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^ Reprinted from The Journal of Organic Chemistry, 1g88,yol. iJ, page J{52 Copyright O 1988 by the American Chemical Socieiy and reprintea ny permission oT ttt" copyright owner.

Synthesis of Analogues of 1,3-Dihydroxyacetone Phosphate and 3-Phosphate for Use in Studies of -1,6-diphosphate Aldolaser

Norbert Bischofberger,2Herbert Waldmann,3Tohru Saito, Ethan S. Simon,aWatson Lees,s Mark D. Bednarski,6and GeorgeM. Whitesides*

Department of Chemistrv,Haruard Uniuersity,Cambridge, Massachusetts 02138

ReceiuedFebruary 9. 1988

This paper describesthe synthesesof five analoguesof dihydroxyacetonephosphate (3-azidohvdroxl' 1-phosphate(5), 3-(acetylamino)hydroxyacetone1-phosphate (12), (R)-1,3-dihydroxy-2-butanone 1-phosphate (18),(+)-1,3-dihydroxy-2-butanone 3-phosphate (26), and phosphonomethylglycolate (31)). The synthesesof 18 and 26 are basedon a new reaction: that is, the introduction of the phosphategroup by reaction of a diazo ketone with dibenzyl phosphate. These methods provide easyaccess to a number of compoundsthat are potential substratesfor the syntheticallyuseful enzvmealdolase (fructose-1,6-phosphate aldolase from rabbit muscle,EC 4.1.2.I3,RAMA) and perhapsfor other enzymesof .This paper alsodescribes syntheses of 14 aldehydes for examination as substratesfor aldolase. When the precursorwas available,ozonolysis of vinyl groupsproved to be the best route to the correspondingaldehydes.

Introduction and its broader applicability in organic synthesisis now Fructose-1,6-diphosphatealdolases catalyze the reaction being actively developed.l8'1eThe conclusionsfrom these of dihydroxyacetone phosphate (DHAP) with n-glycer- studiesare (1) aldolaseaccepts a variety of aldehydesas aldehyde3-phosphate (G-3-P) (eq 1).7'8 The stereochem- substratesand (2) it will acceptonly a few closeanalogues T of DHAP. As part of a researchprogram designedto explore oF^ the U-J-F substrate specificity of aldolaseand to evaluate the utility oHo of its reactionsin organicsynthesis, we required a number x ll -=-*BAMA I xol'.,,{-..,,,.oeo,'- xo(f;{r,oeo,:- (1) of analoguesof the natural substrates.leDHAP and G-3-P t--l are relatively sensitive compounds, and synthesesof H DHAP H FDP structural analoguesof these substancesare not trivial. istry of the reaction is that indicated in eq 1; the enzyme Here we report synthetic routes to five new analoguesof removes the pro-S of DHAP.e The enzyme from DHAP and 14 analoguesof G-3-P. The best synthesisof rabbit muscle (EC 4.I.2.13,RAMA) is commercially DHAP analoguesis based on a new method to generate availableand inexpensive(-$20/500 U, 1 U = 1 pmol of product formed per min with DHAP and G-3-P). It is useful as a catalyst in the synthesis of ,lrl7 Tetrahe-

(1) Supported by the National Institutes of Health, Grant GM 3036?. (2) PostdoctoralFellow 1984-1985;N.B. thanks the OeBWK, Austria and Ciba-Geigy,Basel, for generoussupport. (3) Postdoctoral Fellow 1985-1986;H.W. thanks the Deutsche For- schungsgemeinschaft,West Germany, for generous support. (4) DuPont Fellow, 1986-87. (5) Natural Science and Engineering Research Council of Canada Predoctoral Trainee. (6) American Cancer Society Postdoctoral Fellow, Grant No. PF-2762 1987-88. (7) Morse, D. F.; Horecker,B. L.In Aduancesin Enzyrnologl,;Nord, F. F., Ed.; Interscience: New York, 1968;Vol 31, pp 126-175. (8) Horecker, B. L.; Tsolas, O.; Lai, C. Y. In The Enzymes, 3rd ed.; Boyer,P. D., Ed.;AcademicPress: New York, 19?2;Vol.VII, pp 213-258. (9) Rose,I. A. J. Am. Chem. Soc. 1958,80, 5835. 3458 J. Org Chem.,Vol. 53,No. 15,1988 Bischofberger et al.

oo o a-hydroxy ketonephosphates by reactionof diazo ketones a u t HrN- *Bzlc- - nt'o- 'Cl - with dibenzyl phosphate. The best route for the synthesis on n" \ \an n \.n H \cH, " of analoguesof G-3-P is the ozonolysisof terminal olefins, 14 's 13 (4) when these olefins are accessible.These methods should be useful for the preparationof a number of other C i) o sub- ' B/lC\ t,. -^r. - . " - HO OPO,HNd stancesthat are potential substratesof aldolase,- /t _ _....- - _.-OF)O,OBzl ..- -.. n\.n-- H , \.n ',, tn' phosphate isomerase, sn--3-phosphatede- 16 18 hydrogenase,and perhaps of other enzymesof glycolysis. (a) Isoamylnitrite, MgSOa, PhCH2OH, reflux, 2 h (2i%); (bl We describedetailed studies of the reactivity of these SOClz,reflux; (c) g11rtr. Et2O (igV"); (d) PhCH2O)2P(O)OH, compoundsin reactionscatalyzed by aldolase,and of their PhH,60'C. 12h (89%);(e) 10% Pd-C/H2. AcOH, 12 h; NaHCO" utility in synthesis,in a separatepaper devoted to that Bi %\. subject.le hydrogen of DHAP,9 so we expected that onl-',-the R isomer Results 18 would be a substrate for aldolase. The starting materirri for our synthesis was the enantiomericalll,' lrt,rrzrl Synthesis of Analogues of DHAP. 3-Azido- l)ure. protected lactic acid chloride 15. Previous ,:r- hydroxyacetone 1-Phosphate (5). Following the estab- I)r(.t)iir".1'; of this compottnd have started with tr-bronr,)])r"r rf) j 1-..r:t rri lished procedure for the preparation of halo hydroxy and have required resolution.2:l'2a\\'e prt'1,rrrr.rll , t l- !i,- acetonephosphates,2O chloromethyl ketone I (preparedin and (S)-O-benzvllactit'acid f'rom (1?)-irrrri r :,' :. ::-.jnt. two stepsfrom 1-chloropropane-2,3-diol20was converted respectivelv.w'ith isoarnvlnitrite rrsint lr,.n,,iI .,., l-. , .r: to the azidomethvlketone 2 (eq 2). Ketalization.ester a solvent.tliThe reac'tionproceeclerl riltir r-'' r..',.r''.n

