Synthesis ofC-glycosyl compounds. Part 2. Reactions of aldonic acid lactones with ethyl isocyanoacetate

摘要

2236 J.C.S. Perkin ISynthesis of C-Glycosyl Compounds. Part 2. lt2 Reactions of AldonicAcid Lactones with Ethyl lsocyanoacetateBy Richard H. Hall," Karl Bischofberger, Stephen J. Eitelman, and Amor Jordaan, National ChemicalResearch Laboratory, Council for Scientific and Industrial Research, P.O. Box 395, Pretoria 0001, Republic ofSouth Africa2.3 : 5,6-Di-~-isopropyl~dene-~-mannono-l,4-lactone reacted with ethyl isocyanoacetate and 1,5-diazabicycIo-4.3.0non-5-ene (DBN) to give ethyl 5-(1S)-1,2 : 4,5-di-O-isopropylidene-~-arabinitol-l -yloxazole-4-carb-oxylate (1 ), in contrast with the products, ( E ) - and (Z)-ethyl 3,6-anhydro-2-deoxy-2-formylamino-4,5 : 7.8-di-0-~sopropylidene-D-rnanno-oct-2-enonate, obtained when potassium hydride was used as the base.Similarly,2.3 : 5,6-di-O-isopropylidene-~-allono-l,4-lactone gave the oxazole (9) and the oct-2-enonates (15) and (1 6).respectively, when DBN and potassium hydride were used as the base. With DBN as the base, 2,3-O-isopropyli-dene-4-O-methyl-~-rhamnono-l,5-lactone (20) gave the oxazole (21 ) in low yield, and with potassium hydrideas the base both the oxazole (21) and an oct-2-enonate (23) were obtained in low yield. The reaction with 2,3,4,6-tetra-O-benzyl-D-glucono-1.5-lactone and with potassium hydride as the base gave the oxazole (27) as the majorproduct but no oct-2-enonates. With DBN as the base, elimination occurred and only the unsaturated lactone (24)was identified . S i m i I a r I y, 5,6 - d i - 0 - i so p ro p y I id e n e - 2,3 - d i - 0 - met h y I - L - erythro - hex- 2 -en o n o - 1 ,4 - 1 ac to n e gaveonly elimination products, the lactones (33) and (34).when either of the two bases was used. The oxazoles (1).(9), (21). and (27) were converted into a series of derivatives by a sequence of acetylation, hydrolysis, and hydro-genolysis experiments. The reaction mechanism whereby the oxazoles and oct-2-enonates are produced isdiscussed briefly.IN Part 1 we described the preparation of ( E ) - and(2) -e thy1 3,6-anhydro-2-deoxy-2-formylamino-4,5 :7,8-di-0-isopropylidene-~-manno-oct-2-enonate from2,3 : 5,6-di-0-isopropylidene-~-mannono-l,4-lactone byformylaminomethylenation with ethyl isocyano-acetate (EIA) and potassium hydride in tetrahydro-furan. As the reaction represents a route to C-glycosylcompound^,^ we wished to explore its scope, and nowreport 2 on the effect of changes, similar to those des-cribed5 for aldehydes and ketones, in the reaction con-ditions; the reactions of EIA with other aldonic acidlactone derivatives have also been studied.A comparison of yields in a series of formylamino-methylenation reactions of the mannono-lactone andEIA using a variety of strong bases (b~tyl-lithium,~~'potassium t - butoxide ,5(L sodium h ydride ,5('y and pot as-sium hydride 1 * 5 ~ ) showed that potassium hydride wasthe most suitable.The use of sodium ethoxide inethanol5"-' was not examined in detail when a small-scale experiment showed (t.1.c.) that ethyl (ethyl 2-deoxy-2-formylamino-4,5 : 7,8-di-O-isopropylidene-cr-r,-rnan~zo-~-g~ycero-oct-3-~~0-3,6-furanos~d)o1iate and its D-nzanno-L-glycero-epimer were the major products, asexpected.1 With sodium cyanide in e t h a n ~ l , ~ " ? ~ thelactone was consumed and verj.polar material (t.1.c.)was obtained. An attempt to acetylate this materialgave unchanged lactone in ca. SOY0 yield; consequently,the reaction was not investigated further.Part 1, K. H. Hall, K. Bischofberger, S. J . Eitelman, and A.Jordaan, J.C.S. Perkin I , 1977, 743.Preliminary publication, S. J. Eitelman, K. H. Hall, and A .Jordaan, J . C . S . Chenz. Comni., 1976, 923.D. Hoppe, Angew. Chem. Intamat. Edn., 1974, 13, 789;U. Schollkopf, ibid., 1070, 9, 763. * For recent examples, see L. Kalvoda, J . CarbohydijatesNucleosidcs Nucleotides, 1976, 3, 47; C.M. Gupta, G. H. Jones,and J. G. Moffatt, J . Org. Chem., 1976,41, 3000; T. Huynh-Dinh,J. Igolen, J.