Milbemycin synthesis: synthesis of 6β-hydroxy-3,4-dihydromilbemycin E

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Milbemycin Synthesis: of 6B-Hydruxy-3,4_Dihydromilbemycin

Synthesis

E

Sutia Karim, Emma R. Parmee and Eric J. Thomas* DeprtnmCoCChemislry, University of Manchester, Manchester, Ml3 9F’L. U.K.

The rnilbetnycins biological

and avermeccins

activities.1

The chemistry

have been reported.2+3 However, these compounds,

trimethylsilyll’urans cyclnhexenyl

there remains scope for the development

a Wittig condensation

has been applied to synthesize

milbemycin

bctwecn

approach to the synthesis

to

evaluation. and

are readily availabie by oxidation of 2-

annelation provides a rapid, stereoselective, of the Robinson

of a SR~hydrnxymilhemycin,

of a-milbemycins,

approaches

for biological

an ‘upper fragment’ ylid and a hydroxyhutcnolide,

We now report an extension

and a synthesis

of flexible synthetic

but also to analngues

E (1).4 Hydroxybutenolides

using 102,s and the Robinson

fragment.6 ketones,

interest because of their potent and useful

is being widely studied, ilnd several total syntheses

not only to the natural products themselves,

One approach involves

isopropcnyl

have attracted considerable

uf these compounds

reaction

as a prelude

c.g. (2), and avermcctins,

to include

synthesis of the alkoxymcthyl

to the ayplicalion

together with a significantly

ol’ this itnprovcd

procedure for the aucia1 Wittig coupling.

ref.4

UMc Stirring 3 mixture of furanyl keto-ester containing

aqueous

sodium

hydroxide

(3)4 and henzyloxymethyl

gave the hydroxycyclohexanone

isopropenyl

(6), which precipitated

reaction mixture, and was isolated in 74% yield.8 Reduction using sodium borohydride selectively

(85%), whereas sodium trlacetoxyhorohydride

2269

ketone (5)7 in ethanol out of the

gave the Sn-alcohol 18)

in acetic acid gave the SB-epimer (9) (90%).fi~x The

2270

~imethylsilylfuranyl

keto-ester

required for incorporation Reduction

(4) similarly gave a good yield of adduct (7). This adduct has the functionality

into a milbcmycin

of adduct (7) by sodium triacetoxyborohydridc

excess of retramethylammonium

rriacetoxyborohydridc

(84%). Esterification

using phenylacetic

followed by reduction,

agah

of configuration hydrvxyl

using

was inefficient,

acid followed

tetramethy~amnlo~liulll

hy hydrogenolysis

substituent.

Conventional

procedures

which gave the 5U-alcc>hol (lU) gave diol (ll),s

rrincetoxyborohyctride,

used to convert

and oxidation

effected the required inversion

via intramolecular

were

at C(6).

but could be achieved using an

in acetic acid-acetonitrile

at C(6), giving the dial (12) stereosclcctively

n-imethylsilylethyl epimes,

synthesis, however requires an inversion of configuration

dclivcry af hydride hy the 7dial

(IZ)

ester (14), which was oxidized using ‘102 to provide hydroxybutenolide

into

the protcctcd

(15), as a mixture of

in 88% yield.

pgyBno-pic (3) X = H (4) X = SiMe,

;s;

i_

ii_

$zJFJy OH (9) X = H (10) X = SiMeR

(5) (6) x 1 H” (7) X = SiMu3

3

()

vii - ix

()Hq02Et

TMS

v, vi -,

%-II0 0 tI2)

(13)

0 Y

Ph

x, xi

I xii

OMe (141 (K = CH,CH,SiMe,) Scheme 1. Reagents: i, NaOH, 20 “C [(6) 74% (7) SO%]; ii, for (6), NaBH(OAc13 M~$IBH(OAC)~

(34%); iii, PhCH,CO$I,

DMSO, Et,W (95%); vi, Me4NBH(OAc)3

(95%); vii, SEMCI, PrYNEt (91%); viii, K,CO,,

ix, AgzO, Me1 (62%); x, NaOH, EtOH (39%); xi, Me,SiCH,CH,OH, hv, CH,Cl,,

EtOH (87%);

DCC, DMAP (X0%); xii, &, TPP,

MeOH (88%).

