Structure elucidation by NMR and computer-assisted structure generation of bi- and tri-cyclic products derived from electrocyclic rearrangements in biomimetic synthesis

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Structure elucidation by NMR and computer
-
assisted structure
generation of bi
-

and tri
-
cyclic products derived from electrocyclic
rearrangements in biomimetic synthesis

Barbara Odell*, Tim D.W. Claridge, John E. Moses, Sebastian Bruckner, & Jack E. Baldwin



The Dyson Perrins Laboratory, Department of Chemistry, University of Oxford, OX1 3QY, UK,

Barbara.Odell@chem.ox.ac.uk

INTRODUCTION

Biomimetic

synthesis

of

natural

products

is

a

well

established

area

of

chemistry

with

applications

to

the

pharmaceutical

industry
.

Two

areas

of

interest

to

the

Baldwin

group

at

Oxford

University

are

i)

the

crispatene

family

of

compounds
1

( I )

w h i c h

a r e

b e l i e v e d

be

mild

cytotoxic

agents
;

and

ii)

the

SNF
4435
C

and

SNF
4435
D

family
2

of

hexasubstituted

bicyclo

immunosupressants
2

(II)

isolated

from

the

culture

broth

of

a

strain

of

Steptomyces

spectabilis
.



Although

very

diverse

in

structure,

it

is

believed

that

both

classes

of

compound

are

originally

derived

from

biosynthetic

transformations

involving

propionate

and

acetate
.

One

interesting

aspect

is

that

these

proposed

biosynthetic

schemes

are

believed

to

involve

polyene

intermediates
.


This

prompted

the

Baldwin

group

to

consider

using

polyenes

as

precursors

in

chemical

transformations

using

thermal,

photochemical

and

heterogeneous

catalysis

as

possible

routes

to

biologically

active

molecules
.


Extensive

1
D

and

2
D

NMR

analysis

of

the

resulting

products

was

employed

to

elucidate

the

structures

of

the

rearranged

products
.

The

complexities

we

encountered

in

determining

unambiguous

structures

led

us

to

consider

the

application

of

Computer
-
Assisted

Structure

Elucidation

(CASE)

programs

in

this

task
.



O
O
O
O
C
H
3
O
2
N
(
I
I
)
S
N
F
4
4
3
5
C

a
n
d

S
N
F
4
4
3
5
D
The

process

of

assigning

unique

structures

consistent

with

1
H,
1
H

and

1
H,

13
C

correlation

data

proved

to

be

unusually

challenging

for

these

systems

due

to

four

principle

features
:




the

general

lack

of

vicinal

proton
-
proton

couplings



the

ambiguity

introduced

by

2
J
CH
,

3
J
CH
,

4
J
CH

and

even

5
J
CH

correlations

in

HMBC


experiments

of

these

extended

conjugated

systems




the

potential

variety

and

complexity

of

structures

which

may,

in

principle,

result

from

the


electrocyclisations




the

time

required

for

data

analysis

and

identification

of

candidate

structures

In

general

when

seeking

unknown

structures,

there

may

be

several

candidates

consistent

with

the

available

NMR

data,

but

the

spectroscopist

may

only

consider

one

or

perhaps

a

smaller

subset

of

them
.

Identifying

functional

groups

and

smaller

fragments

is

not

usually

a

problem
.

Connecting

them

together

is

where

the

difficulties

can

arise
.


Hence,

we

wished

to

employ

a

computer

program

which

would

utilize

knowledge

of

the

functional

groups

together

with

correlations

from

2
D

NMR

data

to

produce

all

viable

structures

consistent

with

the

input

data

in

a

short

time
.

The

development

of

expert

systems

(ES)

or

Computer
-
Assisted

Structure

Elucidation

(CASE)

p r o g r a ms

has

flourished

over

recent

years
3
-
9
:

StrucEluc
3
,

X
-
PERT
4
,

RASTR

(STREC)
5
,

COCON
6
,
7
,

and

LSD
8
,
9
.

We

chose

to

examine

the

Nuzillard

program

‘ L o g i c

f o r

S t r u c t u r e

D e t e r mi n a t i o n ’

or

LSD

.