-P. Marquet, E. Bisagni, and J.-M. Lhoste, ibid.,p. 3124; G. Just and S. Kim, Canad. J . Chrm., 1976, 54, 2935;U. Iieichman, C. K. Chu, I . Wempen, K. A. Watanabe, and J . J .Fox, J . HetevocycEic Chem., 1976, 13, 933; K. Arakawa, T.Miyasaka, and N. Hamamichi, Chem. Letters, 1976, 1119.When the lactone was treated with equivalent amountsof EIA and 1,5-diazabicycl04,3,Onon-5-ene (DBN) intetrahydrofuran,6 either by the low temperature pro-cedure or at 25 "C, a product which was less polar thanthe formylaminomethylenation products and formed amonoacetate on acetylation was isolated in moderateyield.Its mass spectrum and an accurate mass deter-mination (MI - CH,) indicated that the compound wasisomeric with the oct-2-enonates and this was con-firmed by the mass spectral and analytical data of itsmonoacetate. The presence of a free hydroxy-groupwas shown by i.r. spectroscopy, and the presence of anoxazole ring in the compound and its monoacetate wasevident from their n.m.r., i.r., and U.V. spectra. Thesedata established that the product was the oxazole (l),which gave the monoacetate (2).To confirm the structure (1) the oxazole was partiallyhydrolysed; the products were acetylated to give threecompounds which were separated by chromatography.The penta-acetate (5) was readily identified by the usualspectral and analytical techniques and the other twocompounds were shown, by their n.m.r.and mass spectraland analytical data, to be isomeric triacetates, eachcontaining one isopropylidene group. However, itcould not be assumed that they were simply the 1,2-0-isopropylidene- and the 4,5-O-isopropylidene-triacetatesbecause acid-catalysed migrations of isopropylidenegroups can take place during acid hydrolysis; moreover,it is unusual for a terminal acetal group in such acyclic( a ) U. Schollkopf, J?. Gerhart, R. Schroder, and D. Hoppe,Annalen, 1972, 766, 116; (b) A. J . Brink and A. Jordaan, Carbo-hydvate Res., 1974, 34, 1 ; (c) K. Bischofberger, A. J. Brink, 0. G.de Villiers, R. H. Hall, and A. Jordaan, J.C.S. Perkin I , 1977,1472; ( d ) D. Hoppe and U. Schollkopf, Annalen, 1972, 763, 1 ;(e) J.C. A. Boeyens, A. J . Brink, R. H. Hall, A. Jordaan, andJ . A. Pretorius, Acta Cryst. B, in the press.ti Cf. M. Suzuki, M. Miyoshi, and K. Matsumoto, J . Org. Chem.,1974, 39, 1980.(a) I. J . Turchi and M. J . S. Dewar, Chem. Rev., 1975,75, 389;(b) R. Schroder, U. Schollkopf, E. Blume, and I. Hoppe, Annalen,1975, 5331977 2237compounds to be retained at the expense of a non- ethanol and DNB (150 "C; 0.1 mmHg). N.m.r.terminal acetal group, under the conditions used.8 The spectroscopy revealed the absence of the ethoxy-groupn.m.r. spectra of compounds ( l ) , (2), and (5) showed H-1 and the structure was confirmed by the usual analyticalsignals at 7 4.05, 4.08, and 3.48 respectively. The and spectral methods. Further, compound (6) was re-corresponding H-1 doublets of the two triacetates occur- converted quantitatively into compound (1) on treat-red at T 4.06 and 3.31, indicating that the compound with ment with sodium ethoxide in ethanol.The reaction ofO d C O 2 E t /"OR4Me2C' 0 4( 7 ) R = H( 8 ) R-ACthe H-1 doublet at T 4.06 had retained the 1,2-0-iso- the lactone (6) with equivalent amounts of EIA andpropylidene group and was the triacetate (3), and that the DBN gave the double oxazole (7), which yielded theother compound contained a 1-0-acetyl group. Simi- monoacetate (8) on