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TETRAHEDRONLETTERS

T L ( 1

D iS

A A ( A EC P

PedrodeArmas,* * FernandoGarcfa-~elli@o,*‘*J os4

J . Marrero-Tellqdo,5uanaAbl:s $

tI P N yA . S

lnvestigacionesCientfficas.‘lttstituto Univemittuiode Bicqgdnica “Antonio

Gmrdtez,” Universidadde 1ALagutta,.AstmffaicmFranciscoSdnchez3,

382~ ~ ~gum Tenerife,S@n.

Received15September1997;revised23October1997;accepted24October1997Abs!mct:A formaltotal synthesisof (+)-preussinwasachievedby usingD

mannoseas the startingmaterial. The key step involveddiasteremelectiveadditionofailyltrimethylsilaneo [email protected] nghti reserved.

The potentantifungalantibiotic(+)%ewsin (L-675S%3)1, has ban isolatedfromthe microorganismsPreussiasp andAspergit’fuschraceusATCC 22947.’

Due to its interestingactivities,to the best of ‘durknowledgesix total syntheses of 1 havebeendescribed.zThesestrategiesemploydifferentproceduresfor the installationof theRcotilgurationof theC5nonylsidechain.

Herewedescribea diastereoselectiveormalsynthesisof (+)-preussin.Our syntheticstrategyis outlinedin Scheme1.

4 3..’

T

l

,

.

T

o

,5,.. .,, * “ m “ e

n~19° N “, nqH,9,.’” “o,,.,

“%,,N

*N

~ IJ

I& W5

1 2 4 ‘

5 6

Thekeystep,is theLewisscid-pmmotedadditionoftdlykrimethylsihuteo thebicyclicketal5 to introducethecorrectRccdgmation atC5.

Severalauthon$%ave shown that undercertainconditionsthe stereochemicalcourseof the Lewis acid-aided reactionsof acuttdwith nucleophileis an SN2 like displacement.Also, compound5 incorporatetherequiredC2, C3 stereochemistryfor 1,whichare transfereefromD-mannose.

Our synthesis, commencedwith that of the epoxide 6 (Scheme2).This was readly obtained from

commerciallyavailable l,2:3Sdi@isopropylidene-ct-D-mannofuranosenW%overallyield. The ringopeningsof epoxide 6 with PhMgCl, catalized by CUI, gave the secondmy alcohol 7. Conversion to the

0040-4039/98/$19.001997ElsevierScienceLtd.Allrightsreserved.PI]:SO040-4039(97)1468-3

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trifluommethanesulphonateester, followed by treatmentwith sodium azide in dimethylformamide,gave theinverted azide8. Reductionof8 andbenzyloxy-cdronylationgavethecarbamate9. Thecyclic”derivative5 wasobtainedin goodyield(67%, 2 steps)by removalof the anomericprotectinggroupand ioniccyclization’of 10promotedbyPhIO/12.

75%

f

LPAY’ *“ A ““””

‘W”

9

10 5

8cbeme 2: (a) PhMgCl,CUI,(10 mol%),THF, -30 ‘C,3h; (b) (CF,SO,)Q PY,CHQ N,, -~ “C.lh;(c) NaN,, DMF,N,, rt, lh; (d) LiAlH4,THF,O“C-vt, lh; (e)CICO,Bn,PY.DMAP,O“C-WI,16h; (f) DDQ,CI-JC12:HZ0,19:1,N,, rt, 2h; (g) PhIO(3mmol),12,(1mmol),CH2Cl,(wet),rt, 2h.

At thisstagewewerereadytoexplorethestereoseectivityin theadditionreactionof allyknmethylsilaneto

the ketal5 (Eq l).(Eq 1)

-+’-

-l?:+.Ii?l- 1) ‘(4 mmol)

.- ~

02)TBDMSWf

N*

I& c

5 3a R=H 3b4a R=TBDMS 4b

LewisAcid ReactionConditions Yield(DSRatio)

(2mmol)BF,.O~- CHZC1,,78“C/5min,rt/50min 62%(>95:5)

(2mmol)BF,.OE~MSOTf CH,C12,78‘C/5min,rt/50min 92%(70:30)

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133

Thus, tmatmen?of 5 withdlyltiknsdiylsiianen tbEpresenceof BF,.0~.,gsve 3t@b in good yield(65%)inaratio>95:5. WithacombinationofBF3.0~/IlkfSOTfa3mb~xtum was obtainedin92%yieldbutthedim@r@de@“vity_ to7030.

