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Further applications of endocyclic enamine-enone annulations
FURTHER APPLICATIONS OF ENDOCYCLIC ENAMINE-ENONE ANNULATIONS THE TOTAL SYNTHESES’ OF RAC-SCELETIUM ALKALOID A, AND 3’-DEMETHOXY SCELE’I’IUM ALKALOID A, C. P. Fox~es: G. L. Wm~ae~ mnd A. WlECHF.Rs DqMment of Chanisay. University of Reti. Pmforih Sad Africa
ALbrclbc
lod
ryntbesis of mr-scektium dkabii
&
Mauistionof cndocyctic &ncs 4a-b is pmentod.The Mil synthesis of 2Jdisubstituted pyridks fromA’pym~lines.
.
Ir and of its 3’demctboxyannb@e lb via lk
acceptorL is I usefulsynlbonfor thelwo-slcp
plished by the method of Stevens.‘L The preparationof the 3’&methoxy analogue4b” was simikrlr achkved. Annul&o of the hydrochloridesalts of A pyrrolines 4m8nd 4b with enones SI mnd5b procx&d readilyin relluxint~acetonitrik in 73-N& ykld ovtl IJhr. The multing annul&n products 7a-d were sepantely converted to sceletium alWoid & Ir and 3’dcmethoxy scektium alWoid A.. lb in Ml% yields by relluxing them with a threefold excess of hydroxykmine hydrochloride in %% aqucocuethanol. Scektium alWoid A, obtained in this way was identical in all respects (IR. UV, PMR. MS. m.p.) with the natural product. This two step conversionof the enone k to sceletium8lWoid & is a marked improvement on the four step procedure employedby Stevensutilixiw methyl - 5 - 0x0 - hept - 6 enoat? 8. Enone k is in fact potentially useful as a gmnol e pnrmnor in the synthesisof 23-disubstitutai pytidines’ via endrte or enamine 8nnuktions.t lk synthesesof the enonesh sod 5h were accomplishedby two different pathways. The first approach invdved the regiospeciflc alk?uka of UK dknion of 3-phenykulphinyl+utamne’ 9wnh2-(2-bromopropyl)-l$-dioxduK”tolivetbe intermediate sulphoxide 10 8s 8 pair of dhs~mcti mcenmteswhich underwent thermal elimination of henxenesulpknic acid in r&xii catbon tetrachk& to a&d the enone Sb. However a more elcknt synthesis involved 8s 8 key step the Griguud reaction either of 2 (3 - chloropropyl) - I$ - dioxolmc Ilr or 2 - (3 chloropropyl) - 5.5 - diithyl - I$ - dioxane Ilb with acrokintordardinhi&ykld(84%and69%respectively) the rllylic 8lcohols I& 8nd 12b which were readily oxidized with pyridinium cbbrochromrte” to enonesSrandS)insatisfactoryyklds.lkacetals1la and llb were readily pnpved from 4chlorohutanol by 0xiduiuntot&aMehydewithpyt&iumc~ chromateand subsequentac&fix&n.“Tbc 8bove mentkoedGr&nudreactbnis,tot&bes1of~knowkd#, thetlntex8mpkoftkhi&ykldutilix&nofacetd stMiMedalkylh8MesMdformsthesubjl!ctofrnote publishedelsewhere.” This total synthesisof rceletium alWoii & 8lso formally constitutes 8 totd synthl!sisof tomw#rmiat h tEnon50isalorcstabklos~aUcthu’cMmeSI*ahba& t’& cotnpounbwe hbik Md UC we4 directlyrltcr lbcir which has previously been dcrival from natural prepdon [see Ref. t Ill. scektium alWoid & by catalytic hydropcnolysis.’
The 6rowia interest in the alWoiis obtained from various Scdaim specks of the fmily Ai,rumr is nlkcted in the increasingnumberof p8pcrsdealing with their isolation8nd structunl clucid8tion A synthesis’8nd biosynthesis! Althou& we hrve isokted nktively krge qtmntitks of some of these alWoiis from S. jo&ttii, several of tkm 8rc not rv8ikbk in sufkknt qu8ntitks for dih&n studks in radk-active tncer umlysis or biobgkal screeni- experiments.Of these we have been particukrly interestedin the pyridinc 8lWoiis scektium 8lWoid &I-* la. tortuosamine- t and N-fomyl tortuosaminc2b. Furthermore, the recent isoktioo of a 3’deoxy9enatai mcsembnne &&ii. mktcoone.’ 6 from S. ~moque~~e, a pknt from which dioxyaryl alkabii (e.g. mcsembr8none)have 8lso ken extncted, and the proven intermedkcy of scektenonc in the biogenesis of the tic - 3 - (3.4 - dimetboxyphenyl) - octabydroindok 81Woiis.ti prompted us to under&e the total synthesisof the Y&methoxy atmlogucof scektium 8lWoii & 8s well. Ttdi compoundh8s hitherto not been isokted from n8tur8l sources. TheacidGtdysedthaml rtprm\pmcnts of cycl+ propyl imines 3 to A’-pytrolines 4. followed by annulatbn with methyl vinyl ketone or m 8n8bguc of it, 8 reactbn sequeacc developed prbmuily by Stevens,“A h8sbeenutilixedutbekeystepinthetotdsynthesesof a variety of dWoids.’ my. we chose 6 - (5.Sdimctbyl-l$-dioun-2-yl)bex-l-en-3-oaekud6(I$-dioxokn-2-yllhexI -to-3-oneLasMkb& acceptors which, after uumktion with 3 - ventryl- 2 pyrroline” L 8nd 3 - 8nisyl - 2 - pyrroline” 4b, provided the masked ISdkarbonyl systems 7ad. which subsequently were readily converted to scektiun. dWoid A, Ir and 3’&nuthoxy scektium 8lWoii A. lb in 9ood yields by treatment with an excess of hydroxykmine hydrochloridein r&u@ !&% ethanol. Tk preparationof tbc cyckpropyl imine JI by cyck prop8n8tion of 3Mimethoxyphenyl acetonitrik. reduction to the aldehydc with diisobutykhuninium hydride and imine farmah. followed by &d-atalysed thermal reur8n6ement to tk enamine 4a ~8.5 readily aczom-
c. P. Fouu
d el.