acetylation. The double oxazoleslarly, the 4-protons of compounds (1) and (2) resonated (7) and (8) were readily identified by their two low-fieldabove T 5.80, whereas those of compounds (3) and (5) and singlets (H-2 of the oxazole rings, T ca.2.0).0 / C02Et "jOR'OR'OR2LMe2( 9) R1 R1 = R3 R3= CMe2, R2=H(10) R ' R ' =R3R3=CMe2, R2=Ac(11 ) R' R' =CMe2, R2=R3=H( 1 2 ) RIR1 =CMe2, R2=R3=Ac(151, (16)(13) R'=R2=R3=H(14) R1=R2=R3=AcCH20R3 1:;(17) RIR1= R3 R3=CMe2,R2=H(18) R1R1=R3R3=CMe2,R2=Ac(19) Ri=R2=R3=ACthe second triacetate resonated below z 5.00, indicatingthat the second triacetate was the 2,3-0-isopropylidenecompound (4). Further first-order analysis of the n.m.r.spectra of compounds (1)-(5) confirmed that the tri-acetates were compounds (3) and (4).Compound ( 1 ) was converted into the lactone (6) byheating a solution in DBN, with simultaneous removal ofH. Zinner, G. Kembarz, and H.P. Klocking, Chem. Bev.,1957, 90, 2688; IJ Lerch, M. G. Rurdon, and J. G. Moffatt, J .Org. Chew., 1971, 36, 1.507.The reaction of 2,3 : 5,6-di-0-isopropylidene-~-allono-1,4-lactone with EIA and DBN (25 "C) gave the oxazole(9) in 56?/, yield, which was converted by a series ofacetylations and hydrolyses into compounds (lo)-( 14),Formylaminomethylenation of the lactone by the methoddescribed for its mannono-isomer gave the expected oct-2-enonates (15) and (16) in 59 and 2 yield, and the oxa-zole (9) (0.50amp;) and the double oxazole (17) (10) as* J . AI. Ballard and euro;3. E. Stacey, Cavbohydvate Res., 1970, 12,3 7 ; M. Haga, M. Takano, and S. Tejima, ibid., 1970,14, 2372238 J.C.S. Perkin Iby-products. (By-products similar to those obtained the expected oxazole (27).The same product wasfrom the formylaminomethylenation of the mannono- obtained in the absence of EIA. The structure (24)lactone were not observed.) Presumably the double was established by conversion into the known12 2,4,6-oxazole (17) was obtained either by reaction of the tri-0-benzoyl-3-deoxy-~-arab~~o-hexono-l $-lactone (25) ;allono-lactone with the self-condensation product of simultaneous hydrogenation and hydrogenolysis ofMe0Qo obsol;c/ 0Me2(20)Meo4 ROhieM eO NH-CHOycov 0 0 C 0,E t' JT - ' (23)EIA,1976 or by a route involving a lactone similar to compound (24) and benzoylation of the products ob-compound (6). Compound (17) was further charac- tained, gave a mixture of (25) and its C-2 epimer (26).terized as the monoacetate (18) and the penta-acetate (19).With EIA and potassium hydride the glucono-lactoneAs an example of a 1,5-lactone, 2,3-O-isopropylidene-4- gave the oxazole (27) in 43 yield. The oxazole (30),O-met hyl-I.-rh amno- 1,5-lac tone (20) wasCH2- OBn1( 2 4 )prepared by which must have been obtained by transesterification,CH2 SOBZ OR2 I ppoto(25) R~=OBZ,R~=H(26) R~=H,R~=OBZ(27) R' =Et, R2 = Bn, R3 =H(28) R1 =Et, R2 = Bn, R3 =Ac(30) R1 = R2=Bn,R3 = H(31) R1=R2=6n,R3=Ac(29) R1 =Et, R2 = R3 = ACoxidation of 2,3-O-isopropylidene-4-O-methyl-a-~-rhamnose.1deg; Reaction of the lactone with EIA andDBN was slow; after 4 days 60 of the lactone wasrecovered and only 13 of the expected oxazole (21) wasobtained. With EIA and potassium hydride, the lac-tone was consumed in ca.1 h but only low yields of anoct-2-enonate (23) (13) and the oxazole (21) (19)were isolated from the complex mixture of products.The oxazole (21) was further characterized as its mono-acetate (22).2,3,4,6-Te tra-O-benzyl-~-glucono- 1,5-lact one l1 withEIA and DBN gave the unsaturated lactone (24) and notlo S. J. Angyal, V. A. Pickles, and R. Ahluwalia, CarbohydrateRes., 1967, 3, 300.l1 H. Kuzuhara and H. G. Fletcher, J . Org. Chem., 1967, 32,2531.and compound (24) were isolated as by-products, but theexpected oct-2-enates were not detected