o c cH o ocH of configuratiotr(as judged f'rotnoplit';li r, r '' :',- :. .,.i)t'it '_* | OCOP- I' ^ oCOPh . N - / ,OH C r '! (27Vo). ()-Benz,r'llat '.'.:trcl \-/ \-/ ./ in modest yield ti,. .r.'.,1.,. ,- : 1 ) to its acid chloride2"and sub-e,lut.n'irr:, :" r ,i.':. ,ri.r- (2) ']'ir.. zomethaneto yield ('onll)orrnrlI (i. 'rr :,' ,:.--':.., . ke- 't-. tone reactedwith dibenzvlirho:pirirlt- 1,, ...' : : tr..t€d t.tlp,eo,n,--4* *. - i - ooo''*' phosphate17. Hvdrogenrttitirlrvr-r 1i.rl. :,ir .:: .-.:r- ,,rt it' acid as soiventgave 1t{in nrorlt,ratt.,,rt..,i::.. :: -,.:'.,,ii,rn (a) NaNr, CH3COCHg-HzO, 12 h (938a); (b) HC(OCH3)g, H2S- in failed. oC, Oa, MeOH, 2 days (73Vo); (c) POCls, pyridine, THF, 0 t h; 1,3-Dihydroxy-2-butanone ii-phos p hat t t lri ) ',\irs pyridine-; ion exchange, Dowex 50W-X1 cyclohexyl- synthesized by using a strategi like th;ri r-,:.L:r tite form (26%), R = c-C6HrrNHs*; (d) Dowex 50W-X1, oC, preparationof l8 (eq5t. I)ue t,,tht.riitti,,lli.'.-..:., rrn- H* form, 60 18 h; NaHCq 01%). o -' hydrolysis, , no--Aoa,n. - t -> BR sro ' - and hydrolysis of the ketal ac.- yielded compound 5. Efforts to reducethe azidegroup of 19 ?0 5 to an amino functionality resulted in reduction of the

ketone group. o o RR .sio' ) - nF ,'. .' 3-(Acetylamino)hydroxyacetone 1-phosphate ( 12) \-/ .Ct 22 23 was synthesized by using a related procedure (eq 3). a,a

o o o b / - toPha-"',/ - - xo -J( oporoBzr. I . i clt v *./-o'-tPh 6 7 )a

o EtO oEt (a) t-Bu(CH3)2SiCl.imidazole. -1 h rSl'-' : h K(tH. \1eOH, AcNH\v,rl.\\.,,o.- Ph acux--)(---o\,-,Ph d oC. " - - (3) H2O,'fHF. -10 "C - 5 ll0 min, {9()(ir: ,1, ( (tt'.,_.I'hH. re- 89 flux, 30 min; (d) CHgCHN2, EtrO. rllrr'1 :l - 2;Ji: {e) 'l'HF. (PhCH2O)2P(O)OH,PhH, 2 h (53%): (f) .\r (lH. Il_( ) relltrx. I h (42Vo);l}Vo Pd-C/H2, MeOH, I h (lott'l , o EtO oEt Ero oEt u / L AcNH\vX\-,/oH - acHH--{_..oPo,R, oPorHNa -AcNH _ _ tered in the debenzylation of 17. we emltlovecl a tr,rf -bu- 12 10 11 tyldimethylsilyl protecting group. oC, (a)TMSCN, 120 2h (86Vo);(b) Zn, Ac2O-AcOH, th (71%); Phosphonomethyl Glycolate (31). The ;rhosphonate (c) c(oEtr)3,H2soa, EtoH, 1 day (68%);(d) 10% Pd-c/H2, 29 was preparedin two stepsfrom dibenzvlphosphonate EIOH, (91%);(e) pyridine, oC, 3 days POCle, THF, 0 30 min; (eq6).26 Cleavageof the sillll protec'tinggro1111 ot'curred pyridine-water;ion exchange,Dowex 50W-X1, H+ form,80 oC,5 h; NaHCOs(80%). D HPO(OBzlr^ HO -POlOBzll2 - Rn S:- I P-i:Fl: Treatment of the acid chloride 621with trimethylsilyl 27 28 .. cyanide gave the acyl cyanide 7. Reduction of 7 with zinc (6) in acetic acidf aceticanhydride22 occurred smoothly with- - ' no.--t- ---o - rrl out affecting the a-alkoxymethyl ketone moiety and u ct-'o,or.,,. - ira r,fr3 yielded 8. Ketalization, deprotection,phosphorylation, and 30 31 (a) Paraformaldehyde, Et3N, PhH, reflux. 2 h QlVc); (b) (CO- deketalization gave 12. 'f The synthesisof (^R)-1,3-dihydroxy-2-butanone 1- Cl)2, PhCH3,21 68q" ): tc) AcOH. H,O. HF. 2-1h (89% ); (d) 10% (100% phosphate (18) illustrates the introduction of the phos- Pd-C/H2, MeOH. I h ). phate group by a reaction of a diazo ketone with dibenzyl phosphate(eq 4). Aldolaseselectively removes the pro-S (23)Levene, P. A. J. BioL.Chem. 1936, /1J, 153. (24) Pinnen,F.; Zanotti,G.; Lucente,G. J. Chem. Soc.,Perkin Trans. I 1982,1311. (20) Hartmann, F. C. Biochemistry 1970,9,1776. (25)Hindley. N. C.:Low,J. A. U.S.Pat.2480326, 1949; Chem. Abstr. (21)Benington, F.; Morin, R. D. J. Org. Chem.1961,26,794 1949,4,?. 9086i. (22) Pfaltz, A.; Anwar, S. Tetrahedron Lett. 1984,25,2977. (26)Phillion. D. P.;Andrew. S. S. TefrahedronLett. 1986,27,1477. Synthesisof Triose PhosphateAnalogues J. Org.Chem., Vol. 53, No. 15, 1988 3459

at room temperature by using a mixture of aqueoustet- , ,a^t'r-curoa h //t\'-- -CHO -\ -__j -', / /' (11) rahydrofuran and as solvent;2?hydrogenation LNAC LNAc 5U 51 removed the benzyl protecting group to give 31. 49 Synthesis of Aldehydes. trf-(Benzyloxycarbonyl)- o 7"'--cuo (3a) was preparedby two procedures: 1.:'--cH,oH (12) aminoacetaldehyde LNEoc \-J".. that shown in eq 7 and ozonolysis. The latter was the 52 53