ia) (b)
~;&~~c-Ia
I I -
3.4dWc)prlphayl 4ur)oryphryl
(52ml: 65%).i&n&al asb&a withan
IRspcccnwemobtainedonrUnicamSP2Wspec~ tomctcr.PMR spectrawereobuind on a Vti HAIOOspeclfDmcter.Musq!ecb88ndacculuemur measurements were madeon a Ik POW21.492B mus ~~~me(cr. Qualitivc tk wnunicdouloasiliapl~G2U)aroa~olidc~N) lypc E) developedwith varyi conccn~&n~ of petrol in EtOAc.Cotumnchmaulogapbywasafried out with silka 6el 60 t7W.W mesh.Merck)or aluminium oxide90 (activencutrnl. prdc HI. Merck).Solventswerepuritkdanddrkd by standud pmc&res.MIRspcctmwererunastbiilUmsktwccnsodium
Y-Dnnahoxy¶uiuiafn~kIb.l7u~m (216ml: 0.54nun00tread u above.PVC afterchmumloqrpby as before.mc-lb (llOm& 81%) u a cbrwuloqrphkally home DCoil. P_ mt) 750. n5. 1030.1173.1245.1~5. 1519. 1572.1603and29Wcm-‘; 8 (Ccl,) lS3.35 (m. l2H. inckdin( an kCH, w u 224). 3.65(s. Oble). 6.55-7.a (M’RR’, pmUhoxypbmylriq protons).7.1 (&I. H. J - 8 and5 Hz, Hx of AMX). 7.41(dd. H. J - 6 md 2 Hr. Hm of AMX). aad6.36(dd. H. J - 5 and 2 Hz, Ha of AMX); massspectrum”(chcmkal ionizationIOQ)m/e (nl intmtsity) 295(100.M + I). 294(45. Iy’). cbbridcdiscsunkuahwii sgecikd. 279 (4. MCH,L 251 (13. M+H,N). 236 (14. yC,H,N): Scdr(iwdLdddA,I~Alolnol7oC79~;Olllmmol:I’ C&N@ requircsz M. 294.1732). (Foun& cpuiv)in %% aqueousEtoH (I2 ml) wastreed with bydroxy- (Found:M. 294.1720. C. Tlb: H. 7.32;N. 9.25%.C,,H,&O rcquim: C. nJ: H. 7.5: lam& bydrochbridc (62.5at6:0.90mmol;5 a&) andr&aed underN, lot 22hr. l’be mixturewas cookd and treatedwith N. 9.5%). Similuly. 7d (I5On16;0.41III&). produced&I &oatue KOH (7 cquiv)in M&H (IJml). The rcsuhii mixturewas WpOfUCdU&~fCdUCdpcuunmdrwicc~aopcdwitb dry lmuene. lbe residue wu &red t?wou& ncutml d III ~101wirbW1)~ia~Aclodwmc-lr(#~; a). m.p. 152-156d’ (EtOAc). idmfkal (UL UV. LOO MHz PMR. MS) with an au&&c specimen(Found:M. 324.1630. C&,N@, requircstM. 324.1837). similuly. ?c (loon(l; 0.25nunol).pmducedrllcr chfonu1*
Pllpdwtr 7tit Tbc PYlrd& 4B” (129011; 0.5a cquiv)wa8 dimotvcdill tiyd clkr (5all) and ua~ed witha satHClether soln(0.1ml; I equivHCl) u Q. YEc ahrrwasrcmowdumlrxfc!d~pcuurrIod*c~alrfespondia6my pyrollinchy$ocbloli&. Ttlc sy&ocata was diilvcd in rnhyd acanwik (5ml). uraled with Ir (125mr. 0.59mlaol.I equiv)rad &uaad uoderdry N, far I5 br. l%emixturewcookd,dilutaJwilbclher(25ml)Mdwubed
mleomuspranoflbcMuuktka~7~~rbond fhcslabkandllkgnoukafylcoajug4tedpyTrolianiulnion(w Ref. II) andlbc rcsonua smbilii cyclicoaoaiumiooduelo rucmrinbritbJ9CN~CO,q(lx5ml)ud~(lx5ml). C2 f~ntation of the acctalmokty as prominentor base nuorgJnicphrewudrkd(M@O~and-lruedcodve PcrLs. lbc CL-*” 8llnuhh podllcl7a u 1 cbromlqnpbially
(lk)
Further applications of endocyclic enamine-enone annulations homogeneous oil in quantitative yield: Vm,n (neat) 803. 1035. 1125. 1248,1460,1510,1605,1680,1700 and 29OOcm-': 8 (CCI,)t 0.65 and 0.66 (two s. m, CH)). 1.07 and 1.12 (two s, 3H. CHj). 1.12-2.80 (rn. 17H. including an NCHj singlet at 2.33). 3.15-3.60 (m, 4H. CH,CMe,CH,). 3.75-3.77 (two s. 6H. two OCHj). 4.154.40 (rn, i.(;cetal-pr~ton). 6.60- 6.90 (m, 3H. aromatic) (Found: M, 431.2618. C'.IH37N0.l requires: M, 431.2671).t The pyrroline 4b.l" (480 mg, 2.5mrnol), was converted to its hydrochloride and treated with 5a (I equiv) in the same way to produce the cis-annulation product":" 7b (770 mg. 76%). Vm,n (neat) 786. 1040. 1117, 1255, 1470. 1522, 1618. 1710. 2830 and 2950 cm-', 8 (CCl,)t 0.65 and 0.67 (two 5, 3H. two CHj). 1.08 and 1.12 (two 5, 3H, two CHj), 1.10-2.60 (rn. ISH, including an -NCH j singlet at 2.34),2.70-2.80 (d. H. angular proton). 