Tk stmoch&istry of themajorstcmoisopmrwqs qnambiguoudydeterminedromthe ‘H-’Hccmpling

constant inpmticularHC2-HC3appearasbroadsingletg 4 NO=Y ee~tiThecarbonbondchainwas extendedby @dStiV@ CkWil# Ofthe aik&Ktud &XlWlttige of *

resultingaldahydeandhydropabon gave2 in41%overallyieidfrom4a.

4ts

G

12 2

MeOH,’L45min; (b)FhCOCl,PY,rt, 16h; (c) i. 0s04, MNO,H@cheme 3: (a)NaCO,,‘BuOH;ii. H20, NaIO&EtOH,rt,(41%from4@

Me@(d) I. CH3(CF$)J~I-,. B&i, ~, -7s”C, IO:&n;ii. 10%Pd/C,-H2(Iatm),

In summary, we have described a disstemomective formxl synthesis of (+)-l%eussin,using a

stemommtdd +@tiO!l of the biCyCliC ketdS.This pcedure maybe extendedto thesyntbodaafdifferentchiralpyrrolidines.Furthtwwork is in

progressto studythescopeand limMionof theallylatkmreacdonas ,weilas t thesyythesisof Rowpyrmlidineandpyfrdizidineantibioticaaalqps.

Aekmewlsd@mse- This*ork wassuppmtedby theSpanishIXHCYT(PB9MW28. JRcthankshe

la f~a ~1 fd~wship.

Refemmces ad Nutas.

1.

2

3

4

5

(a) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L; Honycutt, S.; Garrity, G.; Fromtling,R. A.;OnishiJ.; Monaghan,R..f.Anfibiof.198S,41, 1774.(b) Johnson,J. H.; Phillipson,D.W.; KaMe,A. D.J. Antibiot. 1989,42, 11S4.(a) Pak,C. S., Lee,G.H.J. Org. Chem.1991,56, 112S.(b) Shimazaki,M.;OkazakI, F.; Nakajima,F.

Ishikawa,T.;Ohta,A.Heterocycles 1993,36, 1S23.(c)McGrane,P. L.;Livinghouse,T. J. Am.Chem.

Soc. 1993, 115, 114S5.(d)Overhand,M.;Hecht,S. M. J. Org.Chem.1994, 59, 4721. (e) Deng,W.;Overman,L. E. Y. Am. Chem.Soc. 1994, 116, 11241. (f) Yoda, H.; YamazakI,M.; Takabe,K,

Tetrahedron:Asymmetry 19%, 7,374.

(a)Denmark,S. E.;WiI1son,T, M.J.Am.Soc. 19S9,1113475. (b) Denmark,S. E.;Henke,E.;Weher,E. J. Am. Chem.SW. 1987, 109, 2512. (c) Demnadc,S. E.;Willson,T. M.Selectivitiesin LewisAcidPromotedReucfions,D. SchinzerEd.;KluwerAcademicPublishers:Boston,19S9,247.(a)Choi,V.M.F.;Elliott,J.D.;Johnson,W.S. TetrahedronLett.19S4,25,591. (b)Mori,A.; Ishihara,K.; Arai,L; Yamamoto,H. Tetrahdon 1987, 43, 755. (c) Matsutani,H.; Ichikawa,S.; Yaruva,L;

Kusumoto,T.; Hiyama,T. Y.Am. SOC.1997, 119,454Huynh,C.;Boumechal,F.D.;Linstrumelle,G.TetrahedronLett.1979, 17, 1503.

