Diastereoselectivity in the intramolecular cycloaddition reactions of nitrones derived from 5-alkenals and chiral hydroxylamines

DIASTEREOSELECI-IVITY OF NITRONES

IN THE INTRAMOLECULAR

DERIVED

FROM 5-ALKENALS

S. W. Baldwin,*

CYCLOADDITTON

REACTIONS

AND CHIRAL HYDROXYLAMINES

R. B. McFadyen, J. Aube, and J. D. Wilson Department of Chemistry Duke University Durham,

Recent

studies

in these

laboratories

NC

27706

have

focused

on the construction

of nitrogen

containing materials by nitrone/alkene cycloaddition reactions, particularly intramolecular versions of this proces~.‘,~ Of special interest has been the possibility that nitrones bearing a chin1

substituent

on nitrogen

might

provide

ready

access

to optically

active

isoxarolidines

from achiral aldehyde/alkene nitrone precursors. This possibility was originally explored by Belzecki in bimolecular processes3 and subsequently by others in the intramolecular sense.” In general the diastereoselectivity observed in cycloadditions with chin1 substitution on nitrogen ranges from low to good (1.1-5/l) for both bimolecular and intramolecular examples. During

a recent investigation,

we had occasion

to prepare

the 5.alkenal

listed in Table I,

entry 11, and allow the resulting nitrone derived from a-methylbenzyl hydroxylamine (czMBHA) to undergo intramolecular cycloaddition. Ic Interestingly, the two isoxazolidine products

of this

reaction

3 and 4 were

formed

in a 16/l

ratio,

by far the most

striking

diastereoselectivity seen to date. To understand the structural features which are important for high diastereoselectivity, a series of substituted 5-alkenals 1 was prepared and each treated with aMBHA. Cyclization of the derived nitrones 4 whose ratios are summarized in Table I.

The isomer range from 1.7/l patterns

ratios for the formation (entry

are represented

1) to 16/l

2 then afforded

of fused 13.3.01 products

(entry 11).

in the starting

diastereoisomeric

Although

materials,

several

a consistent

products

from aMBHA different

picture

(entries

alkene

of important

3 and

l-11)

substitution structural

features does not emerge. The two substrates leading to the best diastereoselectivities [(entries 5, (10/l) and 11, (16/l)] have a carboethoxy group trans to the remainder of the alkenal chain. On the other hand, the ratio for the third compound Entries 7 (5.3/l) and 8 (5.0/l) addition, varying alkene diastereoselectivity

(entries

suggest methyl

of this tvoe is more modest (4.0/l. ., entrv ~, 6). I. that the nature of aryl substitution is not important. In substitution led to only minor variations in

l-4).

4431

4432

TABLE

I. Diastereomeric

Ratios from the Chin1 Hydroxylamine-Derived

Some Substituted entry

of

Rz H-

R3 H

CH3 II

H

E! aMB

@’

FI H H

aMB aMB

4.4/l 2.9/l

H

aMB

3.3/l

H H

aMB aMB

10/l 4.0/l

X

1 2

3 HH

3 4

H H

5

H

CH3 CQEt

6 7

Ph Ph

C@Et H

C@Et

H

aMB

5.3/l

8

BDd BDd

H H

CQEt cO-$t

H CQEt

aMB aMB

5.0/I 7.1/l

9 IO 11 12e

CH3 CH3 H H

1.7/I

BDd

H

C@Et

S(CH2)3S

aMB

4.0/l

BDd Ph

CQEt H

H H

S(CHz)3S H

aMB aMB

16/l 1/1e

13

H

I-1

H

H

BZ(OH)

3.3/I

14 15

H BD

H H

H C@Et

H H

CM(OH) NORcOMe)

2.5/l 8.0/l

Entries reaction.

Nitrones

5-Alkenalsa

13-15

employed

The two series

three

defined

different

by entries

chin1

hydroxylamines

for the cycloaddition

1, 13, &14 and 8 & 15 show

that cycloaddition

diastereoselectivity is sensitive to the substituent on nitrogen (intramolecular bonding, sterics, etc.), although it is difficult to pinpoint the origins of the effect.

‘EiIH

),,;

aMB The ratios related

examples

which

are from

BZ(OH) for varying the work

CH3 substitution

of Wovkulic

C;;),,~~

CM(OH)

NOR(OMeP

in Table I (entries

in Table II for a series of substituted

hydrogen

en01 esters

l-4)

are consistent

(entries

and Uskokovic ,4a.b show a trend

l-5).

for alkene

substitution that closely parallels the selectivity observed for the corresponding from Table I. The crotonate ester example (entry 6) follows the same trend.7

with the

These

ratios, methyl

compounds

4433

R3

1

R2

yg2

Rl Y.,J+&,O7

H

A*

TABLE

II.

+ /$z

k.

k

6 5 Diastereomeric Ratios from the aMBHA-Derived Crotonic Esters.

Nitrones

7 of Several

En01 and

El

R1

1

H

II

H

0

GO

15/1a

2 3

H H

CH3 H

H CH3

0 0

GO GO

4.5/1a 1.1/l”

y

4

H

CH3

CH3

0

GO

2.7/Ia

5 6

CH3 H

H CH3

H H

0 GO

C=O 0

2.7/la 2.3/Ib

In attempting

to understand

the origin

of the selectivities

in the above

reactions,

one

must bear in mind that in most cases the absolute sense of optical induction at the newly formed chin1 centers is not known. Although it is tempting to assume that closely related substrates

will cyclize

with the same stereochemical

sense,

this has not yet been established.