in the complexmixture. The oxazoles (27) and (30) were convertedinto compounds (28), (29), and (31) by a series of acetyl-ations and hydrogenolyses.5,6-O-Isopropylidene-2,3-di-O-met hyl-~-erythro-hex-2-enono-1,4-lactone l3 and EIA with DBN or potassiumhydride as base gave only the isomeric unsaturatedlactones (32) and (33) ; these lactones were also formed ontreatment of the lactone with DBN only.The reaction of carbonyl compounds with EIA inbasic and aprotic medium involves 375a an oxazolidehydrate Res., 1974, 36, 185.hydratr! Res., 1975, 45, 45.l2 R.M. de Lederkremer, M. I. Litter, and L. F. Sala, Carbo-l3 J. S . Brimacombe, A. W. Murray, and Z. IT. Hague, Carbo1977 2239anion, with the negative charge at C-4. With aldehydesand ketones the intermediate (34) can undergo only onetype of ring fission, to give a ' pentadienide anion,' which(35)on protonation gives an ;i,t'rylic ester (route a).How-ever, with lactones a spiro-intermediate (35) is formedand ring fission of what was originally the lactone ring isalso possible. This leads to an alkoxide, which onprotonation gives an acyclic oxazole (route b). Asimilar mechanism has been proposed l4 to explain thebase-catalysed conversion of the oxazoline (36) into theoxazole (37).00Meamp; 1RO136) ( 3 7 )R=CH,*CH : CH,Clearly, where base-catalysed elimination reactionscan be suppressed, the size of the lactone ring and thenature of the base employed influence the course of thereaction; oxazole formation (route b) is favoured by the1,5-lactones and by the use of the large, hindered organicbase DBN.E XPE RI M E NT AI,General experimental procedures were as described inl'art 1,' with the following additions.The compounds allexhibited unexceptional i.r. spectra and details are givenonly for compounds ( l ) , (15), (16), and (20), which arerepresentative examples of the oxazoles, lactones, and oct-2-enonates Similarly, the compounds all exhibited unexcep-tional n ni r 5pectra antl details are only given for selected,typical compounds ( l ) , ( 6 ) , (15), (16), (20), (23), (M), and(32). U.V. spectra were recorded for solutions in ethanol(99.90,b), unless otherwise stated. bsol;!'here possible, samplesof oils were distilled under high vacuum (kugelriilire) formicroanalysis. Syrups which could not be distilled werechroniatographed until homogeneous by t .l.c. in severalsolvent systems and until their n.m.r. and i.r.spectra ex-hibited no extraneous peaks ; accurate inass determinationsof molecular ions or of suitable fragment ions were thenobtained by high resolution mass spectrometry.Ethyl 5- ( 1 S) - 1,2 : 4,5-I)i-O-iso~ro~ylidene-u-arnbi~z itol- 1 -yZoxazole-4-i:arboxylate ( 1 ) .- -A solution of 2 , 3 : 5,6-di-0-isopropylidene-u-mannono- 1 ,amp;lactone (2.58 g, 10 mmol),ETA (1.13 g, 10 ~nmol), and DBX (1.24 g, 10 mmol) in drytetrahydrofuran ( 2 5 nil) was stirred for 3 days a t 25 "C; thesolvent was then evaporated off in z~ucuo ( 40 "C) and theresidue was chroniatographed with ethyl acetate-benzene( 1 : 1 ) as eluant to give the oxazole ( 1 ) as an oil (1.82 g, 4974),a,,'* - - g o , v,,,,~,.3 545 (OH), 3 140 (H-CzX), 1 705 (CO),1 605 ( C X ) , and 1 360 cn1-l (Chle,), A,,,,,. 228 nm (log E 3.90),A I Z i 371, 7 2.16 ( 1 H, s, H-2 of oxazole), 4.05 ( 1 H, d, J l , 2q, OCH,*CH,), (.a. 5.80-6.11 ( 3 H, ni, H-4, -5a, -5b),6.66br ( 1 H, ni, simplifies with I,O, H-3), 7.95br ( 1 H, d,JOIr,, 8 Hz, disappears on addition of 1,0, OH), 8.32, 8.48,and 8.66 (12 H, 3 s, 4 CH,), and 8.51 ( 3 H, t, O*CH,*CH,)(Found: m / e , 356.135. C,,H,,SO, requires iZI - CH,,356.135).Acetylativn with acetic anhydride in pyridine, fullowed bychromatography with ethyl acetate--benzene ( 1 : 1 ) aseluant, gave the nzonoacetate (2) as an oil (89y0), ICCJ,l9 -- 62",A,,,a,, 228 nm, (log E 3.88), D1'- 413 (Found: C, 55.2; H, 6.5;N, 3.2. C,,H,,NO, requires C, 55.2; H, 6.5; N, 3.3O;,).5- ( 1s) - 1,4,5- Tri-O-acetyl-2, : ~ - ( ~ - i s o p r o ~ ~ , l i r Z e ~ z e - u -arabinifol- l-yl~oxazole-4-carbox~~lute (4), its I'enta-O-ocetylAnaiogue (5), and its 3,4,5-Tri-O-acetyl- 1,2-C)-isopvo~~~liiZevzeAnalogue (3).