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J . Org. Chem. 1981,46, 2431-2433 2431by EP R spectroscopy. Th e EPR spec tra in all cases havebeen found to be consistent with the respective radicalanion E PR spectra reported previously.2 Th e intensity ofth e EP R signals increases continuously with time an d th eam oun t of th e radical intermediate after a specific timeinterval is given in Table I. Similarly, LiOBu-t andKOBu-t have also been found to generate radical anionswith polynuclear hydrocarbons, but a t a m uch slower ratecompared to th at of LDA.In conclusion, th e above preliminary results representthe first definitive proof that reactions of alkali metalamides and alkoxides with organic substrates such as alkylhalides and polynuclear hydrocarbons can proceed via asingle electron transfer pathway, although these reactionsheretofore have been g enerally considered to be classic SN1or SN2processes.

Ac kn ow led gm ent . We acknowledge supp ort of thiswork by the N ational Science Foundation (G rant No. H PS7504127).RegistryNo. ,77400-57-8; lithium diisopropylamide, 4111-54-0;l i thium tert-butoxide, 1907-33-1;potassium tert-butoxide, 865-47-4;tr i tyl chloride, 76-83-5; tr i tyl bromide, 596-43-0; tr i tyl radical ,2216-49-1; l i thium butylamide, 41487-32-5; 2,2-dimethyM -hexeneradica l, 71880-21-2;1,3,3-dimethylcyclopentaneadical, 77400-58-9;anth race ne, 120-12-7; benz o[a]p yrene , 50-32-8; chrysene, 218-01-9;2,3-benzanthracen e, 92-24-0; phenanthren e, 85-01-8; perylene, 198-55-0; anthra cene radical anio n, 34509-92-7; benzo[a]pyren e radicalanion, 34505-58-3; chrysene radical anion, 34488-57-8; 2,3-benz-anthrac ene radical anion, 34512-30-6; phena nthren e rad ical anion,34510-03-7; perylene radical anion, 34505-65-2.

E C. Ashby,* A. B. Goel, R. N. DePries tSchool of ChemistryGeorgia Ins ti tut e of TechnologyAtlanta, Georgia 30332Received January 29 1981

Ch iral a-Amino Ketones from the Friedel-CraftsReaction of Pro tected A mino AcidsSum mary : Th e Friedel-Crafts reaction employing N -methoxycarbonyl-protected a-amino acids is described.Th is method yields chiral a-amin o ketones which can befur the r used to p repare doubly chiral vicinal amino alco-hols.Sir: Both acyclic an d cyclic vicinal amino ketones an dalcohols constitute widely studied structural classes ofinterest as medicinal agents and as ntermediates in naturalprod uct syntheses.172 One of th e most imp ortant fea turesof such biologically active compounds is the chiralitypresent a t th e asymm etric centers; therefore, useful chiralsynthetic procedures are continually sought. In this com-mun ication, we describe th e novel and prepa ratively usefulappro ach to c hiral a-a mi no ketones via a Friedel-Craftsreaction of N-pro tected am ino acids. Th is retention of

1)(a)Waason , B. K.; Gib son, W. K.; Stu ar t, R. S.; William s, H. W.R.; Yates, C. H. J. Med. Chem. 1972,15,651. (b) Howe, R.; Crowther,A. F.; Stephenson, J. S.; Rao, B. S.; Smith, L. H. Ibid. 1968,11,1100. (c)Morrow, D. F.; Johnson, P. C.; Ton abi, H .; Williams, D.; Wedding, D. L.;Craig, J. W.; Majewski, R. F.; Bra aelto n,J. P.; Gallo, D. G. Ibid. 1973,16,736. (d) Antihypertensive Agents; Eng elhard t, E. L., Ed.; AmericanChem ical Society: W ashington, DC, 1976. (e) Torchiana , M. L.; Porter,C. C.; Stone, C. A. Arch. Int. Pharm cody n. 1968,114, 118.(2) Kornfeld, E. C.; Fome feld, E. J.; Kline, G. B.; Mann, M. J.; Mor-rison, D. E.; Jone s, R. G.; Wo odw ard, R. B. J . Am. Chem. SOC.966, 78,3088. Bowman, R. E.; Evans, D. D.; Guyett, J.; Hagy, H.; W eale, J.;Weyell, D. J. J . Chem. SOC., erkin Trans. 1 1973, 438.

chirality was dependent upon the utilization of the N -methoxycarbonyl derivative.The synthesis of a-amino ketones 3 via a z l a ~ t o n e s ~ * ~worked well (55-90%) for th e forma tion of a five-, six-, orseven-membered ring. However, their known rapid race-mization due to th e high acidity6 of H1n 2 negated theiruse in the form ation of chiral 3.0

3a , n = 1 , R = C H 3 ; b , n = 1 , R = P h ; c , n = 2 , R = C H , ;d , n = 2, R = P h ; e , n = 3, R = CH

Recent publications indicated that the replacement ofth e R sub stituent of 2 by an OR moiety yielded derivativesless prone to racemization? In addition, these synthesesproceeded through the corresponding acid chloride, aninterm ediate potentially useful in a Friedel-Crafts cycli-zation. However, th e AlC13-catalyzed eaction of the acidchloride of Cbz -protected L-phenylalanin e (4a)9producedonly intractable tars presumably due to the generation ofbenzyl carbonium ions from t he Cbz substitue nt.

