (d),

(s),

187

s),

J 1, 7.5

(s),

168.4

(lH,

(lH,

dt,

38.7

J 6,

2.58

4.12

NH)

(d),

ddd,

Hz),

(lH,

(t),

122.9

(16),

12,

11 Hz),

Hz),

(d),

J 5,

(lH,

J 5,

;

ddd,

2.31

m),

(lH,

6,

M+,

478.192617)

(lH,

2 2.5,

(2H,

(t),

5,

1.03

gave

5.62;

M,

N, 5.85%:

J 2.5,

(19d)

from methanol

ddd,

(s),

(2.3

(t),

128.7

173.4

(14),

160

I

(a) (29),

(35).

mg, 13 umol,

in CDC13 (0.3

ddd,

1.88

gave J 6.

(lH,

ddd,

J 3,

(3H, (lH,

(SH, gave

6,

s), br.

J

dt,

t, m),

(20b-d).

J

13

8.5

1.46

2.87

(lH, (20b)

7.15 br.

:

s, 6H

to After

chromatography,

(lH,

(lH,

J 4,

Hz),

tube.

n.m.r.

1.91

Hz),

dd,

(2H,

was added

mg) as a white

15 Hz),

3.5,

7.5

in an

(3.0

18 Hz),

3.96

equiv.)

Thin-layer

(20a) 10,

2.1

ml)

was complete.

in hexane,

(lH,

of

128.8

J 7.5

224

oxidation

2.49

13

(q),

m),

J 7.5

(t),

2.79

3-E-1-demethyl-18-phenylsulphonylvincatine

mg, 6.3

acetate

1.63

d,

28.2

d,

136.0

(56),

(19a-d);

6H (CDC13) 0.80 m),

br.

51.5

2.52

122.2

(17),

123

showed that

30% ethyl

(t),

2.17

35.27

(d),

vmol)

with

(lH,

(t),

(lH,

ddd,

7.5

(19a)

eluting

7.12

6H (CDC13)

m),

br.

1,

acid

15 min ‘H n.m.r.

2.33

6.93

(lH,

(3.0

(lH,

67.71;

1.54

(lH,

m-Chloroperbenzoic of

Similar

7.26

oxidation -

a solution

11 Hz),

(100))

4.15

160 (26),

18 Hz),

3.87

dt,

478

s),

H, 6.32;

(lH,

6,

(lH,

144

(22),

1620 br cm-‘; 14 Hz),

(%)

(lH,

172.8

(Found:

12,

m/z

(d),

1710 br,

2.42

(s):

4.05

Hz),

C, 67.75;

4.14

179.1

12 Hz),

on recrystallisation

J 5,

129.2

J 5,

3-oxo-1-demethyl-18-phenylthiovincatine-IV

ddd,

(d),

dt,

44.0

(s),

(lH,

m),

(lH,

94 (34).

m.p.

J 7.5,

7.5

126.4

187

contained

3000 br,

m),

2.61

(CDC13) 28.0

168.5

(lo),

Hz),

(t),

(d),

C27H30N204S requires

(Nujol)

“max.

J 1,

38.6

(s),

17

(lH,

6c

(t),

210

23%) as a yellow

9,

dt,

122.3

(15),

4,

3.80

NH);

35.5

110.9

(d),

J

s),

(lH,

br.

(t),

td,

6085

Aspidosperma alkaloids-11

to the synthesis of

m), (lH, J

dt, 11

Hz),

(lH,

br.

solid; 1.49

(lH,

1.99

m), 3.5,

13

4.01

(1H,

d,

J

Hz),

9,

7.5

Hz),

(lH,

ddd,

NH). _. (CDC13)

0.92

6086 J

J. W. BroweKser al.

4.5,

12,

1.88

14

(lH,

11.5,

Hz),

ddd,

1.39

J 1, 7,

18 Hz),

2.36

dt,

J 5,

13 Hz),

(lH,

m),

4.12

(lH,

7.13

(lH,

(lH,

br.

br.

1.43

4,

dt, (lH,

2.38

m),

6.99

Hz),

(lH,

ddd,

J 2.5,

7.05

(lH,

dt,

Hz),

7.4-7.65

(lH,

13 Hz),

d,

J 7.5

dt,

J 5,

16 Hz),

ddd,

3.58

J 3,

(3H,

s), dt,

7.5

Hz),

7.65-7.4

ddd,

18 Hz),

3.93

(lH,

14 Hz),

(lH,

5.5,

7.12

J 2,

12,

2.21

Hz),

of

1.52

(lH,

dt,

1.93

(lH,

m),

(lH,

m),

_J 6,

(lH,

Hz),

(lH,

Hz),

(lH,

J 6,

2.79

m),

3.99

J 1, 7.5

Hz),

(SH, m),

8.31

Hz),

2.71 (lH,

7.11

(lH,

isomers g,

nitrogen

into

water

until

The organic

(Mg8C4).

Removal of

was chromatographed

3.8

mmol)

dt,

dt,

J 4,

1.53

m),

(lH,

(lH,

d,

the

(lH,

ether

N, 7.45;

of

was then

N-CE& N-CEi2) , 4.78-5.16

separated,

under

br.

