Polyene synthesis: A comparative study

Tetrahedron Letters,Vo1.26,No.40,pp Printed in Great Britain

POLYENE

SYNTHESIS:

J. Michael

oo40-4039/85 $3.00 + .OO 01985 Peraamon Press Ltd.

4891-4894,1985

A COMPARATIVE

Williams

STUDY

and Glenn J. McGarvey*

Department of Chemistry, University of Virginia Charlottesville, Virginia 22901 As part of an effort to synthesize the polyene macrolide antibiotics, a comparison of several methods of polyene synthesis has been carried out with the finding that superior results were obtained using the Wollenberg vinyl ether method.

ABSTRACT:

The polyene macrolide possess

Common

c0ses.l defined

antibiotics

potent fungicidal

activity

to all members

hydrophilic

are a structurally

(polyene)

As part of an effort to develop

1.).

class of compounds

in the treatment

of this class is a macrocyclic

(polyol) and hydrophobic

tericin B (Figure

complex

which has been exploited

structure

regions,

featuring

as illustrated

a general

synthetic

that

of human myclearly

by ampho-

strategy

to the

Amphoferlcln B

Figure polyene macrolide

flexible

the variation

survey of available applied

allylic

asymmetry

to allow preparation

accommodate

we required

antibiotics,*

enough to tolerate

to the synthetic

a method

and sensitive

of chromophores

found within

olefination

(EtO),PCH,(CH=CH),CO,Et

Route A.

The strategy

intact polyene

by the condensation

strategy

instability

of intermediates

sired trienyl Following

reaction

of a vinyl organometallic stannyl

(Figure 2.). Unfortunately,

condensation

all attempts

en route to 3.

ester 5 contaminated

salt 4 was targeted to execute

Representative

amounts

of the

to result in the C19to implement

of the problems

this by the

encountered,

acrolein 5 4 led to the de-

of ethyl benzoate

compound 5 was observed

A891

insertion

double bond followed

this plan were frustrated

1 (n=l)" with stannyl

with substantial

purification,

as a convergent

to form the C32-C33

species with an aldehyde

phosphonium

of the anion of phosphonate

chromatographic

3

by route A was envisioned

an olefination

With this in mind,

C20 bond.

Eu,Sn(CH=CH),OEt

CH,(CH=CH)“C=NNMe,

depicted

a preliminary

on reagents 1 - 2 as

1.

2

unit through

that was mild

Following

our attention

in Figure

I

polyenes

as well as sufficiently

ranging from four to seven double bonds to

we focused

outlined

9

of preparing

functionality,

this class of compounds.

methods,

approaches

1.

(Figure 2.).

to quantitatively

convert

4892

mSnB”, Ph,F 4 I

to ethyl benzoate through

upon storing at room temperature.

electrocyclic

Route B.

ring closure

followed

This transformation

by aromatization

probably

occurs

via loss of nBu3SnH.5

In an effort to minimize problems due to the handling of unstable intermediates,

more linear approach of Brooks and Kellogg sequence

was adopted

in the study of this route.

using a reagent of type _l_(n=l),2b

to the desired

polyene aldehyde.

To increase

we sought to reduce the number of iterations (n=2).3

A model olefination

Although

the desired

sequence

hexanenyl

required

was carried

species

Given the preliminary

a

results

we chose to explore a Wittig-Horner the overall

through

out using

could be obtained,

efficiency

of the route,

the use of phosphonate

isobutyraldehyde

-1

in Figure 3.

the overall yield was disappoint-

ingly low.

2.

WEAL.

PhMe,

-78’

MexCHO

CO,Et

Figure 3.