-Conipound ( 1 ) (230 mg, 0 .6 mmol) i naqueous acetic acid (30; 5 nil) was heated a t 75 "C. for 10min, the solvents were evaporated off in uacuo, antl the resi-due was acetylatecl with acetic anhydride i n pyritline.Work up in the usual manner followed by clironiatographywith benzene-acetone ( 9 : 1) as eluant gave first a mixture oftwo compounds (ca. 190 mg), as shown by 1i.m.r. spectros-copy, and then the triacetate (3) as an oil (45 mg, 16),,IDzo -36O, A,,,,, 208 and 224 nm (log E 4.32 and 4.l o ) , m/e442 (iW - CH,) (Found: m/e 442.135. C,,H,,NO,,requires M+ - CH,, 442.135).The mixture first eluted was rechromatographed withhexane-acetone ( 3 : 1) as eluant to give the triacetate (4) asan oil (50 nig, 17y0), a,21 +21", 208 and 223 nm(log E 4.13 and 4.09), wz/e 442 (M+ - CH,) (Found: m / e ,442.135. C,,H24NOl, requires amp;If - CH,, 442.135).Further elution gave the penta-acetate (5) as an oil (98 nig,31), +32", AllX,,. 215 nm (log E 3.92), A Z ' 501 (Found:m/e 441.126. C,,H,,KO,, requires Llf ' - CH,CO,H441.127).5-( 1s)- 1,2 : 4,5-Di-O-isopro~ylidene-~-a~a~znitol- 1-yl-oxazole-4-carboxylic A cid Lactone (6) .-2,3 : 5,6-Di-0-isopropylidene-n-mannono-1,4-lactone was treated as des-cribed for the preparation of compound ( 1 ) .After removalof the tetrahydrofuran, the DBS was evaporated off a t150 "C (0.1 mmHg) to leave a residue which, on chromato-graphy with benzene-acetone ( 3 : 1) as eluant, gave a solid.7 Hz, H-1), 5.25 ( 1 H, dd, J 2 . 1 7 , J,,, 2 Hz, H-2), 5.62 ( 2 H,EthylI4 K . Gigg and ('. n. Warren, ,I. Chem. SOC. ( C ) , 1968, 1903J.C.S. Perkin IRecrystallization from acetone-hexane gave the lactone ( 6 )(48), m.p. 186-188 "C, aIDl9 -45', A,,,. 208 and 220 nm(log E 3.63 and 3.58), Mf 325, T 1.02 ( 1 H , s, H-2 of oxazole),H-2), 5.45-6.14 ( 4 H, m, H-3, -4, -5a, -5b), and 8.56, 8.57,8.63, and 8.65 (12 H, 4 s, 4 CH,) (Found: C, 55.4; H, 5.8;N, 4.3.Reconversion of the Lactone ( 6 ) into Compound (l).-Asolution of the lactone ( 6 ) (0.25 g, 0.8 mmol) in ethanol(99.9yo, 15 ml) containing sodium ethoxide (ca.20 mg) wasstirred a t 25 "C for 2 h; t.1.c. indicated that the startingmaterial had reacted completely. Acetic acid ( 5 drops)was added to the solution and the solvents were evaporatedoff in vacuo t o give compound (1) (0.28 g ; contaminatedwith sodium acetate), identical (i.r., mass, and n.m.r.spectra) with compound ( 1) prepared previously.5-( 1S)-1,2 : 4,5-Di-O-isopro~ylidene-~-arabinitoZ- l-yl-4-( 4-ethoxycarbonyloxazol-5-y1)oxazoZe ( 7 ) .-The lactone ( 6 )(0.25 g, 0.08 mmol) was treated with EIA and DBN asdescribed for the preparation of compound ( 1 ) . Similarwork-up and chromatography with benzene-acetone ( 3 : 1)as eluant gave starting material ( 6 ) (59 mg, 23) and thencompound ( 7 ) as an oil (75 mg, 25y0), aID2l +3", A, 218 nm(log E 3.94), M' 438 (Found: m / e , 423.140.CI9H,,N,O9requires M+ - CH,, 423.140).Acetylation, followed by chromatography with ethylacetate-benzene ( 1 : 1) as eluant, gave the monoacetate ( 8 ) asan oil (94), aID2O +49", AnliLx. 221 nm (log E 4.40), M+ 480(Found: m / e 465.152. C,,H,,N,O,, requires Mf - CH,,465.151).Ethyl 5 - ( 1K)- 1,2 : 4,5-Di-O-iosprofiylidene-~-rabitol- l-yZ-oxazole-4-carboxylate ( 9 ) .