(lH,

iminoether

of

the

87%) as a pale

as colourless

or

pillars,

1730,

C02Me),

(2H, m, -CH=CH2),

1640,

3.91

(3H,

5.59-5.90

Hz),

2, 1, 7.5

(a)

To a

solid

water,

gave

had been and dried gum which

in chloroform

as

was obtained (Found :

C, 69.14; 1579 cm-‘; N=C-OMe),

(lH,

with

a yellow

176-179OC

s,

added

3-oxo-1-demethyl-18,19 -

which

1620,

mixture

The suspension

material

with

of

was added

solution

solid

isomers

m.p.

3.82

resulting

3 days.

3% methanol

yellow

18

J 7.5

dt,

(100 ml)

and the

C22H26N204 requires

(Nujol)

(3H, s,

(B)

d,

3-oxo-l-demethyl-18,19-

pressure

with

G (150 g),

d,

-

washed

reduced

_J 2, 6,

(lH,

mmol),

brown colour

(2H, m),

(3H, s),

7.26

br.

1.62

3.56

Hz),

4.08

NE).

13 Hz),

carbonate

vmax. 3.51

24.93

and 10% sodium

M+, 382.18943.

M, 382.189245;

g,

s,

ddd,

6.88

2

(lH,

s), (lH,

br.

(2H, m),

(100 ml)

solvents

g,

of

(lH,

7.12

dt,

3.00

(lH,

m),

J 7.5

13 Hz),

Hz),

13

13 Hz),

2.48

m),

J 5,

J 4,

4.07

(5H, m), 8.4

for

layer

(1.22

(lOH, m),

(lH,

and at room temperature

any traces

the methyl

benzene/petroleum

2.12

in dry dichloromethane

(3.69

on Kieselgel

didehydrovincatine

NH).

(lH,

J 7.5

(15a and 15b)

tetrafluoroborate

stirring

s,

br.

1.71

t,

4.12 br.

13 Hz),

br.

dt,

(lH,

J 6,

12 Hz),

2.33

s),

J 1, 6,

7,

(lH,

(lH,

ddd,

J 2,

(lH,

1.49

(lH,

(lH,

7.65-7.4

m),

1.36

3-oxo-1-demethyl-18,19-didehydrovincatine. -

(1.40

under

7.01

15 Hz),

2.86

ddd,

(2H, m),

3.93

8.4

18 Hz),

3.80

13 Hz),

the more polar

to give

15 Hz),

2.15

m),

(5H, m),

10,

_J 1, 7.5

7.5

removed.

1.09-2.70

2.49

11,

J 5,

dd,

10 Hz),

J 0.5,

was then poured

7.33%:

J 6,

ddd,

(lH,

ddd,

2 7.5

dt,

8,

trimethyloxonium

H, 7.05;

1.90

J 3.5,

didehydrovincatine

eluent

10,

d,

(lH,

dt,

Iminoether of

(lH,

br.

br.

2.10

(lH,

vigorous

(lH,

6H (CDC13) 1.21

m),

was stirred

7.36

1.67

ddd,

m),

J 4,

Hz),

(3H, s),

(lH,

(lH,

solution

dt, br.

m),

3.50

7.26

Hz) I 2.54

Methyl

(lH,

(lH,

(lH,

(lH,

(20d) : 2.04

m),

(lH,

7.04

J 7.5,

(lH,

13 Hz),

m),

J 7.5

ddd,

1.86

J 4,

2.16

(lH,

6H (CDC13) 0.88

(lH,

(2H,

(2H,

NH).

13 Hz),

2.16

s),

1.55

2.38

m),

2.85

d, J 7.5

(2Oc) : Hz),

m),

12 Hz),

(lH,

(lH,

s,

(2H.

from

C, 69.15;

H, 6.86; 6

(CDC13)

3.73-4.14

m, -CH=CH2),

N,

(3H, mr

7.00-7.40

Approaches lothesynthesis ofAspidosperma alkaloids-11 (4H,

m, aromatic);

6087

m/z 382 (46), 202 (loo), 173 (77), 160 (39), 158 (27), 136

(80), 108 (25), 94 (30). (b) Treatment of the less polar isomers 18,19_didehydrovincatine

(14a and 14b) of 3-oxo-l-demethyl-

(1.20 g, 3.2 mmol) in a similar manner gave the methyl (1.01

iminoether of the (A) isomers of 3-oxo-1-demethyl-18,19-didehydrovincatine 82%) as a colourless crystalline solid, m.p. 185-189OC 6.85;

N, 7.35:

7.330;

C22H26N204 requires C, 69.14;

E+, 382.18909.

;, 382.189245);

vmax

C, 69.05; H, 6.86;

(Nujol) 1730, 1635, 1620, 1585 cm-';

1.40-2.70 (lOH, m), 3.50 (3H, s, C02Me), 3.70-4.20 (3H, s, N=C-OMe), 4.62-5.10

(Found:

6

g,

H, N,

(CDC13)

(3H, m, -N-CH, N-CH2), 4.05

(2H, m, -CH=CEi2), 5.40-5.60

(lH, m, -CH=CH2), 7.00-

7.51 (4H, m, aromatic).

-

3-Oxo-1-demethyl-18-

(100 mg, 0.21 mmol) was dissolved

in dry dichloromethane

3-Oxo-1-demethyl-18-p henylsulphinylvincatine phenylthiovincatine

ml) and cooled to -78°C. methane

m-Chloroperbenzoic

(21).