3.10-3.60 (rn,4H, CH,CMe,CH,), 3.75 (s, 3H. OCH)),4.17-4.35 (m, H, acetal proton),6.63-7.3O(ANBB', p-methoxyphenyl ring protons) (Found: M. 401.2562. C,.H),NO. requires: M, 401.2566).t Pyrrolines 4a and 4b were similarly transformed to the annulation products 7c and 7d by annulation with the enone acetal 5b in 80% and 84% yields respectively. 7c had Vma< 760, 790, 1030, 1145, 1255, 1470, 1523, 1595, 1675, 1708 and 2940 crn": 8 (CDCI))t 1.40-1.80 (m, ISH including an -NCH) singlet at 2.40), 2.85 (d. H, angular proton), 3.80-4.00 (m, IOH, two OCH" OCH,CH,O), 4.70-4.93 (m, H, acetal proton), 6.70-7.00 (rn. 3H. aromatic protons). (Found: M-1,388.2215. C"H"NO, requires: M -I, 388.2203).t 7d had Vma< 762, 795. 836. 1035. 1140, 1185, 1255,1465,1618.1678,1710 and 2950cm": 8 (CCI,)t 1.35-2.60 (m, ISH, including two overlapping -NCH, singlets at 2.30 and 2.37), 2.78 (d. H, acetal proton), 6.65-7.32 (ANBB'. p-methoxyphenyl ring protons) (Fouhd: M- I, 358.2085. C"H'9 NO• requires: M- I. 358.2096),t 2-(4-Keto-5-phenylsulphinylhexyl)-I,3-dioxolane 10. BuLi in hexane (20.6 ml; 33 mmolBuLi: 1.6M)was concentrated to a small volumeat 0"under vacuum,dilutedwithdry THF (15 ml),cooledto - 25" and treated with diisopropylamine (2.45 rnl: 36.2mmol). The resultingsoln of lithium diisopropylamide was added dropwise to a mixture of 99 (2.94g: 14.9 rnrnol) and hexamethyl phosphoric triamide(6 ml)in dry THF (6 ml)under dry N,. The resulting deep orange-red soln of the dianion was stirred for 30 min at -25" and treated dropwise with a soln of 2-(2-bromoethyl)- I.3-dioxolane '0 (5.44 g: 30.2 mmol) in dry THF (3 ml) over 20min. The intensely coloured soln became pale yellow on completion of the addition. The mixture was stirred for an additional 1hr at -25", poured into cold sat NH,CI aq. (300ml)and extracted with CH,CI, (5 x 50mI). The organicphase was washedonce with sat NaCIaq. (75 rnl), dried (MgSO,), and concentrated to an oil (9.5 g). Chromatographyover silicagel with increasing quantities of ether in petrol produced the pure 10 as a pair of diastereomeric racemates (2.36g; 63%) and recovered starting material (0.43 g; 15%): V m" 700.755.940,1055, 1140,1376,1410, 1448. 1587, 1711,2890 and 2950 cm-'. The PMR spectrumclearly indicatesa pairof diastereomers.8 (CCI,) 1.19 and 1.30 (two d. J = 3.5 Hz, 3H. CHJ ) , 1.49-1.70 (m, 4H. CH,CH,), 2.30-2.75 (rn,2H. -CH,CG-), 3.45-3.73 (two t.J = 3.5 Hz. H. proton a to sulphoxideand keto groups), 3.70-3.97 (m, 4H. OCH,CH,O), 4.64-4.83 (m, H, acetal proton), and 7.40-7.67 (m, SH. aromatic protons): (Found: C, 60.65: H, 6.70;S, 10.90. C,.IH,oSO. requires: C. 60.78: H, 6.80; S, 10.82%). 6-(1,3-Dioxolan-2-yl)hex:f:en-3-one 5b. The ketosulphoxide 10 (4.5g; 15.2 mmol) was dissolved in anhyd CCI, (150 rnl) and refluxed under dry N, for 20hr. The soln was concentrated to an oil (4.15 g) which was chromatographed over silica gel with increasing quantities of ether in petrol to afford 5b (646 rng; 25%) as a tic homogeneous. but labile' oil: Vma< 1030, 1135,1408.1612, 1668,2850and2920cm-':8(CCI.) 1.60-1.78(m, tThe PMR spectra of the annulation products 7a-d all appeared as superpositions of two partially resolved spectra because these compounds are each formed as a pair of diastereomeric racemates. Hhe annulation products 7a-d were all obtained in a state of good punty and were used directly in the following step of the overall synthesis. They were scnsirive to chromatography over silica gel and alumina and to distillation and so could not be obtained in an analyticall, pure form.
