Intramolecular formal iron-catalyzed ene reactions: The stereoselective and regiocontrolled formation of substituted tetrahydropyrans

Tetrahedron Letters,Vo1.28,No.46,pp Printed in Great Britain

INTRAMOLECULAR

FORMAL

5627-5630,1987

IRON-CATALYZED

REGIOCONTROLLED

ENE REACTIONS:

FORMATION

0040-4039/87 $3.00 + .OO Perqamon Journals Ltd.

THE STEREOSELECTIVE

OF SUBSTITUTED

AND

TETRAHYDROPYRANS

James M. Takacs*, Lawrence G. Anderson, Mark W. Creswell, and Beckie E. Takacs' Department

of Chemistry,

University

of Utah, Salt Lake City, Utah 84112

SUmARY: The iron-catalyzed six-membered ring carbocyclizations of 5-oxa-2,8,10-undecatriene derivatives proceed with high regio- and stereoselectivity to yield trans-3,4-disubstituted tetrahydropyrans. Substrates containing an alkyl substituent at the 4- or the 7-position of the starting triene ether cyclize with high secondary stereoinduction to produce trans,transtrisubstituted derivatives. Diastereomeric (X)- and (.X)-substrates cyclize via complementary [4+4]- and [4+2]-ene reaction pathways.

Transition-metal

mediated

carbocyclization

reactions

are providing

the synthetic

chemist

with an increasingly versatile array of methodologies for the construction 2 ring systems. We have recently reported the bpy*Fe(O) catalyzed carbocyclizations (2E,7!)-,

and (22,7E)-2,7,9-decatrien-l-01

disubstituted

cyclopentanes,

cyclizations

proceed

iron mediated

functionality

within

Treatment iron-catalyzed

to yield

3-8h).

mixture

formation

benzene,

through

is treated

pyran

of substituted

are formed.

2.

with greater

under standard a formal

[4+4I-

Upon complete

ethylene

glycol

to remove

(cat. TsOH,

by flash chromatography

analysis

of the crude acetal

than 5O:l trans simple dias-

pyrans

While additional

5627

the cyclizations

(1:l EtOAc-hexanes)

pyran 3a is isolated

gas chromatographic

proceeds

catalyst

ethers

Florisil

of our of additional

tetrahydropyrans.

25"C, 7h), effects

with excess

Less than 1% of any cis-substituted

trans-substituted

in scope to the construc-

the applicability

this end we have investigated

of cis- and trans-enol is filtered

capillary

shows that the cyclization

are limited

la with the bpy*Fe(O)

The trans-3,4-disubstituted Careful

[4+4]-ene

ring sizes and to the incorporation

ether

and the crude product

yield.5

tereoselectivity. isomeric

mixture

iron catalyzed

in examining

(10 mol% bpy*Fe(O)

a mixture

the reaction

in 84% overall

substrates

Toward

of

and c-1,2-

followed by the regioselective 4 Since many transition to the diene moiety.

to the stereoselective

ene conditions

the iron catalyst THF, 25X,

the ring system.

leading

rise to c-

bond formation

interested

of other

of the (21,8E)-triene

ene cyclization

hydrogen

of acyclic

rings, we were

to the construction

of triene ethers

cyclization,

of an allylic

carbocyclizations

tion of five-membered methodology

These formal

respectively.3

via initial carbon-carbon

transfer

metal mediated

ethers giving

organic

of common

and less than 1.5% of an alkyl substituents

on the

5628

diene moiety

tend to slow down the rate of the iron-catalyzed

methyl-triene

ether

the trans-pyran

lb cyclizes

readily

3b in 57% isolated

under the influence

yield

and greater

OCH,Ph R

(R I CH,)

10 mol% bpy Fe(O)

H

*

/eq 1)

3a (R = H) 3b (R = CH,)

new strategies

is an important

goal

(2?,8E)-triene

substituent

stereochemical

adjacent

bias toward

be expected

acetalization

of transition

ethers

secondary

over the trans,cis-diastereomer 5b in 68% overall

yield

Tt?ANS:CIS

of stereochemistry bond constructions.

could

cyclization-

simple diastereoselectivity of the crude acetal mix-

pyran 5a is formed with a minimum

The 7,10-dimethyl

a

substituent

the iron-catalyzed

gc analysis

and in greater

6

impose a significant

While a simple methyl

Careful

6.