(15

(37 mg, 0.22 mmol) in dichloro-

acid

The mixture was stirred at

(1 ml) was then added dropwise via a syringe.

-78OC for 4 h when t.1.c. analysis showed the absence of any starting material. The reaction mixture was allowed to reach room temperature, and was then partitioned between ether

(50 ml) and 10% sodium sulphite solution

(50 ml).

The

organic layer was separated, washed with saturated aqueous sodium bicarbonate solution

(2 x 50 ml) and dried

pressure left

a

colourless

of petroleum ether.

gum

(MgS04).

Removal of the solvents under reduced

which crystallised

on addition of a small quantity

The material was recrystallised

from benzene/petroleum

ether

to give 3-oxo-1-demethyl-18-phenylsulphinylvincatine -

(83 mg, 80%) as colourless

pillars, m.p. 118-120°C

N, 5.5;

(Found:

C27H30N205S requires C, 65.56;

C, 65.0;

H, 6.11;

(Nujol) 3200, 1720 br, 1625 br, 1040

N, 5.66%;

vmax.

3-Oxo-1-demethyl-18in toluene

(5 ml) and

The resulting solution was

just below reflux and stirred overnight when t.1.c.

concentrated by evaporation

The reaction mixture was

under reduced pressure and the resulting yellow gum

using Kieselgel G (20 g) with 5% methanol in chloroform as eluent.

3-Oxo-1-demethyl-18,19-didehydrovincatine

(11 mg, 30%) was obtained as a colour-

less, crystalline mixture of diastereoisomers,

and was shown to be identical with

an authentic sample of (14 and 15) by comparison chromatographic

-

(50 mg, 0.10 mmol) was dissolved

analysis showed the absence of starting material.

chromatographed

!, 494.187531);

(14 and 15).

a very small amount of calcium carbonate added. brought to a temperature

i+, 494.18761.

cm-‘.

3-Oxo-1-demethyl-18,19_didehydrovincatine phenylsulphinylvincatine

H, 6.0;

behaviour.

of i.r. and n.m.r. spectra, and

J.W. Browsasetal.

6088

3-Oxo-18,19-didehydrovincadifformine --

(9).

-

(a) The mixture of iminoethers of

the (B) isomers of 3-oxo-1-demethyl-18,19_didehydrovincatine dissolved in dry dimethyl sulphoxide

(1.0 g, 2.6 mmol),

(4 ml), was added dropwise to a stirred

solution of dimsyl sodium , prepared from dry dimethyl sulphoxide sodium hydride

(113 mg, 4.70 mmol) under nitrogen at 65OC.

(12 ml) and

The mixture was

stirred at this temperature for 2.5 h, then cooled and poured into saturated brine

The resulting solution was extracted with dichloromethane

(50 ml).

50 ml) and the combined organic extracts were washed with saturated bring and water

(50 ml), then dried (MgS04).

(50 ml)

Removal of the solvents under reduced

pressure gave a yellow oil which was chromatographed with 5% methanol

(3 x

using Kieselgel G (100 g),

in chloroform as eluent, to give two fractions.

The first fraction contained the trans isomer, 3-oxo-18,19-didehydro-20-e&vincadifformine

(16) (291 mg, 0.83 mmol, 32%) as a white foam which was recrystal-

lised from methanol to give colourless needles, m.p. 215-217OC H, 6.25; 7.99%:

N, 7.85;

M+, 350.16285.

M, 350.163032);

(CDC13) 1.15-3.20 4.95-5.30

(Found:

C2,H22N203 requires C, 71.98;

C, 71.8;

H, 6.33:

vmax. (Nujol) 3280, 1675, 1650, 1630, 1610 cm-';

(8H, m), 3.78 (3H, s, C02Me), 3.40-4.10

(2H, m, -CH=CEi2), 5.76-6.10

6

(3H, m, -N-C!, N-CH2),

(lH, m, -CH=CH2), 6.70-7.45

aromatic), 8.88 (lH, s, exchanges with D20), N-H);

N,

(4H, m,

m/z (%) 350 (47), 264 (37),

167 (12), 154 (12). The second fraction contained the cis isomer,3-oxo-18,19-didehydrovincadifformine

(9) (428 mg, 47%) as a white solid which on recrystallisation

methanol gave colourless needles, m.p. 225-228OC N, 8.05;

M+, 350.16285.

M, 350.163032); cm

-1

;

6

(Found:

