Bis(trimethylsilyl) enol ethers as 1,3-dianion equivalents: Regiocontrolled [3+4] and [3+5] annulation reactions

Tetrahedron Printed in

Letters,Vol.30,No.l8,pp Great Britain

BIS(TRIMETHYLSILYL)

2351-2354,1989

0040-4039/89 $3.00 Pergamon Press plc

ENOL ETHERS AS 1,3-DIANION

REGIOCONTROLLED

[3+4] AND [3+5] ANNULATION

+ .Oo

EQUIVALENTS: REACTIONS

GARYA. MOLA~~DER*l AND STEEENW. A~REWS

Department of Chemistzy and Biochemistry, University of Colorado, Boulder, CoJorado 80309-0235 Abstract: In the presence of titanium tetrachloride, 1,3-bis(trimethylsiloxy)-1-methoxy-1,3-butadiene (1) undergoes facile [3 + n] annulation reactions with 1,4- and 1,5-dielectrophiles to generate seven- and eight-membered bicyclic ether adducts. The annulations occur in good yields (49-83%) and are also highly regioselective for substrates containing two distinct electrophilic groups. Cycloaddition efforts to develop

reactions represent the most efficient method for the generation of complex ring systems.

cycloaddition

stimulated by the ever-increasing

approaches

to stereodefined

transannular

trimethylenemethane encountered

interactions.4

dianionic

in construction

and eight-membered3

carbocycles

number of important natural products which contain these ring systems.

reactions leading to seven- and particularly eight-membered developing

seven-*

synthons

Recently,

Cyclization

rings often proceed in low yields due to entropic factors and

we reported

and dicarbonyl

of medium-sized

Current

have been

efficient

partners.5

[3 + 41 and [3 + 51 annulations

This strategy

circumvents

problems

rings by relying on in sifu formation of a five- or six-membered

between normally hemiketal

template which facilitates subsequent cyclization to the desired carbocycles.5~6

Although use of the timethylenemethane ethers, initial attempts to develop a substituted, bis(trimethylsily1)

dianionic synthon provides a convenient unsymmetrical

enol ether of methyl acetoacetate

(1)7 is an effective

2351

approach to simple bicyclic

variant of the synthon failed. 1,3-dianionic

We now report that the

synthon

for these annulation

2352

processes,

and permits complete

regioselectivity

in the synthesis

of functionalized,

unsymmetrical

seven- and eight-

membered carbocycles. TMSO

0th

UT&AS

While bis(trimethylsily1)

=

uOMe

_

enol ethers of this type have been extensively

annulation

reactions,

Precedents

for such a sequence were established

the corresponding

(2) with titanium tetrachloride

-

[3+4] and [3+5] annulation by Chan and coworkers,

employed

processes

in [3+3]* and [4+219

have not been fully developed.

who report that treatment of 2,4-hexanedione

enol ether 1 generates bicyclic ether 4 in an unspecified

and bis(trimethylsily1)

yield.‘”

0

1

+

.Jwy

co,Me

Tic14

Me

”

CH$212,

0

2: n=l 3 : n=2

4: 5:

We initiated our study by re-examining treatment of bis(trimethylsily1) followed

species

generating

the desired

were also suitable

bis(trimethylsily1) cycloadduct

this simple case. Optimal conditions for the annulation were achieved by

2 (0.1 M in CHzCl2).

bicyclic

substrates

for this annulation

process.

enol ether 1 under the standard reaction conditions

yield.

Treatment generated

(4 and 5) were generated

(0.2 M in CH2C12),

resulted in a rapid [ 3 + 41

Homologous

1,5dicarbonyl

of 2,Sheptanedione the corresponding

(3) l1 with

eight-membered

as a 1 : 1 mixture of diastereomers

at

stereocenter.

The discrete reactivity We envisioned

At -78“ C, these conditions

ether product 4 in an 83% isolated

5 in 68% isolated yield. The cycloadducts

the carboxylate

n=l n=2

enol ether 1 (0.2 M in CH2C12) with 1.0 eq of titanium tetrachloride

by addition of 2,Shexanedione

annulation,

““Me hl

Me”“ GY

-78°C

of the two nucleophilic

that the differential

reactivity

annulation process was applied to substrates subjected

1,4-ketoaldehydes

generating

the expected cycloadducts

centers of bis(trimethylsily1)

between containing

613 to the standard

enol ethers is well documented.”

these sites would translate two distinct electrophilic

annulation

conditions.

into high regioselectivity

groups.

The desired

To test this hypothesis, annulation

8 in good yields (Table I, entries l-3). Homologous

714 were likewise cyclized to provide the corresponding

eight-membered

each case, the crude reaction mixtures were uncontaminated

6: n=l 7 : n=2

ring cycloadducts

by regioisomeric

if the

cycloadducts.

8 : n=l 9 : n=2

we

did indeed occur,

1,Sketoaldehyde

substrates

9 (Table I, entries 4-6). In

2353

Table I. [3 + 41 and [3 + 51 Annulation 1,4- and 1,5Dielectrophilic

entry

substrate

Reactions

with

Substrates.

R

n

% isolated yielda

1

6a

Me

1

66

2

6b

t-Bu

1

12

3

6c

Ph

1

49

4

7a

Me

2

77

5

7b

t-Bu

2

71

6

7c

Ph

2

63

7

10a

Mf!

1

79

8

lob

t-Bu

1

82

9

1oc

Ph

1

63

a Satisfactory

1H NMR, 13C NMR, IR, and exact mass spectral data

were obtained for all compounds

Cycloadducts

possessing

complementary

For example, treatment of bis(trimethylsily1)

regiochemistry

enol ether 1 with 1,Cketoacetal

in good yield (Table I, entTies 7-9). Again, annulation Attempts to extend this methodology

These preliminary eight-membered

examples

carbocycles.

especially attractive.

delineate

substrates

with these substrates

to 1,5-ketoacetal dielectrophiles

The diversity

Furthermore,

could be accessed by employing

incorporated

seven- and

within the ring system makes this approach and the steric biases inherent in

selectively with excellent control of stereochemistry.

At present we are

continuing to explore the generality of this process and its application to the synthesis of natural products.

Acknowledgments:

11

regioselectivity.

entry to stereo- and regiodefined

by taking advantage of various alkylation procedures

the system, additional sites can be functionalized

10’3 generates cycloadducts

occurred with complete

(n = 2) were unsuccessful.

a simple, highly efficient of functionality

ketoacetal substrates.

We thank the National Institutes of Health for their generous

support of this research