This

is

made

freely

available

by

Jean
-
Marc

Nuzillard

and

is

reasonably

user
-
friendly

in

terms

of

data

input

which

consists

of

1
D

13
C,

COSY,

HMQC/HSQC

and

HMBC

data
.


1
H and
13
C NMR spectra for the cyclisation product:
note the scarcity of proton resonances and couplings

HMBC of the cyclisation product



The round circles on the HMBC spectrum indicate
4
J
CH

(blue, H
15

to C
19
)

and
5
J
CH

(
red, H
23

to C
22
)
.

Example 1


Photochemical Rearrangement of the all
-
(E) Pentaene

M
e
M
e
A
r
M
e
H
H
C
O
2
E
t
H
H
n
O
e
s
Summary scheme for the all
-
(E) Tetraene

Conclusions

The

work

reported

here

shows

that

the

LSD

Computer
-
Assisted

Structure

Elucidation

(CASE)

program

is

a

powerful

tool

for

utilizing

1
D

and

2
D

NMR

data

to

generate

chemical

structures

with

viable

connectivities
.

In

cases

such

as

the

examples

shown

above,

where

long
-
range

heteronuclear

1
H
-
13
C

NMR

correlations

are

too

complex

to

provide

rapid

solutions

to

the

assignment

problem,

we

discovered

that

the

LSD

‘ELIM’

command

was

very

useful

for

overcoming

assignment

discrepancies

arising

from

ambiguities

over

very

long
-
range

correlations

(n>
3
)
.


We

would

recommend

that

use

of

such

structure

generation

programs

be

augmented

by

additional

nOe

studies

to

cross
-
check

the

proposed

structures

and

to

yield

stereochemical

data
.

Together

they

from

an

integrated

approach

to

3
D

chemical

structure

elucidation

yielding

consistent

structural

and

stereochemical

assignments

for

the

molecule

in

question
.

Spectra for the various products analysed were recorded on: a Bruker DRX500 spectrometer equipped with a triple resonance inv
ers
e probe, a Bruker
AMX500 spectrometer equipped with a broadband probe, and/or a Bruker DPX400 equipped with an inverse probe. The LSD program w
as
run on a
Silicon Graphics O2 workstation. Details of the LSD program can be obtained from:
http://www.univ
-
reims.fr/Labos/UPRESA6013/GNOSIE/LSD/

* = traces of impurities S = starting tetraene I = isomerisation intermediate

THE NMR STRUCTURAL ASSIGNMENT PROBLEM

LSD input file for the cyclisation product



The file format is an edited example of the LSD input file for this compound.

LSD output file for the cyclisation product

C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
X24
O25
O26
; sb1311


;File identity



DISP 1


;Define output format

HIST 1


;Display progress during


structure generation

ELIM 2 5


;Define eliminations for



n
J
CH
> 3



MULT 1 C 2 0

;Define atom numbers,



type, hybridisation &



multiplicity eg
13
C



from DEPT, APT

MULT 22 C 3 3

MULT 23 C 3 3

MULT 24 X 3 0

;Define heteroatoms or



dummy groups eg NO
2

MULT 25 O 2 0

MULT 26 O 3 0



VALE X 1


;Define valence of



dummy groups



HMQC 3 3


;Define HMQC



connectivities

HMQC 5 5

LSD program suggests a crispatene core solution
for the cyclisation product



COSY 9 11


;Define COSY correlations (
2/3
J)

COSY 10 12

COSY 14 20

COSY 3 13



HMBC 1 3


;Define HMBC correlations ( #
13
C
-
#
1
H)

HMBC 1 13

HMBC 1 14

.

.

HMBC 22 23

HMBC 23 5

HMBC 23 3



BOND 4 11 ;Define known bonding patterns eg


within esters, aromatic rings or other


known fragments

BOND 4 12



.