The Wittig condensation adding a solution anhydrous

(90%), for (7),

DCC, DMAP (85%); iv, H,, Pd/C, EtOlI [Yl%); v, (COClb,

oflithium

tetrahydrofuran

between hydroxybulenolide

[15) and phosphonium

salt (16)4 was carried uut by

hexamethyldisilazide

to a solution of the hyclroxybutenolide

at -78 UC1lullowed

by warming to -10 *C. This procedure

presence of the aldehyde derived from the hydroxybutcnolide,

and phosphonium generated

and was found to give consistently

salt in

the ylid in the better yields

227 1.

i iii PPh3+1- OSiBuLMez (16)

(17)/(1s)

VIZ(19)/(20)

R’ = SEM R2 = CH,CH,SiMe, R’ = II R2 = CHZCH2SiMe3

+ diastcreoisorncr f.22)

iv G

(23)/(24) R1 = SiEu’Me, (25)/(26)

R2 = CH,CII,SiMe,

R’ = R2 = H

ClMe Scheme 2. Reagents:

of (17)/(18)

i, (lS),

from (Is)];

3LiN(SiMe,),, ‘I’HF, -78 to -10 OC; ii, CI-l,N,; iii, I, (cat.), benzene [60% iv, Eu,NF. THF [99% of (21)/(22), 7X% of (253/(26)J; v, 12, hu, benzene [92%

of (19)/(2(I)]; vi, silica, CHCl, (98%); vii, DCC, DMAP [4h% from (25)j; viii, DIBAL, (74%). than if the ylid was generated diaznmethane

separately4

The mixture of products

and with a trace of iodine in benzene

from the Wittig reactivn

was trcatcd with

to give the (FE’) dienyl esters (17) and (18), as a I : I

mixture in n yield of 60% from the hydmxybutenot’de.~

Dcprvtection cyclize

using tetrabutylammonium

this mixture,

e.g. using DCC/DMAP,

fluvride

gave the hydroxy

were unsuccessful,

acids (21) and (22), but attempts

only complex

obtained from which none of the desired macrolide could be isolated. However, could be removed

from the Wittig products

sunlitmp. This procedure

(17)/(18) by treatment

left the other silyl protecting

mixtures

being

it was found that the SEM ether

with one mole equivalent

groups unchanged,

of products

to

of iodine under a

and gave the 6-hydroxy-compvunds

(193 and (20) in a 92% yield. Stirring a solution vf these dials in chloroform

containing

a suspension

of silica

2272

induced

and gave an excellent yield of y.lnctones

lacmnimtinn

ammonium

fluoride gave the seco-acids

of this mixrure was carried our using DCC/DMAP

Macrolactonization milbemycin

using temburyl-

following

rhe procedure

used in the

E synthesis4 and gave a single macrolide identified as (27) on the basis of its spectroscopic

selective cyclirarion

of the required diastereoisomer

and (26) has precedent,‘* the unnatural

and is due to transannular

diastereoisomer.

dihydromilbemycin its spectroscopic

Reduction

in a mixture uf diastereoisomers interactions

01. lactone

(27) using DIBAL

a synthesis

include alkoxymethyl

a procedure

of milbemycin isnpropenyl

the Z-(trimethylsilyl)ethyl

E (1) and its 3,4-dihydro

[ourthe synthesis

(25)

required for cyclization

in toluene

gave

(15),g identified

of

6!3-hydroxy-3,4-

by comparison

of

derivative.4

of GR-hydroxymilbemycins

G (2). Of general interest is the extension

which is being applied to

of the Robinson

ketones, the selective removal of the SEM protecting

ester and TBDMS groups, and the effect of the 6Bsubstituent

ACKOWLEDGEMENTS.

data. The

analogous to seco-acids

in the conformarion

E (28) in good overall yield from the hydroxybutenolide data with those of milbemycin

This work establishes complete

(23) and (24). neprotection

(25) and (26).

procedure

to

group in the presence of on macrolactonization.