-2,3 : 4,5-1i-O-isopropylidene-~-allono-1,4-lactone (2.58 g, 10 mmol) was treated with EIAand DBN as described for the preparation of compound (l)..Work-up and chromatography with ethyl acetate-benzene( 3 : 2 ) as eluant gave the oxazole ( 9 ) as an oil (2.04 g, 55y0),alD2o +48", A,.227 nm (log E 3.87), Mi 371 (Found: C,55.3; H, 7.0; N, 3.6. C,,H,,NO, requires C , 55.0; H, 6.7;N, 3.8).Acetylation gave the monoacetate (10) (80y0), m.p. 109-111 "C (from hexane), aID2O +40", Amax. 227 nm (log E 3.93),m / e (M+ - CH,) 398 (Found: C, 55.2; H, 6.5; N, 3.3.C,,H,,NO, requires C, 55.4, H, 6.7, N , 3.4).Ethyl 5-( 1R)-l,2-O-Isopropylidene-~-~~b~tol-l-ylJoxazole-4-carboxylate ( 1 1 ) and Ethyl 5-( lR)-D-Ribitol- l-yloxazoZe-4-carboxylate ( 13) .-Compound ( 9 ) was hydrolysed as des-cribed for compound ( 1 ) . Work-up and chromatographywith ethyl acetate-methanol (7 : 2) as eluant gave compound(11) as an oil (175 mg, 22yo), 6;JD20 +43", A,. 228 nm (log E3.76), M+ 331 (Found: m / e , 316.102.C,,H,,NO, requiresM+ - CH,, 316.103). Further elution gave compound (13)(350 mg, 48y0), 1n.p. 112-114 "C (from ethanol-hexane),0;3,,20 +42" (H,O), hlllax. 221 nm (log E 3.95) (Found: C, 45.1,H, 6.2; N, 4.7. CllHl,NOa requires C, 45.3; H, 5.9; N,4.8).Acetylation of compound ( 1 1 ) gave the triacetate (12) as anoil (76), 61ID2O +57", Anlax- 225 nm (log E 3.72), m / e (M+ -CH,) 442 (Found : m/e, 442.135. C1gH24NO11 requiresM+ - CH,, 442.135). Acetylation of compound (13) gave thepenta-acetate (14) as an oil (89), aIn2O +49", A,. 220 (log E3.93), M+ 501 (Found: C, 50.0; H, 5 . 3 ; N, 2.8. C,,H,,NO,,requiresc, 50.3; H, 5.4; N, 2.8).FormyZaminomethylenation of 2,3 : 5,6-Di-O-lsopropyZi-dene-~-a~lono-1,4-lactone with EIA .-2,3 : 5,6-Di-O-iso-propylidene-~-allono-1,4-lactone 9 (8.0 g, 31 mmol) was4.53 ( 1 H, d, J 1 , 2 8 Hz, H-l), 5.06 ( 1 H, d, J2,, 8 Hz,C15H19N0, requires C, 55.4; H, 5.9; N, 4.3).treated with EIA and potassium hydride as described 1 forits D-mannono-isomer; similar work-up gave an oil (ca.8.7 8).Chromatography with benzene-ethyl acetate ( 3 : 2)as eluant gave the oxazole ( 9 ) (58 mg, 0.5y0), identical (i.r.,u.v., mass, and n.m.r. spectra) with compound ( 9 ) , preparedpreviously.Further elution gave (E)- or (2)-ethyl 3,6-anhydro-2-deoxy-2-formylamino-4,5 : 7,8-di-O-isopropylidene-~-aZlo-oct-Z-enonate (15) as an oil (230 mg, 2), aID2O -224",vmax. 3 300 (NH), 1690 (CO), and 1380 cm-l (CMe,), A,208 and 250 nm (log E 3.89 and 4.03), M+ 371, T 1.69 and1.88 ( 1 H, s, and d, J C H O J H 11 H z , simplifies on addition ofD,O, CHO), 3.24br ( 1 H, d, JxR,CHO 11 Hz, disappears onaddition of D,O, NH), 4.25 ( 1 H, d , J 4 , , 6.5 Hz, H-a),5.12-6.20 (7 H, m, H-5, -6, -7, -$a, -8b, O*CH2*CH,), and8.56-8.76 (15 H, m, 4 CH,, OCH,-CH,) (Found: C, 55.2;H, 6.9; N, 3.6.C,,H,,NO, requires C , 55.0; H, 6.7; N,3.8).Next eluted was the oct-Z-enonate (16) as an oil (6.8 g,5 9 0 / ) , o L ~ ~ O -241deg;, v,,,. 3 400 (NH), 1690 (CO), and 1380cm-l (CMe,), A,,,. 207 and 248 nm (log E 3.62 and 3.98), M+371, T 1.83 and 1.99 ( 1 H, 2 d , JcHo,NH 2 and 11 Hz, sim-plifies on addition of D,O, CHO), 2.89 and 3.16br ( 1 H, s,and d, JNH,CHO 11 Hz, disappears on addition of D,O, NH),4.68and4.71 (1H,2d, J4,56Hz,H-4),5.22-5.44and5.70-6.19 (7 H, m, H-5, -6, -7, -$a, -8b, O*CH,CH,), and 8.49-8.80 (15 H, m, 4 CH,, O*CH,*CH,) (Found: C, 55.3; H, 7 .0 ;N, 3.6.Further elution gave 5- ( 1 R ) - 1,2 : 4,5-di-O-iso~ropylidene-D-ribztol- l-yQ-4-( 4-ethoxycarbonyloxazol-5-y1)oxazoZe ( 17)(1.36 g, lo), aID2O +51", A,. 213 and 261 nm (log 8 3.94and 3.86), M+ 438 (Found: C, 54.8; H, 6.1; N, 6.2.C,,H,,N,09 requires C, 54.8; H, 5.9; N , 6.4) ; the mono-acetate (18) was an oil (91yo), aID2O +49", A,. 213 and 260nm (log E 3.94 and 3.91), M+ 480 (Found: C, 55.0; H, 6.0;N, 5.6. C22H2sN,0,0 requires C, 55.0; H, 5.8; N, 5.8).4- 4-Ethoxycarbonyloxazol-5-yll-5- ( 1 R) -penta-0-acetyl-D-ribitol-l-yZoxazoZe (19) .