cH?oH -CHO ---3- cH(ocH.), /,r^\.y- .z^'- - itrtt^ct-t1ocn,), cbzNH .orrnfY (7) -\l" (13) U 54 55 (a) pyridine(50V"); (b) (COOH)2, PhCHzOCOCI,EtOAc, THF, (a) (b) (COCI)2,DMSO, CH2CI2,EteN; (c) H2O,reflux, 4 days(72%). AczO, CH2CI2@5V"\; PDC, CH2CI2GjVo). preferred method (eq L4). The synthesis of 3-O- A general strategy based on ozonolysis3aof an appro- methyl-n-glyceraldehyde (40) started with fructose priately placed vinyl group followed by a reductive workup (35);28the optical purity of 39 was establishedby meas- (zincf aceticacid3a or dimethyl sulfides5)provided aldeh- - uring its (eq 8). The preparation of 2-O ydes34, 59, 61, 64, and 68 (eq 14-18). In the caseof 34, oH b Ho -ro..,on fnaoo1-o. .o -4 * cozNa'-V - .'.J-Y' (14) ? o ",.;:-O ( - (Y" -"o-A -cHloEt), o, \",^ i \-/ __ \-jl' "# oH I nJI-""l 35 36 37 uru/'\y' c - BocNH^V b '"u-Y" 56 s8 o?' OH d n,co- e -c * ----\:/\ ," . -\ 'cH(oEr), - r..o-A.ro -cH(oEt), acnu*b-acrux^fH(16) 38 39 tl 60610 (a) AcOH, Pb(OAc)r,(COOH)2; (b) HC(OEt)3,NH4NOB, EIOH -- -10 oC * oC; (24%,35 37); (c) CHsSOzCl,pyridine 0 NaOH, OH oApn oA"n I H2O(5380); (d) NaOMe,MeOH, reflux,24 h (76%);(e) HzSO+, 40 I I oc, t2 h (91%). Hrcl\y' € - \c/'^\Z vrJo (t7) 62 63 64n methyl-o-glyceraldehyde (a ) started from mannitol and followed the route leading to the analogous 2-O-benzyl OH OMe OMe (eq To problems in isolation, ti derivative 9).2e circumvent h ,nAH s > ,n* - ,n* ,n/-'Vo ga1 ,'o> Ho--r 65 66 67 68H a:?_""o> ___,-S;:l ==_o "t3=_on (e) (a)PhcHzococl, K2co3, EtoAc/H2o (97%); (b) os, MeoH/ r/-: to. F-ocH3- ""J<:,j cH2clz,znlAcoH (s8-95%);(c) EteN' CH2CI2'(tBuOCO)zO' l-on ) l-o.D LoH \o/ \o/ (91%); (d) AczO (95Vo);(e) NaH, PhCH2Br, THF (67Vo);(f) Or, MeOH/CHzClz, (CH3)2S (60-71%); (g) CH2CH2MgBr, THF (63%); (h) NaH, MeI, THF (71%). (a) NaH, MeI, (CH3OCH2)2,37-40 oC, 16 h (85%); (b) AczO, AcOH, H2SO4$j%o); (c) Dowex 1-X8, IO4- form, H2O (81%). 59 and 61, the correspondingprotected allylamine deriv- ative was the starting material. For the synthesisof al- 43 was oxidized with an anion exchangeresin previously dehyde 68, the addition of vinyl Grignard to benzaldehyde treated with periodate.30 (+)-2,3-Dihydroxy-2- 65 followed by protection of the secondaryalcohol with methylpropanal (48) was synthesizedvia oxidation and methyl iodide precededozonolysis.36 In general,the ap- deketalization of 46, prepared following the literature proach based on ozonolysisgave cleaner reactions and procedure for the preparation of diethyl acetal higher yields of products than did other methods of from acrolein (eq 10).31 forming aldehydes. Acid-catalyzedhydrolysis of the correspondingketals n oEt oEt o il! (eq -L Iead to a-substituted aldehydes 19). The concentra- " - n (10) \-\r *o., ,o-^';14o., "o-^;- xo'o'H'c to *'' CH3Or o ol oL ou .9611, H' tl t-X" "---.-\xB- -\ (19) (a) NHrNO3, EIOH, HC(OCH3)3,40-45 oC, 3 h (68%); (b) KMnOa,HzO (45%);(c) Dowex50W-X4, H+ form (79%). 69,R=N3 70,R=N3 71,R=Cl 72,R=Cl Oxidation of the corresponding N-protected alcohols by 73,R=Br 74,R=Br the method of Swerns2 led to -l[-acetylprolinal (51) and tion of these aldehydeswas measuredin aqueoussolution N-(tert-butoxycarbonyl)prolinal (53) (eq 11 and 12). by using the Willstaedter-Schudelalkaline iodide me- Pyridinium dichromate oxidation of cyclopentane meth- 16o4.ez,ss anol 54 yielded cyclopentanaldehvde (55) (eq 13).33 Discussion for the preparation of (2?) Corey, E. J.; Venkateswarlu,A. J. J. Am. Chern. Soc. 1972,94, Analogues of DHAP. Methods 6190. halohydroxyacetonephosphates have been describedin the (28) Racemic 3-O-methylglyceraldehydehas been reported as its di- mer: Fischer,H. O. L.; Baer, E. Ber. 1932,65,345. (29) Ballou,C. E.;Fischer,H. O. L. J. Am. Chem.Soc. 1955, 77,3329. (34) Ozonation in Organic Chemistry; Bailey, P. S., Ed.; Academic: (30) Harrison,C. R.; Hodge,P. J. Chem. Soc.,Perhin Trans.l 1982, New York, 1978;Vol. I. 509. (35) Pappas,J. J.; Keaveney,W. P.; Gancher,E.; Berger, M. Tetra- (31) Rabjohn,N. Orgonic Syntheses;Wiley:New York, 1963;Collect. hedron Lett. 1966. 4273. Vol. IV, p 21. (36)Brown, C. A.; Barton, D. Synfhesis1974, 434. (32) Omura, K.; Swern, D. Tetrshedron L978,34,1651. (37)Willstaetter, R.; Schudel,G. Chem.Ber. 1918,51,780. (33) Corey,E. J.; Schmidt, G. TetrahedronLett. 1979,399. (38)Baer, B.; Fischer,H. O. L. J. Biol. Chem. 1943,150,223. 3460 J. Org.Chem., Vol. 53, No. 15, 1988 Bischofberger et, al. literature,20but synthetic routes leading to more chal- 3-Azido-2,2-dimethoxy-l-propanol (3). A mixl.ure o{ the lenging analoguesof dihydroxyacetonephosphate, espe- benzoate 2 8.92 g. 17.9 mmol), trimethl,'l orthoformate (20 mL), cially the alkyl-branchedcompounds 18 and 26, have not methanol (10 mL), and concentrated sul{ttrit'acid {twtt rJrops)was After 2 davs of'analvsis, TLC showed been reported. As demonstrated in eq 2-6, the former st,irred at room temperature. that all of the starting ntaterial hacl lteetr cot'tsttnterl(cy'clo- method can be extendedto obtain additional heteroatom hexane/ chloride,/ether 20:I 0:I ). I)otassittm carbonate analoguesof DHAP by nucleophilic displacementof hal- (2 g) was adderl ancl after stirring I'or.itt itrlditiotrai ?l h. the ogens. The alkyl-branchedderivatives were not available reaction mixturc' was p()ured int,, ethl'l a('etate r20()nrl,) and by using standard methods but could be synthesizedby extracted trvice with water and once with satttratecl aqtteotts Na('l. reaction of suitably functionalized acid chlorides,e.g., 15 The organic laver rva-.dried over N'1gS0, and the solvent rva,c and 22, with diazoalkanesto form intermediate azo ke- removed by'evaporation in vacuo. The crude prt.rduct ('1.-1g) u'as tones, followed by introduction of the phosphate group chromatographed isilica gel. hexaneTiethyl acetat,e2:1 to l:2) trr with the aid of dibenzyl phosphate. This method should vield il {J.l g,;',\%l asa c'olttrlessoil: IR (neat)3620.3500,:120 r: rH (CDCIB, (d, = prove generalfor the synthesisof analoguesof DHAP. We cm NIIR ll00 NIHz) 6 3.65 J 5 Hz.2 H). ;1..1 2 H), il.3 (s, 6 H), 2.3 (s. 1 H. OH). found the acid-labile tert-butyldimethylsilyl group to be ls, 3-Azido-2,2-dimethoxy-l-propyl Phosphate, Bis(cyclo- a protecting group. The benzyl superior to benzyl ether as hexylammonium salt) (4). A soluticrttof il-azido-2,2-dimeth- ethers exhibited an unexpected resistanceto hydrogen- oxy-1-propanol ij]) (3.5 g. 15.5 mmril) in tetrahvdrofuran (50 ml,) olysis: we were not, for example,able to prepare 26 from ivas added dnrprvise to a solutiotr ot'1;hosphortts oxt'chloride (11 the benzyl ether correspondingto 24. The convenient mL, 3il mrnol) in pvridine (15 mL) and tetrahl'drofttran (20 mL) o(-'. synthesisof the protected epoxy aldehyde 38 from fructose at 0 oC. After stirring for I h 31 () l0 mL of a solution o1' providesanother potential chiral building block for use in py'ridine/water (1:ll)rvas added.'I'he' solution was cottcentrated organicsy'nthesis. Although the enantiomericexcess of 40 in vacuo and the residue 1'ys,.passed through an ion exchange wasnot establishedindependentl-v-. the method of slnthesis column (Dowex i()\\'-Xi, cvclohexvlammonittm I'orm, irO 10(l x adjusted the suggeststhat it should be high. mesh, 3.5 15 cni). Addition of cyclohexl-lamine solution to pH 8. The solution was evaporated repeatedlJ' ttr DHAP is a substratefor three important enz],'rnes:FDP dryness with continual addition of 2-propanol to remove water. aldolase,triosephosphate isomerase, and sn-glycerol-3- The resulting oil rvasdissolr,ed in a soitttion of 2-propanol/eth1'l oC. phosphatedehydrogenase.3e Derivatives of DHAP have acetaLefether (1:l:1. 1,50mL) and stored overnight at -1o The been suggestedas medicinal agents.a0 The synthetic resulting precipitate was separated b1' filtration and retluxecl in methods describedin this paper provide routes to a variety 100 mL ttf . Filtration remrx,ed insolrrblesalts and the of analoguesof DHAP and should be useful in studying filtrate was diluted with ether t5o mL) and ailowed to stand the enzSrmologyand medicinal chemistry of this substance. overnight. The precipitate was collected b1't'iltration and crys- (, Analogues of G-3-P. The preparationof most aldeh- tailized t'rrlnr water,'acetttne i 1:2.;-ri. ont'etrtratiotl of the m