Even so, there are several examples which form a consistent picture. Single crystal x-ray analysis of the major product from Table I, entry 11 (16/l), ‘C demonstrated that the nitrone made with SaMBHA cyclized to afford a product in which the configuration at C6a was also S as indicated in structure 3. A similar result was obtained for the major product of the cyclization reported

in Table II, entry 2, that is, an S chin1 auxiliary

It has also

been

shown

treatment with S-aMBHA configuration at C6a relative these

experiments

demonstrate

different

afforded Sat C6a4a

5-alkenals

8 derived

from

mannose

afford major product isomers with enhanced to the ratios obtained from methyl hydroxylamine.Ib

are actually

for 5.alkenals

that four

illustrations

an inherent

of a double

tendency

diastereoselection

of an S-a-methylbenzyl

on

levels of S Although

process, chin1

they do

auxiliary

to

produce products that are also S at C6a. Thus, each of the six intramolecular nitrone/alkene cycloadditions from uMBHA known to date affords as the major product that diastereoisomer which

is consistent

examples

with

the above

findings.

As such

it is likely

that many

of the other

from Tables I and II behave in a similar fashion.

Wovkulich and Uskokovic have proposed a model to explain the diastereoselectivity observed for their reaction (Table II, entry 2) in which alkene face selectivity is a consequence of the nitrone toward

rotational

the double

isomer

(I) that directs

bond to minimize

the hydrogen

non-bonded

(small group)

interactions

between

on the chin1 the alkene

carbon

CH3 group

and the remaining CH3 and Ph groups on the chin1 carbon. 4.a It would appear that the major isomer from Table I, entry I1 is better accommodated by the alternative rotational isomer (Ii) that directs between

the large phenyl

alkene

substituents

group

away from the double

and the CH3 and H groups

bond to minimize on the chin1

carbon.

the interactions Although

the

4434

origin of the selectivity observed in the nitrone/aIkene is difficult to pinpoint with accuracy, the information is in fact considerable

CH

stereochemical

reguIaritY.

CH

CHQ

0

I?

‘N

MeA”Ar Ph

I References

(a)

EtO,C

4 H M&H”Ph

8

1.

cycloaddition reaCt&ts discussed above available 5: &is time suggests that there

S. W. Baldwin,

J. D. Wilson,

II and Notes

and J. Aube,

I. Org. Chem., 50, 4432 (1985).

Baldwin and S. C. Gedon, Chem. Commun., 21 (19911, in press. (c) S. W. Baldwin, A. T. McPhail, J. Org. Chem., 56 (19911, submitted for publication. 2.

For pertinent

recent

reviews

of nitrone

cycloaddition

Lander, Jr., J. M. Leginus, and C. M. Dicken, In Advances JAI Press, Inc: Greenwich, CT, 1988; Vol. 1, pp 87-128. Padwa, review

Cycfoaddition Chemistry; 168. A comprehensive appeared.

(c)

I’adwa,

A.;

JAI Press, Inc: Greenwich,

reactions

A. M.

In Advances

S. W.

see (a) P. D&hong,

S. W.

in Cycloaddition; Curran, D. P., Ed.; (b) J. J. Tufariello, In 1,3-Dipofar

A., Ed.; Wiley Interscience, New York, 1984; of intramolecular 1,3-dipolar cycloaddition

Schoffstall,

(b)

J, Aube, and

in Cycfoaddition;

Vol. 2, pp 83. reactions has D. I’., Ed.;

Cum,,,

CT, 1990; Vol. 2, pp l-89.

3. C. Belzecki and I. I’anfil, 1. Org. Chem., 44, 1212 (1979). 4. (a) I’. M. Wovkulich and M. R. Uskokovic, and references

60, 1273; 5.

T. Polanski

reference

and M. R. Uskokovic,

and A. Chimiak,

corresponding

hydroxy

7. S. W. Baldwin

3455.

(b) I’. M. Wovkulich, Chim.

Acta 1977,

Bull. Acad. Pof. Sci. Ser. Sci. Chim. 27, 459 (1979).

Tetrahedron

31, 2595 (1975). ketone.

I. Fleming and R. 8. Woodward,

and J. AubP, unpublished

Society, April 9.14, 1989, Dallas, Texas; of Health is gratefully

(Received in USA 10 May 1991)

Lett., 27,496l

The camphor-derived

See also

0986). oxime

(b) I’. H. Morgan was prepared

and A.

from the

1. Chem. Sot., C, 1289 (1968).

results

8. (a) A portion of this work was presented Institutes

1985,41,

(c) A. Vasella, H&J.

preparation.

6. (a) D. A. Evans and E. B. Sjogren, Tetrahedron,

3956.

therein.

4a for an improved

H. Beckett,

Tetrahedron

1. Am. Ckem. Sm. 1981,103,

at the 197th meeting of the American

Chemical

ORGN 123. (b) Partial support from the National

acknowledged

(GM 31364).