S)-5ba R = b e n z y l ; b,R = CH,

Th us , th e methox ycarbony l derivative 4b,1 via ita acidchloride, p roduced 5b12 in 5 5 7 5 % yields. Th e respectivechiral precursors gave R ) -or (S)-5b12after an aqueoushydrochloric acid workup. Chiral shift NMR analysis*withEu (hf bd 3 evealed none of the opposite enantiomer, in-dicating a c hiral purity of 298 for each isomer.13(3) Carter, H. E. Org. React. 1946 ,3, 198.(4) (a) Cioranescu, E.; Buchen-Barladeanu,L. Izu. Akad. Nauk SSSR,Otlel.Khim . Nau k 1961,149;Chem bstr. 1961,55,18653 . (b) Balaban ,A. T.; Bally, I.; Frangopol, P. T.; Bacescu, M.; Cioranescu, E.; Buchen-Barladeanu, L. Tetrahedron 1963,19, 169.(5) Th e acetyl derivatives (R = CHJ were generated in situ by heatingthe parent amino acid on a steam bath with acetic anhydride for a fewminutes as indicated.(6) Goodma n, M.; Levine, L. J . Am. Chem. SOC.964,86 , 2919.(7) Th e known, partially chiral (R)-2b was cyclized to give 3b, [a]l l . O o (c 0.60, dioxane). Th e optical rotation of (S )-2b used was [a] ;19.78O (c 0.45, dioxane) which im lies, a t best, a 28% enantiom eric ex-

3b, so formed, of only &lo% .(8)McC lure, D. E.; Arison, B. H.; Baldwin, J. J. J. Am. Chem. SOC.1979,101,3666.(9) Jones, J. H.; Witty, M. J. J . Chem. SOC.,Chem. Commun. 1977,281. Jones, J. H.; Wi tty, M. J. J . Chem. SOC., erkin Trans 1 1979,3203.(10) Petri , E. M.; Staverman, A. J. Reel. Trau. Chim. Pays-Ba s 1952,71, 385.11)Heating should be kept to a minimum during the concentrationprocess to remove ether an d POC la. Prolonged heating led to the lcms ofmethyl chlorid e and formation of the N -carboxy anhydride derivative.1Routinely, solvent was removed at 25-30 OC (25 torr and the crude acidchloride used imme diately in the cyclization step.(12)All new compounds exhibited spectral an d microanalytical orhigh-resolution mws spectral properties completely consistent with theassigned structures.

cessS6Chiral shift NMR analysis ndicated an enantiomeric excess for

0022-3263/81/1946-2431$01.25/0 1981 American Chemical Society


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J. Org. Chem. 1981,46,2433-2434 2433Acknowledgment. We thank Ms. Ruth N utt and Drs.Roger Freidinger an d J. R. Huff for helpful discussionsduring the course of this work.Registry No. (*)-4b, 77357-58-5; (R)-4b, 67401-65-4; (S) -4b,41844-91-1; (*)-5b, 77357-59-6; (R)-5b , 77447-92-8; (S)-5b, 77447-93-9; ( i ) - 6 , 77357-60-9; S,S)-6, 77447-94-0; (*)-7, 77357-61-0; R,-R)-7, 77447-95-1; (S,S )-7 , 77447-96-2; (S,S)-9, 32151-02-3; *)-lo,1670-98-0; (S)-l0,59190-99 -7; (i )- ll , 77 35 7- 62 -1 ; S)-11, 77447-97-3.

D. E. M ~ C l u r e , * ~ ~. H. ArisonJ. H. Jones, J. J. BaldwinMerck Shar p Dohme ResearchLaboratoriesRahway , New J ersey 07065, andW es t Poin t, Pennsylvania 19486Received Janu ary 26, 1981