C21H22N203 requires C, 71.98;

~~~~~ 228, 297, 330 nm;

c, 71.90; H, 6.33;

(3H, m, -CH=CH2), 6.7-7.4

exchanges with D20);

H, 6.35: N, 7.99%;

vmax. (Nujol) 3380, 1680, 1650, 1615

(CDC13) 1.6-2.9 (8H, m), 3.75 (3H, s, -C02Me), 4.05-4.40

-N-CH2), 4.5-5.8

from

(QH, m, aromatic), 9.05

(3H, m, -N-CH, (lH, s,

m/z (%) 350 (30), 308 (16), 307 (63), 264 (23), 227 (loo),

214 (41), 195 (53), 182 (12), 171 (20), 154 (28). (b) The mixture of iminoethers of the (B) isomers of 3-oxo-1-demethyl-18,19didehydrovincatine

(0.5 g, 1.3 mmol), dissolved

in dry dimethyl sulphoxide

was added dropwise to a stirred solution of dimsyl sodium prepared sulphoxide

(6 ml) and sodium hydride

manner described above to give a brown

gum.

for 2.5 h, cooled and worked up in the Analysis of this reaction mixture by

(eluting with 7% methanol in chloroform)

number of products.

Chromatography

from dimethyl

(56 mg, 2.35 mmol) under nitrogen at 103OC.

The mixture was stirred at this temperature

t.1.c.

(2 ml),

showed the presence of a large

using Kieselgel G (40 g) gave

3-oxo-18,19-

Approachestothe synthesisof Aspidospenna alkaloids11 didehydro-20-epivincadifformine vincadifformine

6089

(16) (35 mg, 8%) and 3-oxo-18,19-didehydro-

(9) (53 mg, 12%), both of which were recrystallised from methanol

and found to be identical to previously prepared

samples by comparison of t.1.c.

behaviour and i.r. and n.m.r. spectra. Attempted Isomerisation of 3-oxo-18,19-didehydro-20-epivincadifformine 3-Oxo-18,19-didehydro-2o-epivincadifformine

(3 ml), under nitrogen at 65'C.

(5 mg, 0.21 mmol) The mixture was

stirred at this temperature for 2.5 h, then poured into saturated brine and extracted with dichloromethane

(3 x 20 ml).

combined and washed with saturated brine (MgS04).

-

(50 mg, 0.14 mmol) was added to a

stirred solution of dimsyl sodium prepared from sodium hydride and dry dimethyl sulphoxide

(16).

(15 ml),

The organic extracts were

(20 ml) and water

(20 ml), then dried

Removal of the solvent under reduced pressure gave a yellow gum which

crystallised

upon addition of a small quantity of petroleum ether.

this material indicated that it was solely starting material

Analysis of

(41 mg) as verified

by t.1.c. behaviour, and i.r. and n.m.r. spectra.

-

N-Methyl-3-E-18,19-didehydrovincadifformine

(22).

nitrogen 3-oxo-18,19-didehydrovincadifformine

(9) (150 mg, 0.43 mmol), dissolved

in dry dimethylformamide

(2 ml), was added to a solution of sodium hydride

0.86 mmol) in dry dimethylformamide

(2 ml).

temperature for 20 min, then methyl iodide reaction mixture stirred for 10 min. extracted with ether (Na2S04).

In an atmosphere of

The solution was stirred at room (202 mg, 1.28 mmol) was added and the

Water

(5 ml) was then added, the solution

(3 x 20 ml), and the combined organic extracts were dried

Removal of the solvent under reduced pressure gave a yellow oil which

was chromatographed

on Kieselgel G (50 g), with 2% methanol in chloroform as

eluent, to give N-methyl-18,19-didehydrovincadifformine amorphous white solid, m.p.237-239'C 364.17856.

(10 mg,

C22H24N203

Amax. 217, 303, 337 nm;

(Found:

requires C, 72.51; 'max.

C, 72.55;

H, 6.64;

H, 6.98;

(3H, m, -CH=Cfi2), 6.62-7.45

N, 7.40;

fi+,

N, 7.69%; F_l,364.17868);

(Nujol) 1695, 1640, 1600 cm-';

3.05 (8H, m), 3.26 (3H, s, N-(X3), 3.75 (3H, s, -N-CEi2), 4.75-6.10

(22) (123 mg, 78%) as an

C02Me),

6

4.00-4.50

(4H, m, aromatic);

(CDC13) 1.40(3H, m, -N-C!, m/z

(%) 364

(34), 336 (13), 241 (76), 228 (57), 182 (24), 168 (23), 149 (21), 135 (25). 3-Oxc-1,2,18,19-tetradehydroaspidospermidine vincadifformine hydrochloric

-

(9) (200 mg, 0.57 mmol) was dissolved

acid and water

reflux for 2 h.

(23).

3-Oxo-18,19-didehydroin a mixture of concentrated

(1.1, 10 ml) and the resulting solution heated under

The reaction mixture was allowed to cool, then water

added and the solution neuLraliaed with potassium carbonate.

(6 ml) was

The mixture was

6090

J.W. Browsasetal.

extracted with chloroform

(3 x 20 ml) and the combined organic extracts were

washed with water, then dried

(MgS04).

Removal of the solvent under reduced

pressure left a colourless oil which was chromatographed

on Kieselgel G (40 g),

with 3% methanol in chloroform as eluent, to give two main fractions. The first fraction contained starting material

(23 mg) as verified by its

