Stereocontrolled synthesis of substituted 2-alkoxytetrahydropyrans from meso-2,4-dimethylglutaric anhydride

Tetrahedron Letters,Vol.23,No.48,pp Printed in C-r-eatBrltarn

4995-4998,1982

0040-4039/82/484995-04$03.00/0 01982 Pergamon Press Ltd.

STEREOCONTROLLED SYNTHESIS OF SUBSTITUTED L-ALKOXYTETRAHYDROPYRANS FROM MESO-2,4_DIMETHYLGLUTARIC ANHYDRIDE

Davrd M. Walba,*' and Michael D

Wand

Department of Chemistry, Box 215, Unlversrty of Colorado Boulder, Colorado 80309

Abstract Methods for effrcrent syntheses of 4-rrng fragments present In monensrn and several of the nlgerlcln group of ionophores and of a-multlstrlatln are described

Monensin and members of the nigerrcan group comprise one of the largest classes of naturally occurrrng monocarboxyllc acad lonophores '

By virtue of their novel and complex

molecular architecture, development of methods for the efficient construction of structural fragments found in these molecules is an area of consrderable current interest 3

Fart

structure 1 illustrates the AB ring system' present in several members of the group, Including monensin, nlgerrcln, and dranemycln (R=CHzOH, R'=CHs), grrsorlxrn and mutalomvcrn (R=R'=CHs), and septamycrn and antlblotlc 6016 (R=CHa, R'=H)

As outlined by the dlsconnectrons shown in

scheme 1, our approach to the total syntheses of members of this class of lonophores4 involves Scheme 1

4

3

use of tetrahvdropyran (THP) derlvatlves of type 2 (R=CHs or CHaOCHaPh) as key lntermedrates containing the elements of the X-rrng approprrately functlonallzed for further manipulation I% a, tails for preparation of THPs of type 2 by sequential addition of two drf,i,es,nthet;c 21-i ferent nucleoph;les to the carbonyl groups of the readaly avarlable meso-2,4-dlmethylglutarlc anhydride (3) '

Stereocontrol at C-6 (numbering as shown for structure 2) would derive from

the expected tnermodynamlc preference for an a-oraented (equatorial) formyl group In 2

We

report herein methods for accomplishment of this goal, which also afford a highly efficrent preparation of the important pheromone constrtuent a-multrstriatln (4) 6 The syntheses are shown in scheme 2 '

Several attempts at direct reaction of various

nucleophrles with arhydrlde 3 fdlled to provrde the desired keto acid

The carbonyl groups

of 3 were therefore dlfferentlated by the well-known methanolvsls reactronda to give half-acrd

4995

4996

Scheme 3

7a)~1(96%) %llv,v(61%)

2*

+_+

,qeQ.tJ$ c) 95%’

@)vu,vI.~I,Ix(~~%) ~b)v1_1,~111,1~(89%)

T!c)v1(97%)

,

IvreOsx/c;i

0 5, Y=OH

0

c6.

8c)x,v111,1x(91%) __ 0 :

Y=CI

48% v

XV1

‘b-Ph

1

~(63%)

CMe

2, ?=Ch? D, Q =CLy2CH2Fb C, F7=Cy2Ck7

1S __

x111(76%) 65% overall from 14 rwlthout purlflc'n-of

12

* 1) MeOH, reflux, 111 (COCl)z, benzene, 111) MegCuLl, 1~) CH2N2, v) PhCH20H, BFI+H, ~1) CH3CH2Cu, ~11) HC(OMe)3, MeOH, ~111) LlAlH,,, 1~) CrOg'2pyr; X) (HOCH2)2, benzene, TsOH, x1) HPyrOTs, MeOH, ~11) Hg12, HgO, aqu THF; x111) MeOH, K2COJ, reflux, XIV) HPyrOTs, THF, xv) Hg(C!N)p, CaC03, aqu. THF, XVI) NaCNBH3, aqu. THF, pH=2-3

ester

5 followed

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ZO

the

4997

Thus, addition of aldehyde _-. 8a to a tetrahydrofuran (THF) solution of llthlothloformaldlne (9) at -lOO"+OoC resulted in formation of adduct $?a In good yield with the expected

problem

Cram's rule dlastereoselectlon (>95% of a single dlastereomer by 13C NMR analysis)