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6 Procedure for the synthesisof5: a solutionofcompound10(452m 1 m w CH,C12(35ml)containingiodosylbenzene (723 mg, 3.3 mmol)and iodine (278 mg, 1.1 mmol) was stirred at roomtemperaturefor4 h. The reactionmixturewas then pouredintowaterandextractedwith dictdommethane.The organiclayerwas washedwith aqueoussodiumthioaulfateandwater. Concentrationand purification

by flashchromatographyn-hexanelethylacetate 8:2 v/v)gave5 (353mg, 78%)as a colorless oil. [a].+36.76°(CHCIJ);IR (CHCIJ)1725cm”’;‘HNMR(CDCl~,200Mhz) 1.3 (3H, s), 1.4(3H, s), 2.8 (2H,dd, J 13.8,9.8 Hz), 4.27 (lH, dd, J 4.8, 2.6 Hz), 4.5 (lH, q, J 4.9 Hz), 5.03 (lH, m), 5.26 (2H, dd, J16.2Hz), 5.78 (Ih, d, J 4.8 Hz), 7.25 (1OH,m), 8.06 (lH, s). “C NMR26.45, 27.37, 32.98, 60.51,67.26, 74.90, 79.90, 89.02, 112.85, 126.74, 128.70, 129.33, 136.25, 137.10, 154.80, 159.47HRMSc f (C23HZ5QN)M+)411.1681,found411.1664.

7 (a) For a mechanisticdiscussionsee. de Armas, P.; Garcia-Tellado,F.; Marrero-Tellado,J.; Robles, J.TetrahedronLeft.1997,in press.In thepresentcase theoxidationto oxoniumion is favouredby changingbenzeneforwet dichloromethane,whichis capturedby an internalnucleophile.(b) Duringthemanuscriptpreparationwe had knowledgeof Prof. Suarez’preliminaryresults in the synthesisof azasugamusing asimilarprocedure.

8 Procedurefor the synthesisof4a: a solutionof5 (2@5mg,0.63mmol)a a ( m 5

m inCHzCl~7ml) in a dry flask underan argonatmosphere.The mixturewas cooledto -78°C,andBF,.Et,O (0.16 ml, 1.26mmol)was slowlyadded.After5min, the coolingbathwas removed,and themixturewasstirredfor 50min.The organicphasewaswashedoncewith saturatedNaHCOqand oncewithwater and dried over MgSOa.Concentrationand purificationby flash chromatography(n-hexane/ethylacetate7:3 v/v)gavean insepamblemixtureof 3a and3b (135mg, 6270yield).TBSOTf(0.21 ml, 0.9mmol)was addedto a solutionof the mixture3a,b (135mg,0.34 mmol)and Py (O.17ml, 1.4 mmol)atO°Candthe resultingmixturewasstirredat O°Cfor 15minand then warmedto rt.Themixturewas cooledbackto O“Cand pouredintocold sat. aq. NaHCO~.Theseparatedaqueouslayerwas extractedwithether.Concentrationand purificationby flash chromatography(benzeneh-hexane7:3 v/v) gave4a (130.3mg,>95~0)as a lesspolarproductand4b (4.7mg,<5%)as a morepolarproduct.4a: colorless oil [a] ~=+16.13°(CHCQ; IR (CHC1,)1725,1690cm’; ‘H NMR(CDCI,)0.03 (3H, S),0.04 (3H, S),0.82 (9H, S),2.54 (2H, m), 2.78 (2H, dd, J 10.3, 13.5Hz), 3.81 (lH, m), 4.07 (lH, br s), 4.49 (lH, m). 4.91 (IH,

dd, J 3.5, 6.1 Hz), 5.05 (2H, m), 5.14 (2H, d, J 11.7 Hz), 5.76 (lH, m), 7.19-7.35 (20H, m), 7.92(lH,s); “C NMR -3.89, -4.32, 18.38,26.20,36.00,37.23, 60.90, 65.%, 67.65, 76.09, 78.26, 118.47,118.56, 126.99, 128.41, 128.62, 128.98, 129.11, 129.65, 134.89, 138.58, 156.41, 159.95, 160.02,HMRScalcd for CwHwO~NSi(M+-CH2CHCH2)]468.2206,found468.2244.

9 (a)Bemardi,A.;Micheli,F.; Potenza,D.; Scolastico,C.;Villa, R. Tetruhedrrmett. 1990, 31, 4949. (

Thaning,M.; Wistrand,L. J. Org.Chem.1990,55, 1406.

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