t.1.c. behaviour and i.r. spectrum. The second fraction contained 3-oxo-1,2,18,19-tetradehydroaspidospermidine (21 mg, 0.072 mmol, 13%) as a colourless gum requires &_I,292.157555);

6

(CDC13) 1.10-3.29

A

(Found:

M+, 292.15741.

225, 243 sh, 270 sh nm;

max.

(lOH, m), 3.81-4.40

vmax

C1gH20N20 cm-';

1650 br, 1580

.

(3H, m, N-CL! and N-CEi2), 5.10-5.50

ml -CH=CIi2), 5.80-6.20 (lH, m, C;=CH2), 7.01-7.71

(4H, m, aromatic):

(2H,

m/z (%) 297

(7), 264 (19), 263 (16), 184 (7), 170 (9). Action of Polyphosphoric

acid on 3-oxo-1-demethyl-18,19_didehydrovincatine. -

A mixture of 3-oxo-1-demethyl-18,19-didehydrovincatine polyphosphoric

acid

(427 mg, 1.16 mmol) and

(10 ml) was heated, under nitrogen and with mechanical stirr-

ing, to 120-13O'C for 2 h.

The solution was allowed to cool, then water

was added and the resulting mixture extracted with chloroform combined

extracts were washed with water, then dried

organic

-

(50 ml)

(3 x 30 ml). (MgS04).

The

Removal of

the solvents under reduced pressure left an orange oil which was chromatographed on

Kieselgel G (60 g), with 5% methanol in chloroform

unsaturated ketolactam

(24), (67 mg, 17%), which was obtained as white pillars,

m.p. 267-269OC, from methanol 336.14725. A

max. -1 cm ;

(Found:

C, 71.65;

C20H20N203 requires C, 71.41;

216, 240 sh, 263 6H

(CDCl,)

as eluent, to give an

sh

1.75

nm;

vmaX

(lH,dddd,J

(Nujol)

N, 8.0;

H, 6.35;

H, 5.99: 3440,

N, 8.33%:

3200,

1710

br,

M+,

M, 336.147383); 1670,

1640,

1620

1.5, 7, 12, 14 HZ), 1.92 (lH, ddd, J 2, 6.5, 14

Hz), 2.05 (lH, dddd, J 2, 4, 5, 14 Hz), 2.11 (IH, dddd, J 1.5, 6, 12, 14 Hz), 2.23 (2H, m), 2.32 (IH, ddd, J 5, 12, 17.5 Hz), 2.37 (lH, ddd, J 6.5,

(lo, ddd, J

12,

18

Hz),

2.54

(lH,

4, 6, 17.5 Hz), 2.48

ddd, J 2, 7, 18 HZ), 3.90 (lH, m), 4.16

(lH, m), 4.18 (IH, s), 5.42 (lH, d, J 10 Hz), 6.06

(lH,

br. d, J 7.5 Hz), 7.07 (lH, dt, J 1, 7.5 Hz), 7.20

(lH, br. d, J 7.5 Hz), 7.25

(lH,

dt,

2

187

(loo),

109

(24),

1,

7.5

169 91

Hz),

(59),

7.75 163

(lH,

(32),

br.

159

s, (47),

NH): 144

m/z (30),

136

(25).

isomers of 3-oxo-1-demethyl-18,19_didehydrovincatine (ZOO

366

(%)

(49).

(33),

130

318

(27),

(31),

263

123

(24),

(28),

(30).

3-Oxo-1-demethyl-20-desethyl-20-formylvincatine -

methanol

dd, J 2, 10 Hz), 6.84 (lH,

ml)

was

-

A solution of the (B)

(250 mg, 0.68

cooled to -78OC in a dry-ice/acetone

mmol)

in

bath and ozone gas was

bubbled through the mixture until a pale blue colour persisted.

The solution was

Approaches to the synthesis ofAspidospermoalkaloids_11

6091

stirred for a few minutes until all traces of the blue colour had disappeared, then the cooling bath was removed and dimethyl sulphide was continued at room temperature negative.

(2 ml) added.

until test with starch-iodide

Stirring

paper was

The solvent was then removed under reduced pressure leaving a yellow

oil which was partitioned between chloroform

and water.

The chloroform layer

was separated and the aqueous layer extracted again with chloroform, combined organic extracts were washed with water and dried

then the

(MgSO4).

Removal of

the solvent under reduced pressure gave a pale yellow solid which was recrystallised from methanol to give 3-oxo-1-demethyl-ZO-desethyl-20-formylvincatine ._mg, 66%) as white pillars, m.p. 256-259“C _M+, 370.15281.

C20H22N205 requires C, 64.85;

(Nujol) 3180, 1725 br, 1620 br cm-';

'max. (3H,

(Found:

s,

-C02Me), s,

3.45-4.05

-CEO),

10.56

(3H,

m,

-N-CH

C, 64.80;

H, 5.99:

H, 6.30;

and -N-CI12), 6.70-7.22

(lH,

(241,

210

(15),

197

(19),

187

(12),

184

(191,

160

(151,

130

(18),

124

(56),

117

(12).

110

(17),

94

(lH, s, exchanges with

D20,

N, 7.55;

N, 7.56%; M, 370.152861);

6 (CDC13) 1.50-2.60

8.80

(167

(lOH,

3.52

m),

(4H, m, aromatic),

N-H):

m/z

($1

370

159

(531,

146

(21),

(18),

(21,

342

144

(11).

Methyl iminoether of 3-oxo-1-demethyl-20-desethyl-20-formylvincatine -

(26).

-

To a solution of the (B) isomers of 3-oxo-1-demethyl-20-desethyl-20-formylvincatine

(1.42 g, 3.84 mmol) in dry dichloromethane

oxonium tetrafluoroborate

(100 ml) was added trimethyl-

(3.69 g, 24.93 mmol) and the resulting solution stirred

at room temperature under nitrogen for 3 days. into water and 10% sodium carbonate

The solution was then poured

solution added until any traces of brown

colour or solid material had been removed.

The organic layer was then separated