-Compound ( 1 7 ) was hydrolysedwith aqueous acetic acid (30 ; 20 ml) a t 80 "C for 1.5 h.Removal of the solvents left a syrup which was acetylated.Work-up gave a syrup which was chromatographed withethyl acetate-benzene ( 1 : 1 ) as eluant to give the penta-acetate (19) as an oil (254 mg, 20yo), aID2O +a$", A, 209 and254 nm (log E 3.96 and 3.70), m / e (M+ - CH,CO) 526(Found: m/e, 466.122.C,,H,,N,O,l requires M+ -2,3-0- Isopropylidene-4-0-methyl-~-~hamnono- 1,5-lactone(20) .-2,3-O-Isopropylidene-4-O-methyl-cc-~-rhamnose lo(2.18 g, 10 mmol) was oxidized with acetic anhydride anddimethyl sulphoxide, as described for a similar com-pound, to give a solid which on recrystallization from ethylacetate-hexane afforded the lactone (20) (1.88 g, 87y0),m.p.90-91 "C, aID2O - 137", vmax. 1 760 (CO) and 1 380 cm-l(CMe,), m/e (M+ - CH,) 201, -r 5.32 and 5.54 ( 2 H, 2 d,6.5 Hz, H-5), 6.50 ( 3 H, s, OCH,), 6.80 ( 1 H, dd, J 4 , , 9.5,J4,, 5 Hz, H-4), 8.50 and 8.59 (6 H, 2s, ZCH,), and 8.58( 3 H, d, JOH!., 6.5 Hz, CH,) (Found: C, 55.4; H, 7.3.C,,H,,O, requires C, 55.5; H, 7.5).Ethyl 5 - ( lR)-5-Deoxy- 1,2-O-isopropylidene-3-O-methyZ-L-arabinitol- l-yloxazole-4-carboxylate ( 2 1 ) .-Compound (20)(216 mg, 1 mmol), EIA, and DBN were treated as describedfor the preparation of compound ( 1 ) . After 4 days themixture was worked up and the residue chromatographedwith benzene-acetone ( 3 : 1 ) as eluant t o give startingC,,H,,NO,requiresC, 55.0; H, 6.7; N. 3.8).CH,CO - CH,CO,H, 466.122).J 2 .3 = J3,2 8 Hz, H-2, - 3 ) ) 5.76 ( 1 H, dq, J5.4 9.5, J ~ . c H 1977 2241material (1 30 mg, 60). Further elution gave compound(21) as an oil (28 mg, 13), aID1* +43", Am,. 225 nm (log E3.92), M+ 329 (Found: m/e, 314.124. Cl,H20N07 requiresM+ - CH,, 314.124) ; the monoacetate (22) was an oil (goyo),aID1a +15", A,,,, 208 and 225 nm (log E 3.91 and 3.86),M+ 371 (Found: m/e, 314.124. C14H2,N07 requires M+ -(E)- or (2)-Ethyl 3,7-Anhydro-2-deoxy-2-formylamino-4,5-O-zsopropylidene- 6-O-methyZ-~-rhamno-oct-2-enonate (23) .-Compound (20) (1.4 g, 6.5 mmol), EIA, and potassiumhydride, treated as described for a similar compound, gavea syrup. Chromatography, and rechromatograpliy ofmixed fractions, with benzene-acetone (3 : 1) as eluant, gavea solid which, on recrystallization from acetone-hexane,yielded cornpound (23) (270 mg, 13), m.p.157-159 "C,-290", Amx. 207 and 250 nm (log E 4.02 and 3.52),M+ 329, T 1.80 and 1.98 (1 H, 2d, JCHO,NH 1 and 11 Hz,simplifies on addition of D20, CHO), 2.78 and 3.10br (1 H,s and d, JNH,CHO 11 Hz, disappears on addition of D,O, NH),5.12and5.14(1H,2d, J4,,7.5Hz,H-4),5.74and5.76(2H,2q, O*CH,-CH,), ca. 6.24 (2 H, m, H-5, -6), 6.46 (3 H, s,OCH,), ca. 6.84 (1 H, m, H-7), and 8.40-8.88 (12 H, m,3 CH,, O*CH,*CH,) (Found: C, 54.7; H, 6.9; N, 4.3.Cl,H2,N07 requires C, 54.7; H, 7.0; N, 4.2).Further elution gave compound (21) (400 mg, 19),identical (i.r., u.v., mass, and n.m.r. spectra) with thatprepared previously.lactone (24) .-2,3,4,6-Tetra-O-benzyl-~-glucono- l15-lac-tone l1 (1.1 g, 2 mmol), EIA, and DBN, treated as describedfor the preparation of compound (l), gave a syrup. Chro-matography with benzene-diethyl ether (19 : 1) as eluantgave a solid which, on recrystallization from ethanol,afforded com$ound (24) (128 mg, 20y0), m.p.93-94 "C,a,l9 +52", A,,,. (MeOH) 215 and 240 nm (log E 5.17 and4.97), m/e 339 (M+ - CH,Ph), T ca. 2.75 (15 H, m, 3 Ph),4.38 (1 H, d, J3,4 4 Hz, H-3), 5.22 (2 H, s, O*CH,Ph), ca. 5.56(6 H, m, H-4, -5, 2 O*CH2Ph), and ca. 6.40 (2 H, m, H-6a,-6b) (Found: C, 75.3; H, 6.3. C27H2605 requires C, 75.4;H, 6.0).On treating the lactone with 1 equiv. of DBN, compound(24) was obtained in 62 yield.2,3,6-Tri-O-benzoyl-3-deoxy-~-arabino-hexono- l15-lactone(25) and its D-ribo-Analogue (26) .