>98:2

in order to test whether

64% yield with excellent

stereoinduction.

ture shows that the __trans,trans-3,4,5_trisubstituted trans,trans-pyran --

moiety

diastereodifferentiation,

in overall

control

metal catalyzed

4 were prepared

to the 8,10-diene

to impose minimal

LJIASTEREOSELECTIVITY

and predictable

attack on the diene system.

of 4a proceeds

and with excellent

for the efficient

in the investigations

substituted

non-chelating

preference

H

cat TsOH / THF

2

Uncovering

might

to give

HOCH,CH,OH >

SIMPLE

The 7-methyl

catalyst

R

PhH I25”C / 3-8h

(R = H)

of the bpy*Fe(O)

than 96% isomeric purity.

R

H

la

the (21,8E)-lo-

OCH,Ph H

lb

ene reaction,

analogue

than 95% isomeric

4b yields

7O:l

the

purity.

OCH,Ph

I

1

10 mol% bpy Fe(O) PhH/25’C/Bh

2. HOCH,CH,OH,

*

lH$’

+

(eq 2)

4a

(R = H)

5a

(R = H)

4b

(R = CH,)

5b

(R = CH,)

SECONDARY

Similar

results

the (2Z)-olefin overall)

are observed

functionality.

stereochemistry

between

6

STEREOlNDLJCTlON

when a non-chelating

The 4-ethyl

TRANS,TRANS-:TRANS,CIS

is incorporated

(2Z,8E)-triene pyran 8 in which

the three contiguous

stereogenic

Preliminary

applying

studies,

>70:1

substituent

substituted

to give the -trans,trans-2,3,4_trisubstituted

than 3O:l selectivity.

;z&--

H+

centers

molecular

ether

adjacent

7 cyclizes

(60%

the relative

is controlled modelling

with greater

techniques

to

to

5629

evaluate

the steric/strain

in each case cyclization

energies

of the relevant

has proceeded

metallacyclic

intermediates,

suggest

via the most stable of the diastereomeric

that

metallacycles.

OCH,Ph H 1. 10 mol% bpy Fe(O) PhH/25”C/Bh * 2. HOCH,CH,OH

@I

/ H+

7

9 SECONDARY

Considering

the mechanism

clear that the cyclizations proceed

via the initial

mediates. derived

(2!,8E)-triene

formation

1.

Hence,

product

ene cyclization,4

diastereomeric

triene

products

11.

10 cyclizes

only with respect

the regioselective

TFlANS,TRANS-:ClS,TRANS-

and (EL)-triene

are indeed borne out.

w-substituted

[4+2]-ene

12 and 13 differ

iron catalyzed

(21)-triene

of non-interconvertible

speculations

12, while

>30:1

that 10 might give rise to a product

exclusively

formal

trans,exo-metallacycle -diastereomers

These

10 yields

is the regioisomeric

o-bond.

of the intramolecular

Hence, we anticipated

from triene

9 STEREOINDUCTION

of the diastereomeric

Cyclization

metallacyclic

While cyclization (61% overall),

of la proceeds

to the stereochemistry observed

must

inter-

isomeric with that of the

the major

isomer

via intermediate

via the trans,endo-intermediate

C-H bond formation

it is

substrates

13.

The

about the iron-carbon

in the intramolecular

iron-

1. 10 mol% L Fe(O) PhH/25T/8h 2

10

HOCH,CH,OH

i H+

11

REGIOSELECTIYITY:

la

-

3)

3a

L I

bipyridine

94:

L I

pyridine

15

6

:

85

by Fe(O) -

W W’J)

10

5630

catalyzed

ene cyclization

alkoxymethyl

moiety,

is apparently

which

In the bimolecular had observed

that both between

For example,

the bpy*Fe(O)

pyr*Fe(O)

dependency

catalyst

la,

catalyst,

these conditions

cyclizations product,

catalyst

catalyst

based upon recovered the pyrBFe(0) under

[4+2]- and [4+4]-ene

proceeding

products

reaction

modes of la and 10.

preference

for the [4+4]-ene

REFERENCES

AND NOTES

cyclization

selectivity

upon the choice distribution,

of the (2!,8E)-triene

the regioselectivity.

in a ]4+2]-ene

la

3a (50% overall 10 with

The major product ratio.