489
4H. CH,CH,). 2.48-2.70 (rn, 2H, CH,CO). 3.68-4.00 (rn, 4H, OCH,CH,O): 4.79 (t, H. acetal proton): 5.60-6.30 (ABX, 3H. -CH,=CH·CO-): (Found: M-I, 169.0853. C,H 140j requires: M- I. 169.0864). Acknowledgements-s-The authors are indebted to Miss E. Small and Messrs D. Crornarty and D. Hack for their assistance in the preparation of intermediates and to Dr. N. Vermeulen of the Department of Biochemistry. University of Pretoria, for mass spectra and accurate mass measurements. REFERENCES
'For a preliminary account of this work, see C. P. Forbes. J. D. Michau. T. van Ree. A. Wiechers and M. Woudenberg, Tetrahedron Letters [2,935 (1976). ,,,R. R. Arndt and P. E. J. Kruger, Ibid. 37, 3237 (1970) and refs cited; hp. W. Jeffs. R. L. Hawks and D. S. Farrier, 1. Am. Chem. Soc. 91:14. 3831 (1%9). jK. Bodendorf and W. Krieger. Arch. Pharm. 290.441 (1957). '''Po Coggan, D. S. Farrier, P. W. Jeffs and A. T. McPhail, 1. Chem. Soc. B. 1267 (1970): hp. E. J. Kruger and R. R. Arndt, 1. S. African Chem. lnst .. XXIV. 285 (1971): 'P. W. Jeffs. G. Ahmann. H. F. Campbell. D. G. Farrier, G. Ganguli and R. L. Hawks. 1. Org. Chem. 35:10. 3512 (1970): dp. W. Jeffs. P. A. Luhan, A. T. McPhail and N. H. Martin. Chem. Comm. 1466 (1971): '·P. W. Jeffs. T. Capps. D. B. Johnson. J. M. Karle. N. H. Martin and B. Rauchrnann, 1. Org. Chem. 39:[8. 2703 (1974): fE. Smith. N. Hosansky. M. Shamma and J. B. Moss. Chem. Ind. 402 (1961): "F. 0. Snyckers, F. Strelow and A. Wiechers. Chem. Comm. 1467 (1971): hp. A. Luhan and A. T. McPhail.1. Chem. Soc. Perkin 1,2006 (1972): ;P. A. Luhan. A. T. McPhail and P. M. Gross. Ibid. Perkin 2. 51 (1972). -s L. Keely and F. C. Tahk, Chem. Comm. 441 (1968).1. Am. Chem. Soc. 90:20, 5584 (1968): hH. Taguchi and T. Oh-lshi. Tetrahedron Letters 55. 5763 (1968): 'H. Taguchi, T. Oh-Ishi and H. Kugita, Chern. Phurm. Bull. 18(5). 1008 (1970): dM. Langlois. C. Guillomeau. J. Meingan and J Maillard. Tetrahedron 27.5641 (1971): 'T. Oh-lshi and H. Kugita, Tetrahedron Letters 52. 5445 (1968): fRo V. Stevens and M. P. Wentland, 1. Am. Chem. Soc. 90:20. 5580 (1968): "R. V. Stevens and J. T. Lai.1. o-« Chem. 37:13. 2138 (1972): hR. V. Stevens. P. M. Lesko and R. Lapalme. 1. Org. Chem. 40:20. 3495 (1975) and refs. cited: ;G. Otani and S. Yamada, Chem. Pharm. Bull. 21:10. 2130 (1973) and refs. cited: 'J. B. P. A. Wijnberg and W. N. Speckarnp, Tetrahedron Letters 45. 3963 (1975). hop. W. Jeffs and J. M. Karle, Chem. Comm. 60 (1977) and refs. cited: hp. W. Jeffs, W. C. Archie and D. S. Farrier. 1. Am. Chem. Soc. 89:[0. 2509 (1%7): 'P. W. Jeffs. H. F. Campbell. D. S. Farrier and G. Molina. Chem. Comm. 228 (1971). 'For the synthesis of: (i) mesernbrane-type alkaloids. see refs. 1, 5f.g.h; (ii) myosrnine and apoferrorosamine. see: "R. V. Stevens and M. C. Ellis, Tetrahedron Letters 51. 5185 (1967): hR. V. Stevens. M. C. Ellis and M. P. Wentland. 1. Am. Chem. Soc. 90:20. 5576 (1968): (iii) an erythrina-type alkaloid. see R. V. Stevens and M. P. Wentland. Chem. Comm. 1104 (1968): (iv) aspidosperma alkaloid precursors, see R. V. Stevens. R. K. Mehra and R. L. Zimmerman, Ibid. 877 (1969): (v) amaryllidaceae alkaloids. see: "R. V. Stevens and L. E. DuPree, Chem. Comm. 1585 (1970); hR. V. Stevens. L. E. DuPree and P. L. Loewenstein. 1. Org. Chem. 37:7. 977 (1972); (vi) pyrrolizidine alkaloids, see R. V. Stevens. Y. Luh and J. Sheu, Tetrahedron Letters 42. 3799 (1976): R. V. Stevens and Y. Luh. Ibid. 11.979 (1977). "For other syntheses of 2,3-disubstituted pyridines. see a A. van der Gen. L. M. van der Linde and J. G. Witteveen, Recueil 91, 1433 (1972): hW. A. Remers, G. T. Gibbs, C. Pidacks and M. J. Weiss. 1. Org. Chem. 36:2, 279 (1971); 'G. Bouchon, K.-H. Spohn and E. Breitmaier, Chem. Ber. [06, 1736 (1973) and refs. cited; dE. Breitmaier and S. Gassenmann, Ibid. 104,665 (1971) and refs. cited: '·M. A. Kirillova. Y. A. Zaichenko, I. A. Maretina and A. A. Petrov. Zh. Org. Khim. 8. 1575 (1972); /c. Ruangsiyanad, H. J. Rimek and F. Zyrnalkowski, Chem. Ber. 103,2403 (1970);"C. Botteghi,G. Caccia and S. Gladiali. Svnth Comm. 6:8. 549 (1976): hE. Stark and E. Breitmaier. Tetra-
c. P. Foug u d.