(39) Michal, G. In Methods of Enzl,aqlic Analysis,3rd ed.: Berg- meyer, H. U., Ed.; Verlag Chemie: Weinheim, 1984;Vol. VI, p 342. (41)Lang, C.ln Methodsrtf F,nztmotrc Anolrsis.:lrd ed.; Bergmever, (40)Rao, G. V.; Que, L.; Hall, L. D.; Fondy, "1.P. Carbohl'dr. Res. H. tl., Ed.; \IerlagChemie: \\'ernheim.1984: \Iol. \'1. pp 525-5:ll. 1975,40,311.Pero, R. W.;Babiarz-Tracy,P.;Fondy, T. P. J. Med. Chem. (42) For the preparationof acy'lcvanides, -"ee: Huenig, S.: Schaller, t977.20.644. H. ACIEE 1982.21.iJ6. Herrmann. K.: Simchen.(] ^Srnthesis1979, 204 Svnthesis of Triose Phosphate Analogues J. Org. Chem., Vol. 53, No. 15, 1988 3461

2.1(s. ll H). Anai. Calcdfor Cr2H,5NO3:C'.65.1.1; H,6.83; N, product isolatedafter chromatography(silica gel, ether/hexane {i.:l:1.F'orrnd: (.. 64.85;H, 6.60;N, 6.02. 1:1)was a vellowliquid (1.89g, 79%): Ia]p *32" (c 4.8,chloro- IH N -[2,2- Diethoxy-l]- (ben zyloxy )-I -propyllacetamide (9). A form): IR (neat)2100, 1640, 1500, 1100,695 cm-l; NMR (CDCI3, mixtureof the ketone8 (2.0g. 9 mmol).10 mL of ethanol.3 mL 300 MHz) 6 7..1(s, 5 H), 5.7 (s, 1 H), 4.5 (s,2 H), 3.9 (q, J = 8 ( i b mmol) of triethvl orthoformate,and two dropsof sulfuric acid Hz, 1 H). 1.35(d, J = 8 Hz,3 H). The productdecomposed on wasstirred at room temperaturefor 1 dav. Anhvdrouspotassium storing and was used immediately in the next step. carbonate(200 mg) wasadded, and, after stirring overnight,the (.R) -Dibenzy I 3-( Ben zyloxy\ -Z-oxo-1 -butyl Phosphate ( 17 ). mixture wa-sdiluted with ether and extractedwith a dilute solution A mixture of the diazocompound 16 (1.52g,7.4 mmol) and of KOH and then with saturatedaqr:eous NaCl. The organic dibenzylphosphate (2.41 g,8.7 mmol) in (40 mL) was Iavers were dried over NIgSOI and concentrated in vacuo. heated at 60 oC for 12 h. The benzenewas removed by evapo- Chromatographvof' the crude product (silicagel, ether/ethvl ration in vacuo, and the crude product was chromatographed acetate1:1 to ethvi acetate)r'ielded 9 as a vellowishoil (1.8g.689c): (silicagel, hexane/ethyl aceLatefchloroform 2:I:1L