13 can give rise to a ]4+2]-ene

reaction

the ligand

of the (ZL,8E)-triene to yield

for

of ligand.

while the

investigated

3a, formed in a 15:85 11:3a

via the endo-diastereomer ligand directs

Treatment

Treatment

changes

product

product

regioselgctivity

purity).

dramatically

is the [4+4]-ene

and the bipyridine

dependent

We have, therefore,

with unchanged

98% diastereomeric however,

The kinetic

were formed.'

]4+2]:]4+4]

gave a 6:94 mixture.

proceeds

of the

of isoprene with ally1 benzyl ether, we

modes was strongly

gave a 73:27

orientation

donor

ene reactions

these two reaction

of the [4+2]:[4+43

with the pyr*Fe(O)

as the B-hydride

iron-catalyzed

partitioning

analogous

serves

exo/endo of the --

a consequence

Thus, only cyclization

sense overcoming

an inherent

mode.

1. Financial support from the NIH (GM-34927) is gratefully acknowledged. High-field NMR spectra were obtained using 300 MHz instruments purchased with grants from the NSF and DOD. Molecular modelling was carried out using equipment purchased with a grant from the NIH. 2. a. b. c. d. e. f. g. h. i.

Trost, B.M.; MacPherson, D.T. J. Amer. Chem. Sot. 1987, 109, 3483-3484; Nugent, W.A.; Thorn, D.L.; Harlow, R.L. J. Amer. Chem. Sot. 1987, 109, 2788-2796; Wender, P.A.; Snapper, M.L. Tetrahedron Lett. 1987, 28, 2221-2224; Magnus, P.; Principe, L.M.; Slater, M.J. J. Org. Chem. 1987, 52, 1483-1486; Tsada, T.; Sumiya, R.; Saegusa, T. Synth. Commun. 1987, lJ, 147-154; Taber, D.F.; Raman, K.; Gaul, M.D. J. Org. Chem. 1987, 52, 28-34; Negishi, E. Accts. Chem. Res. 1987, 20, 65-72; Hayes, T.K.; Freyer, A.J.; Parvez, M.; Weinreb, S.M. J. Org. Chem. 1986, 51, 5501; Snider, B.B.; Mohan, R.; Kates, S.A. J. Org. Chem. 1985, 50, 3659-3661.

3. Takacs, J-M.; 4. Takacs, J.M.; Organometallics

Anderson,

L.G. J. Amer. Chem. Sot. 1987,

Anderson, L.G.; Madhavan, 1986, 5, 2395-2398.

G.V.B.;

109,

Creswell,

2200-2202.

M.W.; Seely,

F.L.; Devroy,

W.F.

5. The stereochemical assignments of compounds 3, 5, 8, and 11 are consistent with coupling constant analysis of the vicinal hydrogens at 300 MHz. For example, the trans stereochemistry in compound 3a was assigned based upon the observed 9.2 Hz coupling constant between the ring of methine hydrogens (determined by series of decoupling experiments), consistent with the trans diaxial relationship: 3a (300 MHz, CDCl,) 6 5.45 ppm (dq, lH, J = 11.0, 6.8 Hz, CH=CHCH,), 5.15 (ddq, lH, J = 9.0, 11.0, 1.7 Hz, CH=CHCH,), 4.83 (dd, lH, J = 4.8, 4.8 Hz, CH(OR),), 4.14 (dd, lH, J = 4.5, 11.2 Hz, ROCtI,(e)CHR), 3.92 (m, 3H, OCH,Cti,O and 0CH2CHZCH), 3.81 (m, 2H, OCH,C&O), 3.40 (m, lH, 0CH2CH2CH), 3.09 (dd, lH, J = 11.1, 11.2 tlz, OCH,(a)CHR), 2.21 (m, lH, CH=CHCH), 1.79 (ddd, ZH, J = 2.9, 4.8, 13.8 Hz, Cli,CH(OR),), 1.7-1.6 (lH, CHCH,CH(OR),) overlapping with 1.61 (dd, 3H, J = 1.7, 6.8 Hz, CH=CH-CHJ), 1.51 (m, 2H, CH2CH,0), and 1.26 (ddd, lH, J = 4.8, 9.7, 13.8 Hz, CH,CH(OR),). 6. a. Brown, J.M. Angew. Chem. Int. Ed. Engl. 1987, 26, 190-203; b. Apsimon, J.W.; Collier, T.L. Tetrahedron 1986, 42, 5157-5254. 7. Takacs,

J.M.; Anderson,

(Received

in USA

L.G.; Madhavan,

8 July

1987)

G.V.B.;

Seely,

F.L. Anqew.

Chem.,

in press.