BOND 14 26

BOND 14 20



EXIT


;Terminate file


Example 2


Photochemical and Thermal Rearrangements of the all
-
(E) Tetraene


C
O
C
O
C
O
C
O
C
O
C
O
C
O
C
O
2
N
a
N
O
2
O
2
N
O
O
O
M
e
+
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
ppm
*
*
*
*
*
*
*
*
*
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
ppm
S
I
S I
IS
SI
SSISI
I
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
ppm
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
ppm
*
A
r
C
O
2
E
t
C
O
2
E
t
A
r
Photochemical

Cyclised product:
crispatene core
with observed nOes


Intermediate: 1
st

isomerisation
product

Starting tetraene

H
C
O
2
E
t
A
r
H
n
O
e
s
Thermal


Tricyclic core

with observed nOes

References


1

J

E

Moses

,

J

E

Baldwin,

R

Marquez,

R

Adlington,

T

D

W

Claridge

and

B

Odell

Organic

Letters

Vol

5

No

5

2003

661
-
663
.

2

J

E

Moses

,

J

E

Baldwin,

R

Marquez,

R

Adlington

and

A

R

Cowley

Organic

Letters

Vol

4

No

21

2002

3731
-
3734
.

3

K

A

Blinov,

D

Carlson,

M

E

Elyashberg,

G

Martin

E

R

Martirosian,

S

Molodtsov

and

A

J

Williams

Magn

Reson

Chem,

2003
,

41
,

399
-
372
.

4

M

E

Elyashberg,

E

R

Martirosian,

Y

Z

Karasev,

H

Thiele

and

H

Somberg

Anal
.
Chim
.

Acta

1997
,

Vol

337
,
265
.

5
.
M

E

Elyashberg,

VV

Serov,

E

R

Martirosian,

L

A

Zlatina,

YZ

Karasev,

V

N

Koldashov,

Y

Y

Yampolskiy
.

J
.

Mol
.

Struct
.

1991
,

Vol

230
,

191
.

6

T

Lindel

,

J

Junker,

M

Köck
.

Eur
.

J
.

Org
.

Chem
.

1999

Vol

3
:

579
.


7
M

Köck,

J

Junker,

W

Maier,

M

Will,

T
.

Lindel

Eur
.

J
.

Org
.

Chem
.

1999

3

573
.

8

J
-
M

Nuzillard

and

G

Massiot

Tetrahedron

1991
;

Vol

47

3655
.

9

S

V

Ley,

K

Doherty,

J
-
M

Nuzillard

and

G

Massiot

Tetrahedron

1994
;

Vol

42

12267
.



Acknowledgements


We

would

like

to

thank

Dr
.

Jean
-
Marc

Nuzillard

of

the

University

of

Reims,

France,

for

making

his

LSD

program

available

to

us

and

for

helpful

discussions
.

We

also

thank

Mr

Charles

Baker
-
Glenn

for

his

valuable

assistance

in

the

preparation

of

this

poster
.


Crystal

structure

of

the

tetraene

showing

steric

clash

of

adjacent

methyl

groups
;
-

a

driving

force

for

isomerisation

The

unusual

tricyclic

core

suggested

by

NMR

via

LSD

and

nOes

for

the

thermal

rearrangement

was

subsequently

confirmed

by

crystallographic

analysis

of

a

suitable

derivative,

which

also

proved

the

absolute

stereochemistry

(stereo

view

shown)
.

P
d
(
I
I
)
h
v
E

=

C
O
2
E
t
A
r

=

p
-
N
O
2
-
P
h

A
r
E
?
?
?
n
=
2
,
3
O
O
O
C
H
3
O
c
r
i
s
p
a
t
e
n
e
(
I
)
H
A
r
E
3
h

E

=

C
O
2
E
t
A
r

=

p
-
N
O
2
-
P
h
N
O
2
E
t
O
2
C
1
1
1
/
1
2
9
/
1
0
4
2
2
1
6
8
1
8
1
5
1
7
5
7
3
1
3
2
2
1
9
2
3
2
0
/
1
4
1
6
H
A
r
E
A
r
E

h
v
A
r
E
H
H
A
r
A
r
E
E
A
r
P
d
(
I
I
)
A
r
E
h
v
E

H
The

ELIM

command

allows

the

user

to

define

any

number

of

HMBC

correlations

that

may

arise

over

more

than

3
-
bonds
.

Thus

ELIM

2

5

allows

structures

to

be

generated

that

can

have

up

to

2

correlations

arising

over

4

or

5

bonds
.

This

is

useful

when

no

structures

can

be

generated

assuming

n


3

for

all

n
J
CH
.