and the aqueous portion extracted with dichloromethane

(2 x 50 ml).

organic extracts were then washed with water, then dried the solvent under reduced pressure Kieselgel G (250 g).

(MgSO ). 4

Elution with 3% methanol in chloroform

which was obtained from benzene as white needles, m.p.

6.29;

N, 7.29%:

(CDC13)

4.40 m/z

H, 6.35:

N, 7.35;

gave the methyl (780 mg, 55%),

126-128V

(Found:

C,

C21H24N205 requires C, 65.61;

vmax . (Nujol) 1720, 1630 br, 1572 cm-';

H, 6

1.65-2.60 (lOH, m), 3.62 (3H, s, C02Me), 4.12 (3H, s, -N=C-OMe), 3.75-

(3H, m, -N-CH and (%)

M+, 384.16854.

M, 384.16851);

Removal of

left a yellow oil which was chromatographed

iminoether of 3-oxo-1-demethyl-ZO-desethyl-20-formylvincatine -

65.15;

The combined

384

(91,

353

N-CH2),

(31,

201

7.01-7.55 (71,

196

(4H, (17),

m, 173

aromatic),

8.72

(lH,

(loo),

(831,

158

160

s,

-CHO);

(l3),

130

(15).

Dimethyl acetal of 3-oxo-1-demethyl-20-desethyl-20-formylvincatine. -

-

3-0x0-

on

4092

J.W. BOWERS eral.

I-demethyl-20-desethyl-20-formylvincatine trimethyl orthoformate

(200 mg,

0.54 mmol) was dissolved

in

(5 ml) and boron trifluoride etherate (3 drops) was added.

The mixture was stirred at room temperature under nitrogen for 20 h, then poured into dilute sodium carbonate solution

The combined organic extracts were washed with water

(3 x 15 ml). dried

(15 ml) and extracted with dichloromethane

(MgS04).

(50 ml) and

Removal of the solvents under reduced pressure gave a pale

yellow/green oil which was found to contain some trimethyl orthoformate. dichloromethane

solution of this oil was filtered

through a small pad

A

of

basic

alumina and the solvent removed under reduced pressure to give the dimethyl acetal of 3-oxo-1-demethyl-20-desethyl-20-formylvincatine (Found:

M+, 416.194711.

3.55-4.11

(3H, m, N-Q

requires M, 416.194723);

c22~28~206

3200, 2831, 1720 br cm-';

(179 mg, 80%) as a yellow gum

6 (CDC13) 1.4-2.7

vmax. (film) 3430, OMe),

(lOH, m), 3.11 (6H, S, 2 x

and N-(X2), 4.45 [lH, s, CH(OMe)2], 6.80-7.55

(4H, m,

aromatic), 9.48 (lH, s, exchanges with D20, N-H). -

Hydrolysis of 3-oxo-l-demethyl-18,19-didehydrovincatine. isomers of 3-oxo-1-demethyl-18,19_didehydrovincatine dissolved in methanol added.

(400 mg, 1.09 mm011 was

(20 ml) and dilute sodium hydroxide solution

acidified with concentrated

The aqueous solution was then

(100 ml).

hydrochloric acid with cooling to maintain

Extraction of the solution with chloroform

temperature below 1OOC.

from methanol/ether

(3 x 75 ml),

Amax* 223, 256, 286 nm;

tj, 354.157947); cm-‘;

6

C20H22N204

tj+, 354.15706.

N, 7.90;

(CDC13)

1.11-2.80

. (Nujol)

(llH, m), 3.80-4.50

5.10 (2~, m, CH=CII~), 5.69-5.99

m/z

(%) 354

186

144

(341,

(111,

160

(20))

Halolactonisation

159

(loo),

150

(26))

dissolved in a tetrahydrofuran:water (99 mg, 0.99

(260 mg, 1.58

mmol) added.

H,

N, 7.90%;

1720,

1690,

(3H, m, -N-Cg, -N-Cg2), 4.78-

(611, 136

br,

(4H, m, aromatic), 196

(93),

(12)~ 130

187 (841,

(48))

117

acid (27).

acid (27) (70 mg, 0.198 mm011

mixture

mmol), iodine

H, 6.26: 3300

of 3-oxo-l-demethyl-18,t9_didehydrovincatinic

3-Oxo-I-demethyl-18,19-didehydrovincatinic

bicarbonate

3450,

(lH, m, -Cg=CH2), 6.70-7.50

10.6 (lH, s, exchanges with D20, C02H);

C, 67.9;

(Found:

requires C, 67.78; vmax

yellow

to give the required carboxylic

acid (27) (303 mg, 79%) as white needles, m.p. 286-288V

1620

the

(MgS04), and removal of the solvents under reduced pressure gave a

solid which was recrystallised

6.3;

(150 ml) was

The resulting mixture was stirred at room temperature for 24 h, then

cooled to 0-5OC and extracted with ether

drying

The mixture of (B)

(24).

-

was

(1.7:1, 14 ml) with potassium

(400 mg, 1.58

mmol) and potassium

iodide

The resulting mixture was allowed to stand at O-5°C

for 3 days with occasional stirring.

The reaction solution was then extracted

Approaches to thesynthesis ofAspidospermu alkaloids-11

with chloroform

6093

(3 x 20 ml) and the combined organic extracts were washed with

sodium thiosulphate

(20 ml), then dried

Removal of the solvents under

(MgSO4).

reduced pressure gave a pale yellow solid (35 mg, 0.073 mmol, 37%) which was found (Found:

to be that of the required a-iodolactone requires &

M+, 480.05432.

C20H2104N21

480.054782).

3-Oxo-l-demethyl-19-hydroxyvincatinic -

acid lactone

(5°C) of the iodolactone