We thank Rh8ne I’oulenc Korer and the SERC for studentships

(to S.K. and B.K.P.).

KEFERENCES AND NOTES 1. Davies, H. Cr.:Green, R. H., Nat. Prod. Rrp., 1986,3, 87. 2. Schow, S. R.; Bloom, J. D.; Thompson, A. S.: Winzenberg, K. N.; Smith, III, A. B., 1. Am. Chew. SCX.,1986,108, 26662; Williams, D. R.; Bamer, R. A,; Nishitani, K.: Phillips, J. C., .1.Am. Chem. SLY., 1982, 104, 4708: Barrett, A. G. M.; Car-r,R. A. R.; Atwood, S. V.: Richardson, G.; Walshc, N. D. A., J. Org. Chcn., 1986,51,4840; Kocienski, P. J.; Street, S. D. A.; Yeares, C.; Campbell, S. F., J. Chem. Sac., Perkin Trans. I, 1987,2171; B&r, R.; O’Mahony, M. J.: Swain, C. J., J. Chem.. Snc. Perkin Tr~ns. I, 1987, 1623; Crimmins, M. T.; Bankaitis-Davis, D. M.: Hollis, Jr., W. G+.J. Org. Chem., 1988.53, 6.52: Ley, S. V.; Anrhony, N. J.; Armstrong, A.: Brasca, M. G.; Clarke, T.; Culshaw, D.; Greek, C.; Gricc, P.: Jones, A. Ft.; Lygo, B.: Madin, A.: Sheppard, R. N.; Slawin, A. M. 2.; Williams, D. J., Tetrahedron, 1989,4.5, 7161. 3. Hanessian, S.; Ugolini, A.; Hodges, P. 1.; Beaulieu, P.: Dub-e,D.: Andre, C., Pure A&. Chem., 1987, -59, 299; Danishefsky, S. 5.: Armistcad, D. M.: Wincott, F. E.; Selnick, H. G.; Hungatc, R., J. Am. Chcm. SOL, 1989, 7II, 2967; White, J. D.; Bolton, G. L., J. Am. Chcm. Sot.. 1990, 112, 16%; Armstrong, A.: Ley. S. V.: Madin, A.; Mukkcrjcc, S., .?ynletl, 1990, 328. 4. Parmee. E. R.; Steel, P. G.; Thomas, E. J., .I. Chem. &I:., Chem. C<>mmurr., 1989, 1250. 5. Katsumura, S.: Hori, K.: Fujiwara, S.: Ism. S.. ‘/errtJhPdron I-err., 1985,26, 4625. 6. Turnbull. M. D.: Hauer. G.: Lcdeerwond. D. E.. TerrLrh&r,n Leff.. 1984.25. 5449. 7. Suzuki, s.; O&hi, T.; ‘Fujita, Yy; Orera; J.. Syirh. Cammun.. 19& 75: 1i23. 8. This reaction was found tu bc Scnsitivc to snlvenl; for crampIe in a SO:50mixture of ethanol and dichloromethane, (i) and (ii) togelhcr with the open chain intetmediales (iii) were isolated m addition to (6). The structures of lhe Robinson products, and the reduction products obtained from them, were cstablish~~lby cxbnsivc n.nr.r. studies. Wails will be givcu in a full papr.

[iii)

6

The wnrk in this r)aper involved the use of racemic Robinson annelation prductq, and hence gave the mixture of Wittig products. However resolution dfrhedial [lo) has been achieved by esterification usingI~)-acetoxymandclic: acd to give {iv) and (v), and sclcctivc crystaIli7ationof the required diaskrrnisomcr (;v). Hydrogenation or the acetoxymandelates proceeds with cnncomitant hydrogenolysis of both rhe benzyl ether and lhe acetoxy group to give the hydroxyphenylacetate (11).

9.

10. Hughes. M. J.: (Received

Thomas, E.

J.; Turnbull, M. D.; Jones, R. H.; Warner, R. E., J. Chcm. Sac., Chcm. Cummun., 1985, 755.

in UK 11 Febrtrary

1991)