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heha 29.2209 (1913)and mfr.cited: ‘A. Fmkowski and 1. Smith. /bid 33.427( I977l. ‘P&G?
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Ckm. Ml. 7imkbon
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‘~.G.~.A.RV~w,v..K.~radN.A. prahhd& 1. ckn. ckm USSR 31. 1433(Isal). ‘V. P. Fades. G. L wealder d A. wireben. 1. am. PUkh I.inpttr. “N. Ii. Mania. D. Baa&l mmu~ II. I(I976).
md P. W. JcUs. m.
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sot. Sprc-
ALbrclbc
lod
ryntbesis of mr-scektium dkabii
&
Mauistionof cndocyctic &ncs 4a-b is pmentod.The Mil synthesis of 2Jdisubstituted pyridks fromA’pym~lines.
.
Ir and of its 3’demctboxyannb@e lb via lk
acceptorL is I usefulsynlbonfor thelwo-slcp
plished by the method of Stevens.‘L The preparationof the 3’&methoxy analogue4b” was simikrlr achkved. Annul&o of the hydrochloridesalts of A pyrrolines 4m8nd 4b with enones SI mnd5b procx&d readilyin relluxint~acetonitrik in 73-N& ykld ovtl IJhr. The multing annul&n products 7a-d were sepantely converted to sceletium alWoid & Ir and 3’dcmethoxy scektium alWoid A.. lb in Ml% yields by relluxing them with a threefold excess of hydroxykmine hydrochloride in %% aqucocuethanol. Scektium alWoid A, obtained in this way was identical in all respects (IR. UV, PMR. MS. m.p.) with the natural product. This two step conversionof the enone k to sceletium8lWoid & is a marked improvement on the four step procedure employedby Stevensutilixiw methyl - 5 - 0x0 - hept - 6 enoat? 8. Enone k is in fact potentially useful as a gmnol e pnrmnor in the synthesisof 23-disubstitutai pytidines’ via endrte or enamine 8nnuktions.t lk synthesesof the enonesh sod 5h were accomplishedby two different pathways. The first approach invdved the regiospeciflc alk?uka of UK dknion of 3-phenykulphinyl+utamne’ 9wnh2-(2-bromopropyl)-l$-dioxduK”tolivetbe intermediate sulphoxide 10 8s 8 pair of dhs~mcti mcenmteswhich underwent thermal elimination of henxenesulpknic acid in r&xii catbon tetrachk& to a&d the enone Sb. However a more elcknt synthesis involved 8s 8 key step the Griguud reaction either of 2 (3 - chloropropyl) - I$ - dioxolmc Ilr or 2 - (3 chloropropyl) - 5.5 - diithyl - I$ - dioxane Ilb with acrokintordardinhi&ykld(84%and69%respectively) the rllylic 8lcohols I& 8nd 12b which were readily oxidized with pyridinium cbbrochromrte” to enonesSrandS)insatisfactoryyklds.lkacetals1la and llb were readily pnpved from 4chlorohutanol by 0xiduiuntot&aMehydewithpyt&iumc~ chromateand subsequentac&fix&n.“Tbc 8bove mentkoedGr&nudreactbnis,tot&bes1of~knowkd#, thetlntex8mpkoftkhi&ykldutilix&nofacetd stMiMedalkylh8MesMdformsthesubjl!ctofrnote publishedelsewhere.” This total synthesisof rceletium alWoii & 8lso formally constitutes 8 totd synthl!sisof tomw#rmiat h tEnon50isalorcstabklos~aUcthu’cMmeSI*ahba& t’& cotnpounbwe hbik Md UC we4 directlyrltcr lbcir which has previously been dcrival from natural prepdon [see Ref. t Ill. scektium alWoid & by catalytic hydropcnolysis.’
The 6rowia interest in the alWoiis obtained from various Scdaim specks of the fmily Ai,rumr is nlkcted in the increasingnumberof p8pcrsdealing with their isolation8nd structunl clucid8tion A synthesis’8nd biosynthesis! Althou& we hrve isokted nktively krge qtmntitks of some of these alWoiis from S. jo&ttii, several of tkm 8rc not rv8ikbk in sufkknt qu8ntitks for dih&n studks in radk-active tncer umlysis or biobgkal screeni- experiments.Of these we have been particukrly interestedin the pyridinc 8lWoiis scektium 8lWoid &I-* la. tortuosamine- t and N-fomyl tortuosaminc2b. Furthermore, the recent isoktioo of a 3’deoxy9enatai mcsembnne &&ii. mktcoone.’ 6 from S. ~moque~~e, a pknt from which dioxyaryl alkabii (e.g. mcsembr8none)have 8lso ken extncted, and the proven intermedkcy of scektenonc in the biogenesis of the tic - 3 - (3.4 - dimetboxyphenyl) - octabydroindok 81Woiis.ti prompted us to under&e the total synthesisof the Y&methoxy atmlogucof scektium 8lWoii & 8s well. Ttdi compoundh8s hitherto not been isokted from n8tur8l sources. TheacidGtdysedthaml rtprm\pmcnts of cycl+ propyl imines 3 to A’-pytrolines 4. followed by annulatbn with methyl vinyl ketone or m 8n8bguc of it, 8 reactbn sequeacc developed prbmuily by Stevens,“A h8sbeenutilixedutbekeystepinthetotdsynthesesof a variety of dWoids.’ my. we chose 6 - (5.Sdimctbyl-l$-dioun-2-yl)bex-l-en-3-oaekud6(I$-dioxokn-2-yllhexI -to-3-oneLasMkb& acceptors which, after uumktion with 3 - ventryl- 2 pyrroline” L 8nd 3 - 8nisyl - 2 - pyrroline” 4b, provided the masked ISdkarbonyl systems 7ad. which subsequently were readily converted to scektiun. dWoid A, Ir and 3’&nuthoxy scektium 8lWoii A. lb in 9ood yields by treatment with an excess of hydroxykmine hydrochloridein r&u@ !&% ethanol. Tk preparationof tbc cyckpropyl imine JI by cyck prop8n8tion of 3Mimethoxyphenyl acetonitrik. reduction to the aldehydc with diisobutykhuninium hydride and imine farmah. followed by &d-atalysed thermal reur8n6ement to tk enamine 4a ~8.5 readily aczom-
c. P. Fouu
d el.
