A formal total synthesis of (±)-pseudomonic acid A

Tcrruhedron

Vol. 36, No 42. PP. 1631-1634, 1995 Elsevier Science Ltd Printed in Great Britain owe-4039/95 $9.50+0.00

Lam,

Pergamon

0040.4039(95)01590-6

A Formal

Total Synthesis

Yvonne

of (+)-Pseudomonic

J. Class and l’hilip

Acid A.

DeShong*

Department of Chemistry and Biochemistry, The University of Maryland, College Park. MD

20742

Abstract: The pyran nucleus pseudomonic acid A has be&n prepared via a furan oxidation strategy. Introduction of the C-8 sidechain (pszudomonic acid numbering) was accomplished reglo- and stereoselectively by either the Johnson variation of the Claisen rearrangement or by Pd-catalyzed allylic displacement.

Pseudomomc gram-positive

C-X (pseudomomc the requisite nucleus

acid A (lj

bacteria.

is a memhcr

1 A key structural

acid numbering).

stereochemistry.*

and a strategy

ot a class of C-glycoside

A variety

Herein

lor C-8 sidechain

antihkotics

feature of this molecule of methods

have been ulih&

we report a furan oxidation introduction

that exhibit

is the pyran nucleus

strategy

lhaI culminaK!s

to prepare for the

with a formal

potent activity

against

at C-5 and

with a-cis-sidechains dihydropyran

derivatives

with

of the pseudomonic

pTep%hOn

total synthesis

acid

of (+)-pseudomonic

acid A. The retrosynthctic Dihydropyran

strategy

to the synthesis

of pseudomonic

acid A is shown in Scheme

1.

2? has been prepared previously by WhikZa and Curran2b. and can be converted to pseudomonk acid A

by cis-hydroxylation previously

scheme for this approach

and sidechain

demonstrated

extension.

that oxidation

that was developed.

the rclalive

The precursor

of furfuryl

alcohol

stereochemistry

to this dihydropyran derivatives

would

be pyranone

4 results in the formation

of Ihe alcohol

functions

3. We have

of pyranones.4

on the sidechain

In the

are of no

consequence since the wreocentcrs will be removed at a later stage of the synthesis (vide infra).

Scheme A 1.S: 1 mixture

of dlastereomeric

furfuryl

alcohols

S.5 Once compounds

F&aand 5b had been separated

(Scheme

of Sa with m-Ct’~A6

2). Reaction

1:1.2 (a$) converted

ratio of 8 resulted to dihydropyran

tram pcracld

2 (LI&

rr$rn).

provided oxidation

1

5 was obtained

by chromatography. a 1,4(a:fi)

from the coupling each furfuryl

ratio of anomeric

trf Sb. E.ach oithc

The resulta 01 experimenls

alcohol

pyranones

dlastereomeric

conducted

of furyllithium

with aldehyde

was subjected 7 in 94%.

pyranones

with sy?i-pyranonc

to oxidation

Similarly,

a

was subsequently 7 will be described

in

de&L &n-pyranone was then

reduced

7 uas meLhylated with I.iAIHf

to afford

methoxypyranone

to give three of the four possihlc

Y as a 2: 1 (a$) allylic

alcohols

mixture IOa-c.

of anomers Regardless

(Scheme

3) that

of the anomeric

or

7632

hi 7 (c&1:4) 0 6

3.

Separate (95%) 1.5:1

5b Scheme

2

C-3 configuration (pseudomonic acid numbering), allylic alcohol 1Oc.with a cls-relationship between the hydroxyl group and the C-5 sidechain, would ultimately be converted by Claisen rearrangement (vide infra) to cis-pyran 2; while nuns-allylic alcohols 1Oa.b would produce the epimer.