(s,3 H),0.90(s, 9 H), 0.05(s,6 H). The productwas used directly H, CH2CO),3.67 (br, 1 H, OH); 13CNMR (CDCI3)6172.0 (CO), in the next step. 135.5,128.5 and 127.9$ s, aromatic C), 68.2 (CH2PO),60.25 ( + ) -Diben zyl 4-l(tert -B utyldimethylsilyl )oxy I -3- oxo-2- (CH2CO),58.5 and 56.2(2 CH2Ph). Anal. Calcdfor C17H1eO6P: butyl Phosphate Q$. To a solutionof dibenzylphosphate (2.6 C, 58.29;H, 5.46. Found: C, 58.60,H,5.2I. g, 9.3 mmol) in benzene(a0 mL) was added a solution of diazo Phosphonomethyl Glycolate (31). The dibenzyl phosphonate ketone23 (2 g,9.2 mmol) in 5 mL of benzene.The mixture was 30 (150 mg, 0.43 mmol) was treated with I0To palladium on stirred at room temperature for 2 h, the solvent was removed by charcoalas describedfor the phosphate26 to yield 82 mg of 31: distillation, and the residue was chromatographed (silica gel, 13cNMR (D2O)6 174.9(CO), 60.83 (CH2PO), 50.0 (CHzCO); hexane/ethyl acetatefmethylene chloride 3:1:1to 2:1:1)to yield MS(FAB), mf e calcd191.979, mf e fowd 191.980(M*). 24 as a colorlessliquid (2.3g,53%): lH NMR (CDCI3,300 MHz) N-(Benzyloxycarbonyl)aminoacetaldehyde Dimethyl 6 7.3(s, 10 H), 5.2-4.85(m, 5 H), 4.35(s, 2H\,1.45 (d,J = 7 Hz, Acetal (33). Benzyl chloroformate (30 mL, 210 mmol) was added 3 H),0.85 (s,9 H),0.05 (s,6 H). Anal. Calcdfor C2aH35O5PSi: dropwise to a solution of aminoacetaldehydedimethyl acetal (32) C, 60.28;H, 7.38. Found: C, 60.50;H,7.25. (16.9g, 161 mmol) in 50 mL of ethyl acetateand 50 mL of py'ridine (+)-Diben zyl 4-Hydroxy-3-oxo-2-butyl Phosphate (25). A at 0 oC. The mixture was stirred at room temperature overnight, solution of 24 (1.7 g, 3.6 mmol) in a mixture of 30 mL of tetra- and the product was isolatedby distillation as a colorlessoil (20.2 'C hydrofuran, 5 mL of acetic acid, and 10 mL of water was refluxed g,50To):bp 145 (0.03Torr); IR (neat)3465, 3350, 1730, 1305, for t h. The volatiles were evaporated in vacuo and the residue 1220cm-t;13C NMR (CDCI3)6 156.1(CO), 136.1,127.9 and 127.5 was chromatographed (silica gel, methylene chloride/ethyl acetate (aromaticC),102.2 (CH(OCHg)2),69.1 (CH2O), 53.4 (CH2NH), 2:1tn 1:3)to give25as a colorlessliquid (550mg, +2%): lH NMR 41.9(CH3). Anal. Calcdfor C12H17NOa:C,60.24; H,7.16; N, (CDCI3,300 MHz) 6 7.25(s, 10 H),5.2-4.75(m, 5 H), 4.25(s,2 5.85. Found: C, 60.55;H,6.97; N, 5.80. H),3.1 (s,1H, OH), 1.35(d,J= 7 Hz,3H). Anal. Calcdfor N-(Benzyloxycarbonyl)aminoacetaldehyde (3a). A mixture C18H21O6P:C, 59.38;H, 5.81. Found: C, 59.10;H, 5.79. of the acetal33 (2.4g, 10 mmol), oxalicacid (200mg), 20 mL of (+)- -Hydroxy-3-oxo-2-butyl Phosphate (26). A solution tetrahydrofuran, and 10 mL of water was refltxed for 4 days. After of the dibenzvl phosphate25 (180 mg, 0.5 mmol) in 5 mL of evaporation of the solvent, the mixture was chromatographed methanol was h-v-drogenatedin the presenceof 10% palladium (silicagel, hexane leLhyl acetate 2:I to 1:2)to yield 34 as a colorless on charcoal for t h.2? The catalyst was removed by filtration liquid (L.4g,12%): IR (neat)3460, 1730,1770,1320, 1105 cm-I; through Celite, and the filtrate was evaporatedto dryness. The lH NMR (300MHz, CDCI3)6 9.3(s, 1 H), 7.30(m, 5 H), 5.65(br, residuewas dissolvedin water, and the solution was adjustedto 1 H), 5.1 (s, 2 H),4.05 (d, J = 5 Hz, 2 H). Anal. Calcd for pH 5.5 with a solution of 1 N NaOH. The solvent was removed Cr6HllNOs:C,62.77; H,5.74; N,7.25. Found: C,62.57;H,5.87; under reducedpressure to provide 26 in quantitative yield: 13C N, 6.81. NMR (D2O)6 72.8,62.3,17.I.Compound 26 could not be reduced o-Glyceraldehyde Diethyl Acetal (37). n-Fructose(35) (20 by glycerol phosphate dehydrogenase(GPDH) in the presence g, 111 mmol) was dissolvedin 20 mL of water and the solution oC, of NADH in an enzymatic assay.al was stirred with 1 L of glacial acetic acid. After cooling to 16 Dibenzyl (Hydroxymethyl)phosphonate (28). A mixture lead tetraacetate (I02 g,230 mmol) was added with vigorous of paraformaldehyde(1.2 9,40 mmol), dibenzyl phosphonate(27) stirring during 10 min. After stirring for an additional 30 min, (5 g, 19.1mmol), triethylamine (1 mL, 7 mmol), and 10 mL of a solution of oxalic acid (20 g) in 200 mL of glacial acetic acid benzenewas refluxed for 2 h; paraformaldehydeslowly dissolved. was added, and the resulting suspensionwas filtered through a Ethyl acetate (100 mL) was added, and the solution was extracted layer of Celite. The solvent was removed in vacuo,the remaining three times with a solution of 1 N HCI and once with water. After oil was treated with ethyl acetate,and the insoluble matter was drying over MgSO4and concentrationin vacuo,the residuewas removed by filtration. The filtrate was concentrated in vacuo chromatographed(silica gel, methylene chloride/ethyl acetate2:1 to give a colorlessviscous oil 36 which was not characterized.aa (12.5 to methylene chloride f acetone1:1) to yield the phosphonate 28 Triethyl orthoformate (50 mL) and a hot solution of L e as a colorlessoil (1.5g,27To): IR (neat)1320, 1140 cm-l;rH NMR mmol) of ammonium nitrate in 20 mL of'absoluteethanol was (CDCI3,300 MHz) 6 5.05-4.98(m,4 H, 2 CH2Ph),4.35 (br, 1 H, added to 36 with stirring, and the solution n'askept at 30-32 "C OH), 3.8a(dd,4 = 5.8Hz, Jz= 5.9H2,2H, CH2PO);13C NMR for t h and Lhenat room temperature for 15 h. Anh-'-droussodium (CDCI3)6136.1, 128.5 and 127.9(3 s,aromatic C),68.05 (CH2PO), carbonate(7 g) wasthen added. After beingstirred for 1.5h, the 58.8and 56.25(2 CH2Ph). Anal. Calcd for Cr5HrTOaP:C, 6i.64; mixture wasdiluted with 200mL of ether ar-rdthe insolublematter H, 5.86. Found: C, 61.48;H, 6.04. was removedby filtration. Evaporationofthe solventsin vacuo (Dibenzylphosphono)methyl 2-O -(tert -B utyldimethyl- left an oil that was dissolvedin 70 mL of methanol and added silyl)glycolate (29). Oxalyl chloride (2 mL,23 mmol) was added to a solution of 18 g of sodium methoxide in 300 mL of methanol. dropwise to the protected acid 21 (1.33g, 7 mmol) in 39 mL of After stirring the reactionmixture at room temperature for 2 h, . The reaction mixture was stirred for 30 min at room 5 mL of water was added and was bubbled through temperature and was heated at 80 oC for 30 min. Approximately the reaction mixture to neutralize the alkoxide. The resulting 15 mL of liquid was removed by distillation at atmospheric precipitate was separatedby filtration, the filtrate was concen- pressure,and the remaining mixture was slowly added to a solution trated in vacuo,and 150 mL of ether was added to the residue. of 1 g (3.4mmol) of alcohol 28 in 30 mL of pyridine at 0 oC. After After filtration and concentration in vacuo, chromatography (silica being stirred at room temperature for 24h, the reaction mixture gel, chloroform to chloroform/methanol 10:1) followed by dis- was concentratedin vacuo. The residue (in 100 mL of ether) was tillation yielded 37 as a colorlessoil (4.32g,24To yield basedon 'C extracted three times with a 1 N solution of sodium bicarbonate fructose): bp 85 (0.5Torr); [o]"o +30.3' (c 1.04,ethanol); and once with water. After drying over MgSOa,the solvent was lH NMR (CDCI3,300 MHz) 6 4.49 (d, J = 5.i Hz, 1 H, CH), evaporatedat reduced pressureand the material was chroma- 3.85-3.5(m, 7 H), 2.48(br, 1 H, OH), 2.2(br,1 H, OH), 1.23(t, tographed (silica gel, hexane/ethyl acetate 2:l) tn yield 0.9 g (58%) J = 7 Hz,3 H, CH3),I.2I (L,J = 7 Hz, 3 H, CHr). Anal. Calcd of ester29: IR (neat) 1775,1310, 1140 cm-l; lH NMR (CDCI3, for C7H16Oa: C,5I.2I; H, 9.82. Found: C, 51.17;H, 9.48. The 300MHz) 6 7.33(m, 10 H),5.08-5.04(m, 4H,2 CH2Ph),4.38 product was further identified by conversionof the free aldehyde oC (d, J = 8.6 Hz, 2 H, CH2PO),4.2(s, 2 H, CH2CO),0.89 (s,9 H, (obtainedby treatment of 37 with 0.1 N H2SO4at 35 over 20 oC, ((CH3)3C),0.06 (s, 6 H,2 CHr). Anal. Calcd for C23H33O6PSi: h) to its dimedone derivative;mp 199 [a]n +216' (c 0.6, oC, C, 59.46;H,7.I7. Found: C, 59.68;H, 6.99. ethanol);lit.44 mp 196-198 [o]o 2I0 (c 0.6,ethanol). (Dibenzylphosphono)methyl Glycolate (30). The fully o-Glycidaldehyde Diethyl Acetal (38). A solutionof 4.11 protected ester 29 (300mg,0.64 mmol) was dissolvedin a mixture g (25 mmol) of o-glyceraldehydediethyl acetal (37) in 15 mL of oC of 3 mL of acetic acid, 1 mL of tetrahydrofuran, and 1 mL of water pyridine was cooled to -10 and 2.98 g (26 mmol) of meth- -5 oC and was stirred at room temperature for 24 h.n The solvents were anesulfonyl chloride was added with stirring at -10 to over oC evaporatedat reducedpressure, and the residuewas chromato- 20 min. The reaction mixture was kept at 0 for 1.5 h and then graphed (silica gel, methylene chloride/ethyl acetate 1:2) to yield evaporated to dryness. The resulting residue was partioned 200mg (89Vo)of 30 as a colorlessliquid: IR (neat) 1750,1320, tH 1130cm-l; NMR (CDCI3,300 MHz) 67.23(m, 10 H), 5.02-4.89 (44) Perlin, A. S. In Methods in Chemisfry; Academic (m, 4 H, 2 CH2Ph),4.29 (d, J = 8.7Hz,2 H, CH2PO),4.03 (s, 2 Press: New York, 1962;Vol. 1, p 61. Synthesis of Triose Phosphate Analogues J. Org. Chem., Vol. 53, No. 15, 1988 3463 betweenmethylene ctrloride (80 mL) and cold water (10 mL). The The residuewas partitioned between water (100mL) and chlo- organic layer was washedthree times each with saturated solutions roform (200 mL). The organic layer was washedthree times with of sodium bicarbonateand NaCl, dried over MgSOn,and con- water. dried over Na2SOa,and concentratedin vacuo. Trituration centrated in vacuo to yield a colorlessoil. Chromatography (silica with n-hexanelielded 42 as colorlessneedles after filtration (11.49 gel, chloroform/ethanol 10:1) gave a colorlessoil which was g,85Vc). An analyticalsample was recrystallizedfrom hexane: oC: -69.6' 1H identified by its tH NMR spectrumto be the 3-O-mesylateof 37: mp 83-84 [alp (c 0.5,CHCI3): NMR (CDCI3)6 5.06 lH NMR (CDCI3)6 4.48(d, J = 6 Hz,1 H, CH), 4.42(dd, Js"^ (d,4"- = 5.9Hz. 2H,2 OCH2"O).4.56(d, 2H.2 OCH2bO)'4.33 = ll H4 J,i" = 4.4 Hz,1 H, CI{2'OSOz),4.3 (dd, Jge^= l1' Hz, (dd, Jn.