ia) (b)
~;&~~c-Ia
I I -
3.4dWc)prlphayl 4ur)oryphryl
(52ml: 65%).i&n&al asb&a withan
IRspcccnwemobtainedonrUnicamSP2Wspec~ tomctcr.PMR spectrawereobuind on a Vti HAIOOspeclfDmcter.Musq!ecb88ndacculuemur measurements were madeon a Ik POW21.492B mus ~~~me(cr. Qualitivc tk wnunicdouloasiliapl~G2U)aroa~olidc~N) lypc E) developedwith varyi conccn~&n~ of petrol in EtOAc.Cotumnchmaulogapbywasafried out with silka 6el 60 t7W.W mesh.Merck)or aluminium oxide90 (activencutrnl. prdc HI. Merck).Solventswerepuritkdanddrkd by standud pmc&res.MIRspcctmwererunastbiilUmsktwccnsodium
Y-Dnnahoxy¶uiuiafn~kIb.l7u~m (216ml: 0.54nun00tread u above.PVC afterchmumloqrpby as before.mc-lb (llOm& 81%) u a cbrwuloqrphkally home DCoil. P_ mt) 750. n5. 1030.1173.1245.1~5. 1519. 1572.1603and29Wcm-‘; 8 (Ccl,) lS3.35 (m. l2H. inckdin( an kCH, w u 224). 3.65(s. Oble). 6.55-7.a (M’RR’, pmUhoxypbmylriq protons).7.1 (&I. H. J - 8 and5 Hz, Hx of AMX). 7.41(dd. H. J - 6 md 2 Hr. Hm of AMX). aad6.36(dd. H. J - 5 and 2 Hz, Ha of AMX); massspectrum”(chcmkal ionizationIOQ)m/e (nl intmtsity) 295(100.M + I). 294(45. Iy’). cbbridcdiscsunkuahwii sgecikd. 279 (4. MCH,L 251 (13. M+H,N). 236 (14. yC,H,N): Scdr(iwdLdddA,I~Alolnol7oC79~;Olllmmol:I’ C&N@ requircsz M. 294.1732). (Foun& cpuiv)in %% aqueousEtoH (I2 ml) wastreed with bydroxy- (Found:M. 294.1720. C. Tlb: H. 7.32;N. 9.25%.C,,H,&O rcquim: C. nJ: H. 7.5: lam& bydrochbridc (62.5at6:0.90mmol;5 a&) andr&aed underN, lot 22hr. l’be mixturewas cookd and treatedwith N. 9.5%). Similuly. 7d (I5On16;0.41III&). produced&I &oatue KOH (7 cquiv)in M&H (IJml). The rcsuhii mixturewas WpOfUCdU&~fCdUCdpcuunmdrwicc~aopcdwitb dry lmuene. lbe residue wu &red t?wou& ncutml d III ~101wirbW1)~ia~Aclodwmc-lr(#~; a). m.p. 152-156d’ (EtOAc). idmfkal (UL UV. LOO MHz PMR. MS) with an au&&c specimen(Found:M. 324.1630. C&,N@, requircstM. 324.1837). similuly. ?c (loon(l; 0.25nunol).pmducedrllcr chfonu1*
Pllpdwtr 7tit Tbc PYlrd& 4B” (129011; 0.5a cquiv)wa8 dimotvcdill tiyd clkr (5all) and ua~ed witha satHClether soln(0.1ml; I equivHCl) u Q. YEc ahrrwasrcmowdumlrxfc!d~pcuurrIod*c~alrfespondia6my pyrollinchy$ocbloli&. Ttlc sy&ocata was diilvcd in rnhyd acanwik (5ml). uraled with Ir (125mr. 0.59mlaol.I equiv)rad &uaad uoderdry N, far I5 br. l%emixturewcookd,dilutaJwilbclher(25ml)Mdwubed
mleomuspranoflbcMuuktka~7~~rbond fhcslabkandllkgnoukafylcoajug4tedpyTrolianiulnion(w Ref. II) andlbc rcsonua smbilii cyclicoaoaiumiooduelo rucmrinbritbJ9CN~CO,q(lx5ml)ud~(lx5ml). C2 f~ntation of the acctalmokty as prominentor base nuorgJnicphrewudrkd(M@O~and-lruedcodve PcrLs. lbc CL-*” 8llnuhh podllcl7a u 1 cbromlqnpbially
(lk)
Further applications of endocyclic enamine-enone annulations homogeneous oil in quantitative yield: Vm,n (neat) 803. 1035. 1125. 1248,1460,1510,1605,1680,1700 and 29OOcm-': 8 (CCI,)t 0.65 and 0.66 (two s. m, CH)). 1.07 and 1.12 (two s, 3H. CHj). 1.12-2.80 (rn. 17H. including an NCHj singlet at 2.33). 3.15-3.60 (m, 4H. CH,CMe,CH,). 3.75-3.77 (two s. 6H. two OCHj). 4.154.40 (rn, i.(;cetal-pr~ton). 6.60- 6.90 (m, 3H. aromatic) (Found: M, 431.2618. C'.IH37N0.l requires: M, 431.2671).t The pyrroline 4b.l" (480 mg, 2.5mrnol), was converted to its hydrochloride and treated with 5a (I equiv) in the same way to produce the cis-annulation product":" 7b (770 mg. 76%). Vm,n (neat) 786. 1040. 1117, 1255, 1470. 1522, 1618. 1710. 2830 and 2950 cm-', 8 (CCl,)t 0.65 and 0.67 (two 5, 3H. two CHj). 1.08 and 1.12 (two 5, 3H, two CHj), 1.10-2.60 (rn. ISH, including an -NCH j singlet at 2.34),2.70-2.80 (d. H. angular proton). 