mmol)

(30 mg, 0.06

(28).

-

To a cold solution

in benzene was added under an atmos-

phere of nitrogen two drops of tributyl tin hydride.

The resulting solution was

stirred at room temperature under nitrogen for 24 h and then the solvents were removed under reduced pressure to leave a red solid consisting of the required lactone and tributyl tin hydride. lactone

Recrystallisation

(28) (13 mg, 61%) as pale yellow prisms

from methanol/ether gave the

(Found:

M+, 354.15741.

C20H22N204 requires M, 354.157947). 3-0xo-14-phenylselenyl-l8,l9-didehydrovincadifformine diisopropylamine phosphoramide lithium

mmol)

in tetrahydrofuran

To a solution of

(5 ml) and hexamethyl-

(0.035 ml) at O°C under nitrogen a hexane solution of 1.8M n-butyl

(0.37

for 10 min.

(58 mg, 0.57

(29). -

ml, 0.57 mmol) was added and the resulting solution stirred at O°C The reaction mixture was then cooled to -78OC in a dry ice/acetone

bath and 3-oxo-18,19-didehydrovincadifformine tetrahydrofuran

(100 mg, 0.286 mmol) dissolved in

(2 ml) was added dropwise over a 5 min period.

The solution was

stirred at -78OC for 40 min, then phenyl selenyl chloride

(60.5 mg, 0.315 mmol)

dissolved

The mixture was then

in tetrahydrofuran

(2 ml) was added dropwise.

stirred at -78'C for a further 30 min before being warmed to room temperature. The reaction mixture was then poured into water form (2 x 50 ml). hydroxide (MgS04).

(70 ml) and extracted with chloro-

The combined organic extracts were washed with dilute sodium

(50 ml), water

(50 ml) and dilute hydrochloric

acid (50 ml), then dried

Removal of the solvent under reduced pressure gave a pale yellow solid

which was recrystallised

from methanol to give 3-oxo-14-phenylselenyl-18,19-

didehydrovincadifformine

(91 mg, 0.18 mmol, 63%) as colourless plates, m.p. 218-

22O'C

(Found:

H, 5.18;

C, 64.65;

N, 5.54%);

1611 cm-'; 6

amax

H, 5.25;

. 237, 291, 327 nm;

(CDC13) 1.10-3.10

N-C2 and N-Cz2), 4.95-S-40

N, 5.50.

C27H26N203Se vmax .

requires C, 64.16;

(Nujol) 3360, 1678, 1641,

(7H, m), 3.75 (3H, s, C02Me), 3.30-4.20

(2H, m, -CH=CE12), 5.50-6.25

(3H, m,

(lH, m, -CH=CH2), 6.70-7.85

(9H, m, aromatic H), 8.81 (lH, s, exchanges with D20, N-H);

m/z

(%)

505 (17), 349

(100). 18,19-Didehydro-3-oxotabersonine vincadifformine

(30).

-

3-Oxo-14-phenylselenyl-l8,l9-didehydro-

(46 mg, 0.091 mmol) was dissolved

in dichloromethane

(5 ml) and the

6094

J.W. HLOWXIUefal.

resulting solution cooled to -70V solution of m-chloroperbenzoic

in a dry-ice/acetone

bath under nitrogen.

acid (18 mg, 0.091 mmol) in dichloromethane

A

(2 ml) The

was then added and the mixture stirred at -78OC under nitrogen for 10 min.

solution was then allowed to warm to room temperature and poured into water (10 ml).

The organic layer was separated and the aqueous layer extracted with

dichloromethane

The combined organic extracts were then washed with

(8 ml).

dilute sodium bicarbonate solution

(10 ml) and water (10 ml), then dried

(MgSD4).

Removal of the solvent under reduced pressure gave 18,19-didehydro-3-oxotabersonine

(30 mg, 93%) as a colourless gum;

3400, 1720, 1655, 1603 cm-';

Amax

.

230, 286, 328 nm;

vmax .

(CHCJ3)

(CDC13) 1.10-3.20 (4H, m), 3.81 (3H, s, C02Me),

6

4.0-4.5 (3H, m, N-C!, N-CH2), 5.10-5.40

(2H, m, -CH=CJi2), 5.71-6.10

(lH, m,

-C;=CH2), 6.11-6.56

(2H, dd, J 18, 9 Hz, -CH=CH-CO), 6.70-7.50

9.91 (lH, s, N-H):

m/z (%) 348 (55), 347 (17), 320 (20), 291 (23), 278 (19), 263

(14), 262 (13), 227 (59), 195 (loo),167

18,19-Didehydrovincadifformine

(31).

(42), 154 (17).

-

3-Oxo-didehydrovincadifformine

0.143 mmol) was dissolved in dry dichloromethane tetrafluoroborate

(4H, m, aromatic H):

(23 mg, 0.157 mmol) was added.

(50 mg,

(5 ml) and trimethyloxonium The resulting solution was

stirred at room temperature, under nitrogen, for 20 h, then the solvent was removed under reduced pressure.

Ethanol

(5 ml) was added, and the reaction mixture was Sodium borohydride

cooled to O°C in an ice/salt bath.

(11 mg, 0.286 mmol) was

then added and the mixture stirred at room temperature for 16 h. was then poured

into water

(50 ml) and extracted with ether

The solution

(3 x 50 ml).

combined organic extracts were then washed with water (50 ml), and dried

The (MgS04).

Removal of the solvent under reduced pressure gave 18,19-didehydrovincadifformine (32 mg, 66%) as a yellow gum 336.183768);