- = 10.?Hz, J,i, = 4.9Hz,2H,2 OCH2,CH),3.6 (dd, J"i" -- J,i"= 4.3H2,1 H, CFl2bOSOr),3.83 (m, 1 H, CH), 3.85-3.7(m, = ca.'0 Hz, 2 H, CH2bCH),3.55 (ddd, Ju.i,, 9.5 H4 2 H, 2 4H,2 CH2"CH3),3.7-3.5(m,2 H, 2CH2;C}{),3.06(s,3 H, SCH"), CHOCH3),3.37 (s, 6 H, 2 OCH',).3.31 (dd, Jui.' = 10.2Hz,2 H, 2.42(d,J = 4Hz,1H, COOFI),I.23and 1.21(2t,J = 7 Hz,6 2 CH(O)CH(O)).Anal. Calcdfor CrsHlsO6:C,51.28:H,i.74. H, 2 CHJ. This material was usedin the next step without further Found: C, 51.20;11,,7.74. characterization. 2,5-Di-O-methyl-o-mannitol (43). A solution of 42 (10.78 A solution of 1 N NaOH was added to a solution of 37 in 20 g, 46 mmol) in 40 mL of glacialacetic acid and 90 mL of acetic oC mL of water at 30'C containingphenolphthalein (l% in ethanol) anh5'dridewa-s cooled to 0 and 0.2 mL of concentratedsulfuric as an indicator; 16.5mL of NaOH solution was added during 60 acid wasadded. After the reactionmixture wasstirred at room min to keep the pH of the mixture slightly basic. The reaction temperaturefor 80 min. the solutionwas poured into ice water mixture was then extracted three times with 20 mL of methylene (700ml,). and this mixture was stirred for t h and then rvas chloride. The combined extractswere washedwith brine, dried extractedfottr timesrvith chloroform (200 mL). The combined over MgSO4, corcentrated in vacuo, and distilled at reduced organiclayers were u'ashed rvith a saturatedsolution of'sodium pressureto yield I.94 g of 38 (53% basedon n-glyceraldehyde bicarbonateand with water,dried overNa,SO.. and evaporated diethylacetal): bp72"C (24Torr); [o]t8o+7.2" (c 1, ethanol); in vacuoto yield an oil that was not characterizedbut was dis- lH NMR (CDCI3)6 4.32(d, J = 4.3}{z,1 H, CH), 3.8-3.6(m, 2 solvedin 200 mL of a solution of 1 N HCI in methanol and kept H, 2 CH1.CH3),3.6-3.4 (m, 2 H, 2 CHzbCHr),3.08 (m, 1 H, at room temperature for 24 h. After evaporationof the solution CHCH2),235 (m,2 H, CHCH2),I.23 and 1.2 (2 t, J = 7 Hz,2 in vacuo,crystallization from chloroform yielded colorlessneedles oCl -20.3o(c i:rC CHr). Anal. Calcd for C7H1aOs: C, 57.52;H, 9.65. Found: C, of 43 (5.84g.60%): mp 55-57 [rv]p 1, CH.OH); 57.09;H, 9.28. NMR (DMSO-d6)6 81.57,68.61,60.73, 58.02. Anal. Calcdfor 3-O-Methyl-o-glyceraldehyde Diethyl Acetal (39). A so- CsHlsO6:C.15.72: H,8.63. Found: C,45.78:H.8.66. lution of the epoxide38 (1.46g, 10 mmol) in 5 mL of methanol 2-O-Methyl-o-glyceraldehyde (44). Ion exchangeresin was added to a solution of sodium methoxide (100mg, 1.85mmol) (Dowex 1-X8. IOl- form. preparedfrom the chlorideform (2 g) in 45 mL of methanol and the resultingsolution was refluxed for accordingto the procedttreof Harrisonand Hodge30)was added 24 h. Carbon dioxide then was bubbled through the solution. and to a soltrtionof 13 {.120mg. 2 mmol) in'1 mL of water.and the the mixture was concentratedin vacuo and triturated with 20 mL mixture rvasstirred at rttomtemperature for:l h. The resinu'a-' of ether. The resulting precipitate was separatedby filtration removedblr filtration and the filtrate rvasdiluted rr'ithwater to and the filtrate was evaporatedto leave a colorlessoil that was 10 mL. The concentrationof aldehyde11 in this solutit)n\l'as purified by distillation under reducedpressure to yield 1.35g of 325mM (81% yield) accordingto the Willstaedter-Schr.rdeial- 'C lH (1 3g (76%);bp 111 (27Torr); [a]p +31.6(c 1,ethanol); NMR kaline iodine method.37'38An aliquot mL) of this solution was (CDCIJ 6 4.46(d, J = 3.7Hz,1 H, CH), 3.8-3.4(m, 7 H), 3.37 added over a 10-min period to a solutionof 2,4-dinitrophenyl- (s,3 H, OCH3),2.37 (d, J = 3.5H2, \ H, CHO.FI),I.27 (2 t, J = hydrazine(5? mg, 0.29mmol) in 1.3mL of 2-methoxyeth-"-lether 7 Hz,2 CHr). Anal. Calcdfor CsHlsOa:C,53.92; H, 10.18.Found: (diglyme)and 0.2 mL of aceticacid. After being stirred for 17 C, 53.71;H, 10.40. h, the yellow solution was diluted with water (2 mL) and the 3-O-Methyl-n-glyceraldehyde (40). A solution of 891 mg resulting precipitatew€Ls removed by filtration, washedwith water. (5 mmol) of 39 in 5 mL of 0.1 N sulfuric acid was heated at 40-42 and dried in vacuo (65 mg, 79%). Recrystallizationfrom methanol oC; oC for 12 h. The solution was neutralizedwith 1 g of ion exchange gaveyellow needles: mp 150-151 Ia]p *48o (c 0.5.CHClrt; resin (Dowex 1-X8, HCO3- form), the resin was removed by fil- 1H NMR (CDCI3)6 9.11(d, J = 2.6H2,1 H), 8.33(dd, J1 = 9'5 tration, and the filtrate was concentrated in vacuo. The con- Hz,J2= 2.6H2,1H),7.93 (d, J = 9.5H2,1H).7.45 (d, J = 6.it centration of 40 in the aqueoussolution was 4.58M (91% yield) Hz, 1 H), 4.02(m,1 H), 3.95-3.7(m, 2 H). 3.46(s, 3 H), 2.07(t, accordingto the Willstaetter-Schudel alkaline iodine method.37'38 J = 6.5 Hz, 1 H); HRMS, mf e ca\cd287.075,m/e found 287.075. Identification of 40 as its (2,4-dinitrophenyl)hydrazonewas as 2-Methylpropenal Diethyl Acetal (46). A hot solutionof follows. An aliquot (0.1 mL, 0.458 mmol of aldehyde) of the 870 mg (11 mmol) of ammonium nitrate in 15 mL of ethanol was aqueoussolution was added to a mixture of 81 mg (0.41mmol) added to a stirred mixture of freshly distilled methacrolein(45) of 2,4-dinitrophenylhydrazine,2 mL of 2-methoxyethylether (16 g, 228mmol) and triethyl orthoformate(30.7 g,20i mmoi). oC (diglyme),and 0.3 mL of aceticacid. After being stirred at room and the resulting suspensionwas heated at 40-45 for 3 h. A temperature,the solution was diluted with 5 mL water, and the precipitateformed and was removedbv filtration. Anhydrous precipitate that formed was separatedby filtration, washed with sodium carbonatewas added to the filtrate. and the mixture was water, and dried in vacuo to give a yellow solid (74 mg, 64%). stirred at room temperatureovernight. The reactionmixture was Recrystallization from ethanol/water yielded 40 [(2,4-dinitro- filtered, concentrated in vacuo, and distilled to yield 46 as a oC; phenyl)hydrazonelas yellow needles: mp 122-123 [a]o -21'.9" colorlessliquid (20.2g,68%),bp 142-143"C. This compound (c 0.33,chloroform/methanol 2:1); lH NMR (CDCI3)6 9.1 (d, J-ut" was identified by convertingit to its (2,4-dinitrophenyl)hSrdrazone = 2.5H2,1H, H-3'),8.31(dd, Jo.tho = 9.5H2,1H, H-5'),7.9(d, as follows: To a solution of 179 mg (0.9 mmol) of 2,4-dinitro- 1H, CI{2"OCHr),3.63(dd, Jui" = 5.2H2,1 H, C,F/2bOCH3),3.43 phenylhydrazine in a mixture of 5 mL of 2-methoxyeth5'lether (s,3 H, OCH3),2.86 (d, J = 5.2Hz. 1 H, OH), 1.55(s, 1 H, NH); (diglyme)and 0.7 mL of aceticacid wasadded l44mg (l mmol) HRMS, mf e calcd 284.075,mf e found 284.075. of acetal46 in 0.5 mL of diglyme,followed by 2.5 mL of water. oC 2,5-Di-O -methyl- 1,3;4,6-di-O -methylene-D-mannitol (42). After stirring at 30*35 for 48 h, the precipitate that formed To a stirred suspensionof 1,3;4,6-di-O-methylene-D-mannitolas was removed by filtration, washedwith water, and dried in vacuo' (41) (11.96g, 58 mmol) in 1,2-dimethoxyethane(200 mL) was Crystallizationfrom ethyl acetatefurnished orangeprisms (20-9 oC oC). added 16.8g (0.35mmol) of a 50% dispersionof sodium hydride mg,84To): mp 203-204 (lit.46mp 206-206.5 in oil. After 15 min a solution of 34.1 g (0.24mmol) of methyl r,t -2,3-Dihydroxy-2-methylpropanal Diethyl Acetal ('17). iodide in 10 mL of 1,2-dimethoxyethanewas added dropwise A suspensionof acetal46 Q0 g, 139mmol) in 170mL of water oC during 10 min. The mixture was stirred at room temperature for was cooledto 0 and a solution of potassium permangalrtate(22 oC 3 h and then at 37-40 oC for 16 h. Methanol (20 mL) was added, g, 139mmol) in 420mL of water wasadded at 5-8 during 3 the mixture was stirred for an additional 30 min, then water (10 h. After stirring at room temperaturefor 3 h and heating at 100 oC mL) was added, and the reaction mixture was evaporated in vacuo. for t h, the manganesedioxide precipitatewas separatedand