3.10-3.60 (rn,4H, CH,CMe,CH,), 3.75 (s, 3H. OCH)),4.17-4.35 (m, H, acetal proton),6.63-7.3O(ANBB', p-methoxyphenyl ring protons) (Found: M. 401.2562. C,.H),NO. requires: M, 401.2566).t Pyrrolines 4a and 4b were similarly transformed to the annulation products 7c and 7d by annulation with the enone acetal 5b in 80% and 84% yields respectively. 7c had Vma< 760, 790, 1030, 1145, 1255, 1470, 1523, 1595, 1675, 1708 and 2940 crn": 8 (CDCI))t 1.40-1.80 (m, ISH including an -NCH) singlet at 2.40), 2.85 (d. H, angular proton), 3.80-4.00 (m, IOH, two OCH" OCH,CH,O), 4.70-4.93 (m, H, acetal proton), 6.70-7.00 (rn. 3H. aromatic protons). (Found: M-1,388.2215. C"H"NO, requires: M -I, 388.2203).t 7d had Vma< 762, 795. 836. 1035. 1140, 1185, 1255,1465,1618.1678,1710 and 2950cm": 8 (CCI,)t 1.35-2.60 (m, ISH, including two overlapping -NCH, singlets at 2.30 and 2.37), 2.78 (d. H, acetal proton), 6.65-7.32 (ANBB'. p-methoxyphenyl ring protons) (Fouhd: M- I, 358.2085. C"H'9 NO• requires: M- I. 358.2096),t 2-(4-Keto-5-phenylsulphinylhexyl)-I,3-dioxolane 10. BuLi in hexane (20.6 ml; 33 mmolBuLi: 1.6M)was concentrated to a small volumeat 0"under vacuum,dilutedwithdry THF (15 ml),cooledto - 25" and treated with diisopropylamine (2.45 rnl: 36.2mmol). The resultingsoln of lithium diisopropylamide was added dropwise to a mixture of 99 (2.94g: 14.9 rnrnol) and hexamethyl phosphoric triamide(6 ml)in dry THF (6 ml)under dry N,. The resulting deep orange-red soln of the dianion was stirred for 30 min at -25" and treated dropwise with a soln of 2-(2-bromoethyl)- I.3-dioxolane '0 (5.44 g: 30.2 mmol) in dry THF (3 ml) over 20min. The intensely coloured soln became pale yellow on completion of the addition. The mixture was stirred for an additional 1hr at -25", poured into cold sat NH,CI aq. (300ml)and extracted with CH,CI, (5 x 50mI). The organicphase was washedonce with sat NaCIaq. (75 rnl), dried (MgSO,), and concentrated to an oil (9.5 g). Chromatographyover silicagel with increasing quantities of ether in petrol produced the pure 10 as a pair of diastereomeric racemates (2.36g; 63%) and recovered starting material (0.43 g; 15%): V m" 700.755.940,1055, 1140,1376,1410, 1448. 1587, 1711,2890 and 2950 cm-'. The PMR spectrumclearly indicatesa pairof diastereomers.8 (CCI,) 1.19 and 1.30 (two d. J = 3.5 Hz, 3H. CHJ ) , 1.49-1.70 (m, 4H. CH,CH,), 2.30-2.75 (rn,2H. -CH,CG-), 3.45-3.73 (two t.J = 3.5 Hz. H. proton a to sulphoxideand keto groups), 3.70-3.97 (m, 4H. OCH,CH,O), 4.64-4.83 (m, H, acetal proton), and 7.40-7.67 (m, SH. aromatic protons): (Found: C, 60.65: H, 6.70;S, 10.90. C,.IH,oSO. requires: C. 60.78: H, 6.80; S, 10.82%). 6-(1,3-Dioxolan-2-yl)hex:f:en-3-one 5b. The ketosulphoxide 10 (4.5g; 15.2 mmol) was dissolved in anhyd CCI, (150 rnl) and refluxed under dry N, for 20hr. The soln was concentrated to an oil (4.15 g) which was chromatographed over silica gel with increasing quantities of ether in petrol to afford 5b (646 rng; 25%) as a tic homogeneous. but labile' oil: Vma< 1030, 1135,1408.1612, 1668,2850and2920cm-':8(CCI.) 1.60-1.78(m, tThe PMR spectra of the annulation products 7a-d all appeared as superpositions of two partially resolved spectra because these compounds are each formed as a pair of diastereomeric racemates. Hhe annulation products 7a-d were all obtained in a state of good punty and were used directly in the following step of the overall synthesis. They were scnsirive to chromatography over silica gel and alumina and to distillation and so could not be obtained in an analyticall, pure form.