-Compound (24) (250 mg,0.6 mmol) was hydrogenated over palladium (25 "C; 24 h ;50 lb in-2) in aqueous tetrahydrofuran (10 ; 15 nil).Themixture was'then filtered and the solvents were removed invacuo to give a syrup which was benzoylated in the usualmanner. The residue so obtained was chromatographedwith benzene-acetone (8 : 1) as eluant t o give compound (25)(55 mg, 20y0), m.p. 157 "C (1it.,l2 158-160 "C), aID2O +31"aqueous acetone (90y0) {1it.,l2 + 27" aqueous acetoneFurther elution gave the isomer (26) (57 mg, 21y0), m.p.115-117 OC, aID2O -10" aqueous acetone (go), m/e(M+ - COPh) 369 (Found: C, 68.2; H, 5.0. C27H220Rrequires C, 68.3; H, 4.7).CH3 - CH, CO, 314.124).2,4,6-Tri-O-benzyZ-3-deoxy-~-erythro-hex-2-enono- 1,5-(90)l.Formy laminomethylenat ion of 2,3,4,6- Tetra-O-benzy l-D-glucono- 1,5-Zactone with EIA .-2,3,4,6-Tetra-O-benzyl-~-glucono- 1,5-lactone ( 10 g, 18 mmol) , EIA, and potassiumhydride, treated as described for a similar compound, gavea syrup which was chromatographed ; mixed fractions wererechromatographed with benzene-acetone (4 : 1) as eluantto give compound (24) (206 mg, 2.5y0), identical with thatprepared previously.Further elution gave benzyl 5- ( 1 R)- 1,2,3,5-tetra-O-benzyZ-D-arabinitol- l-y6JoxazoZe-4-carboxyZate (30) as an oil (580 mg,4), aID2O +21", A,,,,, 209 and 232 nm (log E 4.44 and 3.81),M+ 713 (Found: C, 73.8; H, 6.0; N, 1.9.C,,H,,NO,requires C, 74.0; H, 6.0; N, 2.0yo); the monoacetate (31)was an oil (650/,), aD20 +25", 209 and 230 nm (log E4.53 and 3.90), m/e (M+ - CH,Ph) 664 (Found: C , 72.8;H, 6.1; N, 1.8.C,,H,,NO, requires C , 73.1; H, 5.9; N,1.8).Next eluted was ethyl 5 - ( 1R)- 1,2,3,5-tetra-O-benzyZ-n-arabinitol- l-yloxazole-4-carboxylate (27), as an oil (5.2 g,43y0), aID2O +28", Amax. 216 and 331 nm (log E 4.83 and 4.57)(Found: m/e, 560.228. C,,H3,N08 requires M i - CH,Ph,560.228); the monoacetate (28) was an oil (say(,),+37", Amax. 216 and 231 nm (log E 4.16 and 3.89), M+ 693(Found: C, 71.0; H, 1.9; N, 6.4. C41H4,NOg requires C,71.0; H, 2.0; N, 6.2).Ethyl 5 - ( lR)-Penta-O-acetyl-~-arabinifol- l-yloxazole-4-carboxylate (29).-Compound (27) (490 mg, 0.7 mmol) wasdebenzylated as described for compound (24) and the pro-duct was acetylated in the usual manner to give a syrup.Chromatography with ethyl acetate-benzene (1 : 1) aseluant gave a solid. Recrystallization from ethyl acetate-hexane gave the penta-acetate (29) (190 mg, 57y0), m.p.130-131 OC, aID2O +64", 227 nm (log E 4.87), M+ 501(Found: C, 50.4; H, 5 . 3 ; N, 2.7. C,,H2,NO13 requires C,50.3; H, 5.4; N, 2.80/,).(E) - and (2) -2,3-Dimethoxy-6-hydroxyhexa-2,4-dien-4-olides (32) and (33) .-5,6-O-Isopropylidene-2,3-di-U-methyl-~-erythro-hex-2-enono-1,4-lactone l3 (210 mg, 0.85mmol), EIA, and DBN, treated as described for the prepar-ation of compound (l), gave an oil. Chromatography vAthbenzene-ethyl acetate (4 : 1) as eluant gave a solid which onrecrystallization from ethyl acetate-hexane yielded theisomer (32) (100 mg, 69y0), m.p. 80-81 OC, O", Amax. 208and 258 nm (log E 3.92 and 3.90), M+ 186, T 4.50 (1 H, t,J5,8 7 Hz, H-5), 5.61br (2 H, d, J 6 , , 7 Hz, sharpens onaddition of D20, H-6a, -6b), and 5.86 and 6.08 (6 H, 2 s,2 OCH,) (Found: C, 51.6; H, 5.4. C8H1005 requires C,51.6, H, 5.5).Further elution gave the isomer (33) (10 mg, 7), m.p.36-38 "C (from hexane) aIDl9 O", A,,,. 205 and 260 nm (logE 3.93 and 4.22), M+ 186 (Found: C, 51.6; H, 5.7. C8Hlo0,requires C, 51.6, H, 5.5).With potassium hydride as the base the isomers (32) and(33) were obtained in ca. 30 yield, with only DBN presentthey were obtained in ca. 80 yield.7/626 Received, 13th April, 1977