Biomimetic Approach to laeocarpus Alkaloids. ASynthesis of *)-ElaeocarpidineSummary: A shor t, convergent synthesis of (f) -elae o-carpidine 2) is described wherein th e final step featuresa regioselective condensation between tryptamine (3) andam ine bisacetal 5 . T he la tter u nit is readily assembledfrom acrolein and cyanide in six steps.Sir: The Elaeocarpus alkaloids com prise a relatively newclass of abo ut 20 biogenetically interesting plant productsth at contain th e indolizidine or pyrrolizidine ring system.'All of these alkaloids conceivably can arise from a commonbiosynthetic intermediate, 3-(l-A1-pyrrolinium)propion-aldehyde l ) ,which may be derived from ornithine and athree-carbon biorea gent. T he incorporation of 1 in severalElaeocarpus alkaloids is shown in Scheme I.Although several synthesis of selected Elaeocarpus al-kaloids have been none addresses this generalbiogenesis postulated4 for these alkaloids. We delineateherein a synthesis of (*)-elaeocarpidine (2) involving th ein situ generation of 1 and its subsequent condensationwith tryptamine (3),as shown retrosynthetically in Schem e11.We anticipated th at am ine dialdehyde 4, obtained byhydrolyzing amine bisacetal 5,5 would clearly prefer cy-clizing to 1 (5-exo-trig6) tha n to the alternative four-membered-ring immonium ion (4-exo-trig) or to reactingintermolecularly with tryptamine (3). Furthermore, im-monium aldehyde 1, once formed, is predestined to react

(1) For a review, see: Johns, S. R.; Lamberton, J. A. Alkaloids N Y )1973, 14, 325.(2) For previous syntheses of 2, see: (a) Harley-Mason, J.; Taylo r, C.G. J.Chem. Soc., Chem. Commun. 1969,281; (b)Gribble, G. W. J.OrgChem. 1970 ,35, 1944.(3) (a) Hart, N. K.; Johns, S. R.; Lamberton,J. A. A u t . J.Chem. 1972,25, 817. (b) O naka, T. Tetrahedron Lett. 1971,4395. (c) Tanaka, T.;Ijima, I. Tetrahedron 1973,29,1285. (d) Ho ward, A. S.; Meerholz,C. A.;Michael, J. P. Tetrahedron Lett. 1979, 1339. e) Tufariello, J.;A i , S. A.Ibid. 1979,4445. 0 Schm itthenne r, H. F.; Weinreb, S.M. J.Org. Chem.1980,45,3372. (9) Watanabe, T.; Nakashita, Y.; Katayama, S.;Yamauchi,M. Heterocycles 1980, 14, 1433. (h) H oward, A. S.; Gerrano, G . C.;Meerholz, C. A. Tetrahedron Lett. 1980,1373. (i) Watanabe, T.;Naka-shita, Y.; Katayama, S.; Yamauchi, M. Heterocycles 1981, 16, 39.(4) Onaka, T. Tetrahedron Lett. 1971, 4395.(5) The acid hydrolysis (pH 5.83) of 4-aminobutyraldehyde diethylacetal proceeds without nitrogen assistance: Anderson, E.; Capon, B. J.Chem. SOC., erkin Trans. 2 1972, 515.(6) Baldwin, J. E. J.Chem. Soc., Chem. Commun. 1976, 734.

0 0 2 2 - 3 2 6 3 1 8 1 1 1 9 4 6 - 2 4 3 3 $ 0 1 . 2 5 / 0

Scheme I

eloeocarpidine ( 2 ) eloeocorpine

.C3H$@

elaeokanine A eloeokonidine A

Scheme I12 OMe

Meoc1 4

with tryptamine (3) in th e desired regioselective fashionto give elaeocarpidine (2).Th e starting am ine bisace tal5 was synthesized as fol-lows. 3-Bromo-1,l-dimethoxypropane6) was preparedfrom acrolein (HBr, MeOH, 0 C; MeOH , 25 C; 70%)'and then converted to 3-cyano-1,l-dimethoxypropane7)8(aqueous NaCN, cat. n-B uaN, reflux, 2 h; 86%).g Re-

duction of 7 to 4-amino-1,l-dimethoxypropane8) wasaccom plished with LiA1H4 (E bO , reflux; 62%)'O or b etterwith sodium ( EtOH , reflux; 77% .ll Trifluoroacetylationproceeded smoothly to give 9 (TFAA,Et2 0, Et3N, 0 C;25 C, 2 h; 94%) as an oil [bp 85 C (0.65 t ~ r r ) ] . ' ~ J ~RqoMe6 R = E r )

f:MeR - N

R = C N )8 ( R ' C H z N H 2 ) Me0 OMe9 ( R z C H z N H C O C F 3 ) 1 0 ( R = C O C F 3 )

(7) We used a modification of the procedure reported by: Ayer, W.(8) This material can also be purchased from ROC/RIC Corporation,(9) Procedure of: Reeve s, W. P.; W hite, M. R. Synth. Commun. 976,10)Lukes, R.; Trojanek, J. Chem. Listy 1952,46,383; Chem.Abstr.

(11) Manske, R. H. F. Can. J. Res. 1931 ,5, 598.(12) Satisfactory analytical dat a (combustion or high-resolution maw

A.; Dawe, R.; Eisner, R.; Furuichi, K. Can. J. Chem. 1976 ,54, 473.Belleville, NJ.6, 193.1953,47,4282.

spectrum) were obtained for this new compound.

1 9 8 1 American Chemical Societv

cathinone f c

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