(45) Haskins, W. T.; Hann, R. M.; Hudson, C. S. J. Am. Chem. Soc. 1943.65. 67. 3464 J. Org Chem.,VoL. 53, l',1o.15, 1988 Flist'hollrerge,ret al. washedthoroughly with water. The combinedfiltrates were ctxrled 11.07(m, I H. methinei.li.i;r :'i.;lti(nr. f FI,N(lH,t. J.i:t 1.,1 inr. ':t and 335g of anhydrouspotassium carbonate was added. After 2 H,2 CHrt. l.-1ii.irrr1 I ;,i {:. tl" Hoci. four extractionswith ether, the combinedorganic layers were dried Cyclopentanaldehy'de ("i5). .'\ .olttltottttf l.0 g lio ttrtlttli over MgSOn,the solventswere removed in vacuo,and the product of cvclopentanettrethanoir.i.1 tanci ,"tr-l ! riJ mtnrrl)ol 1lrrrtlirrittm wasdistilled under reduced pressure to yield 47 (11g,45%) as dichromate3irin 25 ml, of trrethrlt'trt',hi,,ritle u'lts s1 irre(l rtl roottt lH ''iitir a colorlessliquid: bp 108"C (1?Torr); NMR (CDCI3,300 temperatr.trelirr i da1. I)iitttron t'11','1i,l;r rrri,i. f iltr.tit(,11. MHz) 6 4.35(s, 1H, CH),3.9-3.8(m,2H,2 CH2uCH'r).3.72(dd, and purificationorr siirca gel (elttuttt:ht'rlttte eliii'l ace1,,1s.l:.il JHa-ou= 5.3 Hz, JHa-s.= 11.4Hz,I H, CH2.IOH),3.65-il.;r (m. providecl1()ii mg il\c'i,l,rf'55u'hosr' iH \\lf { .Jrt't'lrlirlirllirl('h€'(l 2H,2 CH2"CH3),3.38(dd, JH-ori = 7.i H41 H. CH".OH).2.49 that reptlrtecl.{e (dd,1 H, CH2OH),1.22(2 t, J = 7 Hz,2 CH3).1.11 (s, 3 H. CH,r). N-(Benz1'loxycarbonyl)ally'lamine (57). .\ I L r.11111i- D,L-2,3-Dihydroxy-2-methylpropanal(48). A mixture of 47 bottomed flask eqrrippedwith a nragnetit'stirring bar rvast hargerl (535mg, 3 mmol) and ion exchangeresin (Dowex50W-X4, H* with ir.7()g(1()() rttnrolitrl'allr-lamine (56), 150 rnl of'qater. il-l.'r form) wasstirred in water (6 mL) at 30 oC for 100min. The re-qin g (25(tnrnrol.) of pot,assiumcarbottate. attd I50 inl, of ethvl a('etate. was removed by filtration and the filtrate was concentratedin The flask u'as cooled in an ice itath and 15.7ml, (9it7r.l0i nttrioli vacuo and then diluted with water to a volume of 10 mL. The ol benzl l lhiorolormate was adcltrcldtrritig ilt) mir-r by usirtg a concentrationof 48 in this solution was 238 mM (i9% vield).31'ei sr-ringepurnp. After stirring at r')()rnlemperature f