In an effort to streamline this sequence through a reduction in the number of required manipulations, aldehyde

we examined

oxidation

hydrazones as a model,

reagents which would afford

state directly.

as introduced

..x,

With this in mind, the utility

by Corey and co-workers

was investigated.6

the lithium anion of the reagent derived

densed to afford 7 (Figure 4.).

unsaturated

Unfortunately,

carbonyl

of metalated Using

from sorbaldehyde

numerous

attempts

compounds

-

!! Figure 4. of 1 to trienal 8 resulted

in the formation

of complex mixtures

smoothly

con-

the conversion

-NM.% LI

rn.-cno

N,N-dimethyl-

isobutyraldehyde

(&n=Z)

to effect

in the

of products.7

4893

These disappointing Wollenberg

results

led us to turn our attention

(3,n=2), which has been shown to effect

reagent

has only rarely been applied

limited

use in the preparation

lithium

salt derived

(THF,-78°C) dienal

of aldehydes

possessing

from 3(n=2) via transmetalation'

10 was obtained

cleanly

exposure

twice conveniently

approach

is the ready availability possessing

To demonstrate

sequence

as a single

the dienal

isomer

is applied

total synthesis

to the protected

adduct

route to produce

THF

produced

a single

to the attractiveness

of this

propionate

provided

(IH and 13C NMR),13

of amphotericin

(cat.) in aqueous

for polyene macrolide

key intermediate

to the sensitive

The desired

the preparation

of

double bonds.

of this strategy

the desired

now have in hand a reliable

to TsOH

The

with isobutyraldehyde (SiOz),

of the reagent 2(2=1), I1 thus allowing

the viability

As indicated,

Figure 5.).

Adding

overall yield.

an odd number of conjugated

plied this olefination

condensed

isomer following

and has seen

conjugation.g

purification

of this sequence

by

To date, this

compounds

highly extended

Repetition

aldehyde -11 in respectable

polyolefins

carbonyl

as a single

hexaenyl

introduced

homologations.'

complex

to give 2 as ai oil stable to chromatographic

at ro0mtemperature.l'

yield

similar

to structurally

to a reagent

synthesis,

region of amphotericin

-13 was obtained

the Corey modification

of 13 suitable

B(1212,

in very good overall

in the first iteration.ga3b quantities

we ap-

for unmasking As a result, we

for completion

of the

B.14 OEt

I. Li-

OMEM

Me.,,,

THF, -7w

2. MsCI. NE+,, CH,CI,. TBSO

,‘%Me

-43* OEt

I. Li-

THF, -7B” w

4 Me”‘”

CHO

2. TsOH. $0.

12

THF, Oe

I. LIWOE’ 2.

THF, -78’

TrOH. \O,

-I3

THF, O”

(48%

overall

)

Figure 5. In this comparative polyolefinic

aldehydes,

study on the relative

ether methodology

to be the most promising

The incorporation

of this strategy

well as other highly unsaturated Acknowledgement

merits

we have found an iterative

is made to the National

of preparing

products, Institutes

unbranched

based upon the Wollenberg

in terms of generality

in the synthesis

natural

of methods

strategy

vinyl

and ease of operation.

of the polyene macrolide will be reported

antibiotics,

as

in due course,

of Health for their generous

support

of

this work. References 1.

and Notes --

For general see:

reviews on the chemistry

(a) Hamilton-Miller,

"Polyene Antibiotics-Present Hammond, 2.

(b)

in this area:

Brooks,

z., B

Chem. Commun. --

(1982),

* Viti, S. M. 2. m.

D:'S. J_. &.

m.

Lett.

g.

antibiotics

(9) Tereshin,

of Tokyo Press,

R. P. Tetrahedron

(1982), 5307. (e)

(1982), 104,

(d)

E.

1976, Japan.

5521.

1378. (g)

(1982), 4991.

Nicolaou,

Ma, P.; Martin,

(1982), 5,

I. M. (c)

105.

(a) Floyd, D. M.; Fritz, A. W. Tetrahedron

1292.

Chem.

of the polyene macrolide

(1973), 37, 166.

University

(1977), 3,

D. W.; Kellogg,

M .; Vei, M. Tetrahedron

Rev.

and Future,"

S. M. Prog. -Med. Chem.

For other studies 2847.

and biology

J, M. T. m.

K. C.; Uenishi,

V. S.; Masamune

(f) Masamune, Masamune,

Lett. (c)

(1981), Hirama,

J. 2. Chem.

S.; Sharpless,

S.; Kaiho, T.; Garvey,

S.; Choy, W. Aldrichim.

Acta

K.