Treatment

of hydroxy-ketal ."_.. 10a with pyrldlnlum tosylate" in dry methanol gives the crystallne THP derlvatlve __-. lla (mp 92-94'C) In 78% o Isolated yield after flash chromatography The stereochemistry of compound . lla at both C-2 and C-6, and therefore that of 10a at C-6 IS unequivocally ..__ __established by single crystal X-ray analysis I2 THP W-W Ila exists In the crystal in a twist boat conformation in which the a-orlented methoxyl substltuent at C-2 enjoys anomerlc stabilization Hydrolysis of the thloacetal function of ___ lla in the presence of the cyclic ketal 1s accomplished by allowlng _..__ lla to react with mercuric iodide and excess mercuric oxide In aqueous THF affording aldehyde 12a Treatment of this material with potassium carbonate In -.__ refluxlng methanol for one hour gives a readily separable mixture of eplmerlc aldehydes 13a VW_ and ___ 12a In a 6 1 ratio The desired aldehyde *__ 13a may be obtained In 58% Isolated yield by Analysis of the lH NMR spectrum of -.-__ 13a suggests it exists in the indicated chair conformation (Js,6=10Hz) The rather dlsappolntlng extent of eplmerlzatlon 1s flash chromatography

presumably a result of loss of anomeric stablllzatlon in THP ___ 13a While compound 5-w 13a IS epimeric with septamycin A-ring fragment 2 (R=CH3) at C-2, W-V 13a represents a useful protected synthon for the septamycin A-ring system since deprotectlon of the ketal moiety will proceed with eplmerizatlon to the thermodynamicallypreferred B-hydroxyl conflguratlon Preparation of the desired monensin A-ring fragment 2 (R=CHzOCHzPh)requires addltlon of a methanol dlanlon equivalent to acid chloride 6 in place of methyl

After several approaches

for direct addition of a benzyloxymethyl group failed to provide ketone WI 7b, the required transformation 1s accomplished in two steps by diazoketone formation followed by flouroborlc acid catalyzed addltlon of benzyl alcohol

Conversion of ketone _7b to hydroxy-ketal ___ lob proceeds In a straightforwardmanner, affording __a lob in 50% overall yield from acid chloride 6 Treatment of hydroxy-ketal _..+_ lob with pyrldlnlum tosylate in methanol gives a single dlastereomerlc cyclic ketal assigned structure WV_ llb by analogy with the cycllzatlon results obtained with VW-_ 10a Removal of the MTF grouping and base catalyzed epimerlzation gives aldehydes -.__ 13b and 0-m 12b In a 3 1 ratio as judged by 'H NMR The poor stereoselctlvltyIn the epimerization and great difficulty In separation of these eplmerlc aldehydes prompted us to search for a Treatment of _...e 10b with pyrldlnlum tosylate in dry THF at reflux for two hours gave the THP derlvatlve _W 14, epimerlc with __ lib at C-2, in good yield None of the eplmer ___ llb was detected In the crude reaction mixture, and -..._ lib treated under ldentl-

more efficient pathway to 2 (R= CHzOCH2Ph)

14, when cal condltlons gave an enol ether resulting from ellmlnatlon of methanol Compound __ 14 1s a kinetic treated with pyrldlnlum tosylate In methanol gave THP ___ lib, lndlcatlng that __ llb IS thermodynamicallyfavored in methanol product of cyclization in THF, while ___ Removal of the MTF grouping of __ 14 under the same condltlons successfully utlllzed for deprotectlon of 11 gave a mixture of aldehyde _I 15 and a blcyclic product resulting from hydrolWV However, this deprotectlon IS efficiently accomplished with mercuric ysls of the methyl ketal The 'H NMR cyanide and calcium carbonate In aqueous THF to cleanly afford aldehyde VI 15 spectrum of _-_ 15 1s best ratlonallzed In terms of the expected chair conformation shown In scheme 2 (J5,6=2Hz)