3-(Benzyloxy)-l-butene (63). A solution of sodium hydride ((-'Dclir,300 MHz) 6 i.40-7.25 (m, 5 H), 6.00-5.90(m, 1 H), (4.80 g of r,-t\Vcdispersion. 1()0mrnol) in dry'THF (60 mI-) was 5.35-5"28(m. 2 H), 4.65-4.6I(br d, I H), 3.35(s, 3 H). o(' warmed to 45 in an oil bath and benzyl bromide (6.0 mL. 50 2-Methoxy-2-phenylethanal (68).uuA solutionof 67 (0.49? mmol) was added.ird:.1-Hvdroxvhut-1-ene (62) (1.08g. l5 mmol) g, ii.4mmol) in 10mL of methylenechloride/methanol (9:1) was in THF (20 mL) w'asadded dropwise dr.rring20 min. After being cooledt<' -lR "('. treatedwith ozone,and worked up as described heated ftir an additional 45 min. the reaction rnixture was allorved for coml;onnd64 to give0.30 g (60%) of 68: lH NMR (250MHz) to crrol t.o room temperat.ure and water was adcled unt,il er.'olution r59.58 (rl,..J = 1.7.1 H). i.4l-7.32(m,5 H),4.63(d, J= 1.7,1H), of hydrogen ceased. The aqueous layer was separated and ex- 3.411(s. ll Hi. tracted twice with ether; the combined urganic solutions were 2-Azidoacetaldehyde (70). A solutionof acetal69 (1 g, 7.6 washed rn'itha saturaled solution o{.NaCl. dried over NIgSO,. anrl mmol) in a stilutionof acetone(3 mL) and water (0.5mL) con- evaporated in r-acuo. Purificirtiorr rlr -silicagel iherane eihrl taining appr