OCH3

OCH,

9 (mqz2:l)

\

&Hz

OCH3 ioa

lob

v Trtkwsries

Scheme

J. Cis-series

(1 : 1 : 1)

3

The isomeric nilxmre of allylic alcohols IOa-c was subJectcd10 the Johnson modification of the Cl&en7 rearrangement lo imroduce the C-X sidechain as outlined m Scheme 4. Upon heating with triethyl orthoacetate and propionic acid, alcohols 10 were smoothly converted to an rnseparahle mixture of esters lla-c with retention of the relative configuration from the C-6 position. Tream~ent 01 the ester mixture with TiClq/Et3SiHs reduced the anomeric center as well as removed the silyl protecting group. Oxidation of the resulting alcohols gave a mixture of pyran 2, with cis-sidechains. and epi-2. with substituents in a tmns-relationship. Careful comparison of spectral data with the spectra that pyran 2. Ihe precursor lo pseudomonic acid A, was the minor component furnished by White2a and Curran*b showed _ of the mixture (2: I )

,f)lY& ,GlL OCH3

c(“r$J%_Eto,,~+Y~ +,,,,,,,,Qp--B OCH~

&H,

iOa,b

(2.1)

&H,

Ila,b 1. Et3SaH.

‘Oc

2. I

EtO&

llc

(62%)

+ PCC

(77%)

EtO,C,/.

epi-2 Scheme

TtCl.,

1

(2:l)

2

7633

This series of transformations confirmed thar reduclion of pyranone 7 occurred stereoselectively to afford tramisomers. Accordingly, inllersion of the C-6 stereocenter of the mixture of allylic alcohols 10 should provide pyran 2 as the major adduct after Claisen rearrangement (Scheme 5). Alcohols lOa-c were subjected to Mitsunobu conditions9 to give the allylic benzoates. Saponification of the benzoate esters gave a new mixture of allylic alcohols (lOa,c,d) that by comparison of the 1H NMR spectra was diflerenl Tom the alcohol mixture lOa,b,c prior to Mitsunobu isomerization. Subjection of lOa,c,d to the Claisen rearrangement, reduction. oxidation sequence now afforded cis-pyranone 2 as the major product (2: 1). CA1 c

d“‘“i,

1 2toy3

+ ,f--l;Y-~

OCH,

( 52%;

6CH3 IOC

lOa,b

(yY-=

+

OCHJ

&H3 IOa

IOc,d

(21)

&v&

I

1. Claisen (79%) 2. Et3SiHITiC14(55%) 3. PCC (91%)

EtO&,,,.. epi-2 Scheme

5

In a manner analogous to the syrl-pyranone, cilltc-pyranone 8 was converted to cis-pyran 2 demonstrating that separation of furfury alcohols 5a.b was unnecessary (Scheme 6). oti

OH OTBS

T OCH3

,Gm-

Known

,~;\qs

EtO&,\.o

Cy-r’Y

Methods-

PseudomonicAcidA

1-

5b

OCH3

Scheme 6 While the prcparatnm of cls-pyran 2 consututes a tormal synthesis of pseudomonic acid A. the introduction of the intact C-8 sidechain was not possible usmg the Cl&en approach due to the difficulty in the preparation of the intact sidechain with an orthoester functionality. Alternatively. a IVi-catalyzed approach to the stereoselective introduction of the C-8 sidechain was developed (Scheme 7) An anomeric mixture of cis-syll-allylic benroates 11 was reduced with Et3SiHITiClq according to the method of Gray.8b The resulting benzoate 12 was then allowed to react with the amon of methyl phenylsulfonylacetate in the presence of I’d(dppe)? 10 afford a I I mixture ofdlastcreomeric sulfones 13. Sulfone reduction, silyl ether cleavage, and oxidation of the resulting alcohol afforded dihydropyran 2 and confirmed that the phenylsulfonylacetate anion attacked the rr-ally1 palladium complex with complt~t~ replo- and stcrcoselectivity. ‘2. 13 While the unoptimized yield

7634

of coupling product is low in this case. it is obvious that the I’d-cataJyzed methodology can be employed for the introduction of the intact sidechain at C-8 with high regio- and stereoselectivity.