~~~~

(CDC13) 1.40-3.50

bj+, 336.18310.

(Found:

vmax

258, 298, 332 nm;

.

requires E,

C21H24N202

(film) 3400, 1670, 1610 cm-';

(13H, m), 3.72 (3H, s, C02Me), 4.50-6.60

6

(3H, m, Cg=CE2), 6.60-

7.50 (4H, m, aromatic H), 8.82 (lH, s, exchanges with D20, N-H);

m/z

(%) 336 (8),

292 (3), 147 (14), 122 (loo), 115 (2). 18,19_Didehydrotabersonine mmol) was dissolved borate

(1).

18,19-Didehydro-3-oxotabersonine

-

in dry dichloromethane

(4.4 mg, 0.03 mmol) was added.

(2 ml) and trimethyloxonium

(8 mg, 0.02 tetrafluore

The resulting solution was stirred at room

temperature under nitrogen for 18 h, then the solvent was removed under reduced pressure. ice/salt

Ethanol bath.

(2 ml) was added, and the mixture was then cooled to O'C in an

Sodium

borohydride

(2 mg, 0.04 mmol) was added and the mixture

stirred at room temperature for 16 h. (10 ml) and extracted with ether

The solution was then poured into water

(3 x 20 ml).

The combined organic extracts Were

Approaches to the synthesis of Aspidospermo

washed with water

(20 ml), and dried

reduced pressure gave

(NaS04).

alkaloidsII

Removal of the solvents under

(f)-18,19-didehydrotabersonine

gum, identical in chromatographic

6095

(3 mg, 57%) as a pale yellow

behaviour in two solvent systems

(2% methanol

in chloroform, and 10% ether in benzene) and in mass spectrum with authentic 18,19_didehydrotabersonine

17

(Found:

E', 334.16836.

C21H22N202 requires

M, 334.168118). Acknowledgement:

We thank the S.E.R.C. for a maintenance

award (to

J.W.B.).

References: 1.

G. Costello

2.

R.Z. Andriamialisoa, L. Diatta, P. Rasoanaivo, N. Langlois, and P. Potier, Tetrahedron, 1975, I, 2347.

3.

C. Kan-Fan, B.C. Das, H.-P. Husson, and P. Potier, Bull.Soc.Chim.Fr., 2839.

4.

R.Z. Andriamialisoa, N. Langlois, and P. Potier, Tetrahedron Lett., 1976, 163; N. Langlois, L. Diatta, and R.Z. Andriamialisoa, Phytochemrstry, 1979, 3, 467; N. Langlois and R.Z. Andriamialisoa A. Rabaron, M.H. Mehri, T. Sevenet, and M.M. ~l$+$$&~mlZ7tZ;,+~7~~6~, 1452.

5.

N.R. Farnsworth, 0, 106.

6.

C. Caron, L. Le Men-Olivier, M. Plat, and J. L&y, 545.

7.

H. Mehri, M. Koch, M. Plat, and P. Potier, Ann.Pharm.Fr., Bull.Soc.Chim.Fr., 1972, 3219.

8.

O.L. Salerni, R.N. Clark, and B.E. Smart, J.Chem.Soc.

9.

D. Swern, A.J. Mancuso, and S. Huang, J.Org.Chem.,

10.

E.J. Corey and C.V. Kim,

11.

W. E. Savige and A. Fontana, J.Chem.Soc., Chem.Commun., Pusztay, and L. Szabo/, Synthesis, 1979, 276.

12.

C.C. Price and T. Yukuta, J.Org.Chem.,

13.

T. Rodeheaver and D.F. Hunt, J.Chem.Soc.,

14.

J.Y. Laronze, J. Laronze-Fontaine, 1974, 491.

15.

J. L&y, 1579.

16.

R.F. Borch, Tetrahedron

17.

We thank Dr. P. Potier for the gift of an authentic sample of l8,19-didehydrotabersonine.

18.

G. Huge1 and J. L&y,

19.

J.B. Cloke and F.J. Pilgrim, J.Am.Chem.Soc.,

and J.E. Saxton, preceding communication.

1974,

R.N. Blomster, A.N. Masoud, and I. Hassan, Lloydia, 1967,

J.Am.Chem.Soc.,

Heterocycles,

1981, 16,

1972, 30, 643;

(C), 1966, 645.

1978, 43, 2480.

1972, 94, 7586. 1976,

599;

K. Szab&

1969, 34, 2503. Chem.Commun.,

J. L&y,

1971, 818.

and J. Le Men, Tetrahedron

Lett.,

J.Y. Laronze, J. Laronze, and J. Le Men, Tetrahedron Lett., 1978, Lett., 1968, 61.

J.Org. Chem.,

1986,

SJ,

1594.

1939, 61, 2667.