4894

(1982), 3,

47.

(i) Masamune, 49, 2834. (1984),

(h)

Lipshutz,

B. H.; Kozlowski,

S.; Ma, P.; Okumoto,

(j)

1123.

H.; Ellingboe,

(k)

Blanchette,

S.; Roush, W. R.; Sakai, T. Tetrahedron

Wadworth,

Jr., W. S. m.

4.

Prepared

5.

React.

from propargyl

For related

alcohol

PCC, CH2C12, aromatization

(1965), 30, 2218,

(b)

(1984), 2, Chem.

B. J. Chem. a.,

Lett.

1147.

(1984),

Chem. Commun. --

M. A.; Choy, W.; Davis, J. T.; Essenfeld,

Masamune,

ii.

a.

J. W.; Ito, Y. -J. u.

Liang, D.; Pauls, H. W.; Fraser-Reid,

3.

(cat.),

J. A. 2. m.

A. P.;

(1984), 2183.

(1977), 25, 73. in two steps and 54% overall yield:

i.

HSnBuB,

AIBN

RT. reactions

see:

(a)

Byers, J. 2. Q.

Spangler,

3.

C.; Woods, G. G. J, a.

(1983), 3,

1515,and

Chem.

references

cited

therein. 6.

Corey,

E. J.; Enders,

E. J.; Enders,

D.; Bock, M, G. Tetrahedron

D. Tetrahedron

Lett.

(1976), 7.

See also:

Corey,

Lett. (1976), 3, 11.

7.

In our hands, the best conditions for unmasking trienal g was through treatment of

8.

Wollenberg,

R. H. Tetrahedron

(a)

E. J.; Clark, D. A.; Goto, G.; Marfat,

hydrazone 1 with BF3*OEt2/CH2ClZ

9.

Corey,

HammarstrSm,

at 0°C to give a 5-10% yield

Lett.

S. ---J. Am. Chem. Sot. (1980), 102,

Goto, G. 2. --Am. Chem. Sot. (1980), 102,

6607.

van der Gen, A. --Rec. Trav. Chim. &-bas 10.

Dienals

such as -10 are useful For an alternative

actions.

Sot. (1980), 102, 11.

Wollenberg,

12.

Full experimental

13.

The all trans geometry

details

precursors

A.; Mioskowski,

1436. (c)

(b)

Corey,

C.; Samuelsson, E. J.; Marfat,

de Witt, P. P.; Van Schaik,

(1984), 103,

B.;

A.; T. A. M.;

369.

to substrates

three step synthesis

K. F.; Peries,

will be reported

was assigned

resolved

Hz) and the partially

vinylic

resolved

0.05 (s,3H), 0.85 (d,J=7.0

for intramolecular

of -10 see:

Diels-Alder

re-

Roush, W. R. 2. -Am. Chem.

protons

lH), 4.70 (d,J=7.5

Hz, lH),

6.72 (dd,J=lO.O,

7365.

shortly.

to -13 based upon the magnitude

spectrum

Hz,3H),

R. 2. &n. -Chem. Sot. (1977), 2,

in the dienyl

and tetraenyl

of the J values precursors

for

(J's=9-16

for -1312: 'H NMR (CDC13, 360 MHz) 6 0.02 (s,3H),

0.92 (s,9H),

1.04 (d,J=6.9 Hz,3H),

3H), 1.90 (m,lH), 2.46 (m,lH), 3.40 (s,3H), 3.50-3.60

6.60(m,9H),

product.

1390.

R. H.; Albizati,

the completely

of the desired

(1978), 717.

4075 (d,J=7.5 14.3 Hz, lH),

Hz,lH),

5.82

1.08 (d,J=6.2

(m,3H), 3.69 (m,ZH), (dd,J=7.9,

7014 (dd, J=11.3,

15.5

Hz,

3.90 (m,

Hz, lH), 6.05-

15.1 Hz, lH), 9.56 (d,

J=7.9 Hz, 1H). 14.

Compound

-13 may serve as a substrate

by Masamune, LReceived

Rousch in

USA

and co-workers.2k 1 July

1985)

for a mild olefination

procedure

recently

reported