932 ,

’

ElsSiH TiC&

;‘ym

932 ,c,*y,

PhSO,CH,CO$H, NaH. PWW;;,

c

/.f;‘ym

1. Na(Hg) (64%) 2. HF/H$S.iF~ (99%) 3. PCC (71%) c

2

(20%) c

3

OCH, 11

12

2 Y“ PhOfi 13

Scheme

7

Acknowledgments. We thank Dr. Yiu-Fat I.am and Ms. Caroline Homonnay-Preyer for their assistance in obtaining NMR and mass spectral data. We also thank Professors James White and Dennis Curran for providing spectral data of dihydropyran 2 and related derivauves. The generous financial support of the National Institutes of Health and an unrestricted grant from Lederle Laboratories is acknow,ledged. References

and Notes.

1. Fuller, A.T.; Mellows. G.; Woolford, M.; Banks, ti.T.; Barrow. K.D.; Chain, E.B. hrnrure 1971, 234,416. For a review of the published syntheses of the pseudomomc acids see: Class, Y.J.; DeShong, P. Chem. Rev. 1995. in press. (a) White, J-D.; Theramongkol, P.: Kuroda. C.; Engcbrecht, J.R. J. Org. Chem. 1988,53,5909. (b) Cut-ran, D.P.; Suh. Y.-G. Tetnzhrdron Len 1984. 25.41W. 3. Intermediate 2 has been prepared hy both White*” and Curran2b ’as the methyl ester. This material has been prepared by DeShong as both the methyl and ethyl ester, hut will be referred to as the same compound (2). The spectra1 data for the ethyl ester 2 is analogous to that provided by White and Curran. 4. Shimshock. S.J.: Walternine. RI.; DeShong. P. J. Am. Chrm. Sot. 1991, 113, 8791. 5. (S)-3-Hydroxybutanal 6 can be prepared from an enantioselecuve reduction of ethyl acetoacetatelO or by the stereoselective aldol condensatkm between (R)-2-hydroxy-1.2,2-triphenylethyl acetate and acetaldehyde.l 1 2.

6. Lcfebvrc, Y. Tefrahrdmrr &X 1972, 2. 133. 7. Johnson. W.S.; Werthemann. l,.; Bartlett, W.K.; Brocksom, T.J.; 1.1.T.-T.; Faulkner, D.J.; Peterson, M.R. J. Am. Chrm. Ser. 1970. 92. 14 1. 8. (a) Kursanov, D.N.; Parncs. /.N.; Joim. NM. S~!U~I(,.)I.IIY74. 633-651. (b) Rolf, D.; Gray, G.R. J. Am. Chem. Sot. 1982,104.3539.

Mitsunobu, 0. Synr/tt~.si.r.1981. I. IO. (a) Sih, C.J.; Chcn, C.-S. Aqc!+ C/tern.. lrrf. Ed. Eql. 1984, 23, 570. (b) Noyori. R.; Ohkuma, T.; Kitamura, M.;

9.

Takaya. H.; Sayo, N.; Kumobayashi. H.; Akutagawa. S. J. Am. Chrm. Sot 1987, 109, 5856. 11. (a) Braun, M.; Devant, K. Tefmhedron Lerr. 1984, 2.5.5031. (b) Dtuzgal, T.J.; DeShong, P., unpublished results. 12. Curran and Baer have reported analogous results in Pd-catalyzed processes in carbohydrate derivatives. Baer, H.H.; Hanna, Z.S. Cctn. J. Chrm. 1981.59, 8x9. Curran. LIP.; Suh. Y.-G. Carh. Res. 1987, 171, 161. 13. We have demonstrated that subtle electronic effects in these systemshave a profound effect upon the regioselectivity of the Pd-catalyzed coupling reaction. Additional studies on the regioselectivity of the Pd-catalyzed coupling in pyran derivatives will be reported in due course.

(Received in USA 12 July 1995; uccepted 18 August 1905)