489
4H. CH,CH,). 2.48-2.70 (rn, 2H, CH,CO). 3.68-4.00 (rn, 4H, OCH,CH,O): 4.79 (t, H. acetal proton): 5.60-6.30 (ABX, 3H. -CH,=CH·CO-): (Found: M-I, 169.0853. C,H 140j requires: M- I. 169.0864). Acknowledgements-s-The authors are indebted to Miss E. Small and Messrs D. Crornarty and D. Hack for their assistance in the preparation of intermediates and to Dr. N. Vermeulen of the Department of Biochemistry. University of Pretoria, for mass spectra and accurate mass measurements. REFERENCES
'For a preliminary account of this work, see C. P. Forbes. J. D. Michau. T. van Ree. A. Wiechers and M. Woudenberg, Tetrahedron Letters [2,935 (1976). ,,,R. R. Arndt and P. E. J. Kruger, Ibid. 37, 3237 (1970) and refs cited; hp. W. Jeffs. R. L. Hawks and D. S. Farrier, 1. Am. Chem. Soc. 91:14. 3831 (1%9). jK. Bodendorf and W. Krieger. Arch. Pharm. 290.441 (1957). '''Po Coggan, D. S. Farrier, P. W. Jeffs and A. T. McPhail, 1. Chem. Soc. B. 1267 (1970): hp. E. J. Kruger and R. R. Arndt, 1. S. African Chem. lnst .. XXIV. 285 (1971): 'P. W. Jeffs. G. Ahmann. H. F. Campbell. D. G. Farrier, G. Ganguli and R. L. Hawks. 1. Org. Chem. 35:10. 3512 (1970): dp. W. Jeffs. P. A. Luhan, A. T. McPhail and N. H. Martin. Chem. Comm. 1466 (1971): '·P. W. Jeffs. T. Capps. D. B. Johnson. J. M. Karle. N. H. Martin and B. Rauchrnann, 1. Org. Chem. 39:[8. 2703 (1974): fE. Smith. N. Hosansky. M. Shamma and J. B. Moss. Chem. Ind. 402 (1961): "F. 0. Snyckers, F. Strelow and A. Wiechers. Chem. Comm. 1467 (1971): hp. A. Luhan and A. T. McPhail.1. Chem. Soc. Perkin 1,2006 (1972): ;P. A. Luhan. A. T. McPhail and P. M. Gross. Ibid. Perkin 2. 51 (1972). -s L. Keely and F. C. Tahk, Chem. Comm. 441 (1968).1. Am. Chem. Soc. 90:20, 5584 (1968): hH. Taguchi and T. Oh-lshi. Tetrahedron Letters 55. 5763 (1968): 'H. Taguchi, T. Oh-Ishi and H. Kugita, Chern. Phurm. Bull. 18(5). 1008 (1970): dM. Langlois. C. Guillomeau. J. Meingan and J Maillard. Tetrahedron 27.5641 (1971): 'T. Oh-lshi and H. Kugita, Tetrahedron Letters 52. 5445 (1968): fRo V. Stevens and M. P. Wentland, 1. Am. Chem. Soc. 90:20. 5580 (1968): "R. V. Stevens and J. T. Lai.1. o-« Chem. 37:13. 2138 (1972): hR. V. Stevens. P. M. Lesko and R. Lapalme. 1. Org. Chem. 40:20. 3495 (1975) and refs. cited: ;G. Otani and S. Yamada, Chem. Pharm. Bull. 21:10. 2130 (1973) and refs. cited: 'J. B. P. A. Wijnberg and W. N. Speckarnp, Tetrahedron Letters 45. 3963 (1975). hop. W. Jeffs and J. M. Karle, Chem. Comm. 60 (1977) and refs. cited: hp. W. Jeffs, W. C. Archie and D. S. Farrier. 1. Am. Chem. Soc. 89:[0. 2509 (1%7): 'P. W. Jeffs. H. F. Campbell. D. S. Farrier and G. Molina. Chem. Comm. 228 (1971). 'For the synthesis of: (i) mesernbrane-type alkaloids. see refs. 1, 5f.g.h; (ii) myosrnine and apoferrorosamine. see: "R. V. Stevens and M. C. Ellis, Tetrahedron Letters 51. 5185 (1967): hR. V. Stevens. M. C. Ellis and M. P. Wentland. 1. Am. Chem. Soc. 90:20. 5576 (1968): (iii) an erythrina-type alkaloid. see R. V. Stevens and M. P. Wentland. Chem. Comm. 1104 (1968): (iv) aspidosperma alkaloid precursors, see R. V. Stevens. R. K. Mehra and R. L. Zimmerman, Ibid. 877 (1969): (v) amaryllidaceae alkaloids. see: "R. V. Stevens and L. E. DuPree, Chem. Comm. 1585 (1970); hR. V. Stevens. L. E. DuPree and P. L. Loewenstein. 1. Org. Chem. 37:7. 977 (1972); (vi) pyrrolizidine alkaloids, see R. V. Stevens. Y. Luh and J. Sheu, Tetrahedron Letters 42. 3799 (1976): R. V. Stevens and Y. Luh. Ibid. 11.979 (1977). "For other syntheses of 2,3-disubstituted pyridines. see a A. van der Gen. L. M. van der Linde and J. G. Witteveen, Recueil 91, 1433 (1972): hW. A. Remers, G. T. Gibbs, C. Pidacks and M. J. Weiss. 1. Org. Chem. 36:2, 279 (1971); 'G. Bouchon, K.-H. Spohn and E. Breitmaier, Chem. Ber. [06, 1736 (1973) and refs. cited; dE. Breitmaier and S. Gassenmann, Ibid. 104,665 (1971) and refs. cited: '·M. A. Kirillova. Y. A. Zaichenko, I. A. Maretina and A. A. Petrov. Zh. Org. Khim. 8. 1575 (1972); /c. Ruangsiyanad, H. J. Rimek and F. Zyrnalkowski, Chem. Ber. 103,2403 (1970);"C. Botteghi,G. Caccia and S. Gladiali. Svnth Comm. 6:8. 549 (1976): hE. Stark and E. Breitmaier. Tetra-
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