Given the axial orlentatlon of the formyl group of __ 15, it

was anticipated that

4998

eplmerlzatlon in base would proceed efficiently to the desired a-orlented (equatorial)conflguration Indeed, treatment of aldehyde -_ 15 with catalytic potassium carbonate In refluxlng methanol gives complete epimerlzation within the limits of detectabllity (~2% of 15 at I_ equillbrlum) affording the desired monensin A-ring fragment 2 (R=CHzOCHzPh)in 50% overall yield from hydroxy-ketal $0 The highly stereoselectiveaddltlon of MTF anion 9 to aldehydes 8a and 8b, coupled with __ II the observed deprotectlon of hydroxy-ketals 10a and 10b without eplmerlzatlon suggested an ef-..+_ -__ ficient route to a-multistrlatin utilizing this approach Thus, ethyl ketone 7c was prepared --. by treatment of acid chloride 6 with ethyl copper Interestingly,attempted protection of the ketone grouping of __ 7c as the dlmethyl acetal resulted in eplmerlzatlon of the C-3 methyl However, ethylene ketal formation under standard condltlons proceeded smoothly to give aldehyde-ketal _." 8c after manlpulatlon of the ester function

Addition of MTF anion 9 proce-

eded In a highly stereoselectlvemanner as expected producing hydroxy-ketal lOc, which upon ___ hydrolysis of the thloacetal gave aldehyde 16 in good yield Reduction of the aldehyde functlol _and concomitant hydrolysis of the ethylene ketal unit then afforded cr-multistriatinIn seven steps, and 36% overall yield from acid chloride 6 In conclusion, we have developed efficient methods for stereocontrolledsynthesis of structural fragments found in several lonophores from readily available materials

Also, It

may be noted that, to our knowledge, the route provides the most efficient stereocontrolled preparation of a-multlstrlatln reported to date Acknowledgment

Grateful acknowledgment is made for the support of this work through Public

Health Service Grant HL22778 from the National Heart, Lung, and Blood Institute References and Notes Alfred P Sloan Foundation Fellow, 1982-1984 Dobler, M "Ionophores and their Structures", Wiley-Intersclence New York, 1981. Wierenga, W "The Total Synthesis of Ionophores" In ApSlmon, J "The Total Synthesis of 3) Natural Products" Vol IV, Wiley-Intersclence,New York, 1981, pp 263-351 Walba, D M , Edwards, P D- Tetrihedron Lett 1980, 2, 3531-3534. 4) Allinger, N L J Am. Chem Sot ___.1959, g, 2321236 5) Bartlett, P A Tetrahedron Jg$), 36, 67-68 6) All compounds prepared in this work are racemic All new compounds gave consistant 'H, 7) Yields are of isolated and 13C NMR, IR, and mass spectra, and were homogeneous by TLC marerial or compounds except 83, 1212,1_3b,and 16 8) a) Bartlett, P A , Adams, J L J Am Chem Sot 1980, 102, 337-342 b) Masamune, S , All, S A , Snitman, D L , Garvey, D S Angew Chem"-?Gt Ed Engl 1980, 19, 557-558 c) Murayama, K , Ishlhara, Y , Yamamoto, Y Tetrahedron Lett 1981;"&, 4235-4238 Chen, C S , Fujimoto, Y , Sib, C J J Am Chem Sot !9_82,&"3<80-3582 9) 10) Balanson, R D J Org Chem 1977, 42, 393-394 11) Miyashita, M , Yoshlkoshl, A y"&eco, P A J Org Chem 1217, 42, 3772-3774 12) Full details of the crystal structure determination of compound lla will be reported In We thank Mr R Curtls Haltiw"a;;ger for his invaluable a full paper descrlblng this work assistance with the X-ray crystallography Questions regarding this aspect of our work should be addressed to him at the University of Colorado

1) 2)

(Received

In USA 6 August

1982)