Ethyl (5R,2E)-5-(benzyloxy)-4,4-dimethyl-6-oxohex-2-enoate its synthesis from (lS,SS)-( +)-a-pinene (12). The configura-(9) was prepared from (R)-(-)-pantolactone (3) by a series of tion of the hydroxy group at C-4 in 10 was determined from straightforward reactions. The reaction of 9 with sama-NOE studies on the epimiric 17. The radical 4-exo-trig-cyclirium(I1) iodide produces enantiomerically pure ethyl zation of optically active (2E)-6-oxohex-2-enoates with sama-(1S,3R,4R)-(-)-[3-(benzyloxy)-4-hydroxy-2,2-dimethylcyclo-rium(I1) iodide opens a new pathway to enantiomerically butyllacetate (10) in 60% yield. The absolute configuration pure cyclobutanol and cyclobutanone derivatives, which are at C-1 and C-3 was confirmed by the conversion of 10 to the of interest as building blocks in natural products synthesis. crystalline 15a, whose absolute configuration is known from Bei der radikalischen Cyclisierung des Pent-4-enyl-Radikals tritt keine 4-e~o-trig-Reaktion[~] zu dem Cyclobutylmethyl-Radikal ein. Es ist jedoch bekannt, dafi durch elektronenziehende Substituenten an der Doppelbindung die radikalischen exo-trig-Cyclisierungen allgemein giinstig beeinflufit werden. So konnten Newcomb et al.C3] aus dem 5-Cyan-2,2-dimethyl-4-pentenyl-Radikal (l), das nach der Zinnhydrid-Methode erzeugt wurde, durch eine 4-exo-trigCyclisierung das Cyclobutan-Derivat 2 herstellen. Um die absolute Konfiguration von 10, das als 0 1 anfallt, bestimmen zu konnen, wurde 10 in die kristalline Verbindung 15a ubergefiihrt. 15a wurde schon von Mitra und KhanraI4I aus a-Pinen (12) erhalten. Da jedoch die physikalischen Daten (Schmp. und spezif. Drehwert sowie die NMR-Daten) ungenugend ubereinstimmten, haben wir 1% aus kauflichen (+)+Pinen rnit 99.5% Enantiomerenreinheit durch geringfugig abgeiinderte Reaktionen selbst hergestellt. Da 15a gut kristallisiert, wurde es bis zum konstanten spezif. Drehwert umkristallisiert, so dafi es enantiomerenrein vorlag. Der Schmelzpunkt und spezif. Drehwert von dem aus 10 und 12 erhaltenen 1% erwiesen sich als identisch. Die 'H-und '3C-NMR-chemischen Verschiebungen (s. Tab. 1) von 15a beweisen seine Struktur.Die relative Stellung der Hydroxygruppe an C-4 in 10 zu den Substituenten an C-1 und C-3 wurde auf folgendem Weg bewiesen: Swern-Oxidation von 10 fiihrt zum Cyclobutanon-Derivat 16, das durch NaBH4-Reduktion in Ethanol das C-4-Epimere 17 von 10 ergibt. NOE-Untersuchungen von den Epimeren 10 und 17 zeigten, da13 die Protonen an C-I, C-3 und C-4 von 10 in trans-und die von 17 in cisStellung stehen, womit fur 10 die absolute (IS,3R,4R)-Konfiguration bewiesen ist. Diskussion der ErgebnisseDie Herstellung von optisch aktiven Cyclobutanen beschrankte sich bisher auf [2 + 21-Cycloadditionen mit anschliefiender Racematspaltung oder ging von natiirlichem a-Pinen aus, in dem der chirale Vierring bereits vorgebildet ist. Die radikalische 4-exo-trig-Reaktion von optisch akti-

Key Words: Ginkgolide derivatives / 1QEpiginkgolide derivatives / Ginkgo biloba L.3,14-Didehydro-10-hydroxyginkgolide[*1 (1) was prepared by 3c by means of a free-radical reduction with tri-n-butyltin reaction of 3,lO-dihydroxyginkgolide (3) (ginkgolide " A ) by hydride/u,u'-azobis(isobutyronitri1e) (AIBN). By heating the reaction with phosphoryl chloride in pyridine. Catalytic hy-14-epiginkgolides 2a and 2b and the ginkgolides 3a and 3b drogenation of 1 leads to 10-hydroxy-14-epiginkgolide (2a), in acetonitrile with DMAP an equilibrium on the side of the which was epimerized with 4-(dimethy1amino)pyridine ginkgolides was established. The constitution and configura-(DMAP) in acetonitrile to give 10-hydroxyginkgolide (3a). 14-tion of the compounds were proven by their 'H-and I3C-NMR Epiginkgolide (2d) and ginkgolide (3d) were obtained from spectra. 2a and 3a via the 10-0-phenylthiocarbonyl derivatives 2c and In 1971 we reported on the first studies toward the synthesis of the ginkgolide~[~'. These experiments were stopped because we were able to isolate the ginkgolides A, B and C in multigram quantities in that same year. Their constitution and configuration were established by X-ray Despite the undisputable methodical progress demonstrated by the multistep total synthesis of Corey and co-workers[61, it is of little interest as a practical route to ginkgolides.The ginkgolides show exceptional chemical properties.They are -despite the lactone rings -stable against acids but very susceptible to alkali. In this paper we report on the preparation of the ginkgolide skeleton 3d and its 14-epimer 2d in order to study their chemical and biological properties. be easily separated by flash chromatography on silica gel (toluene/acetone). Reaction of 2a/3a with 0-phenyl chlorothioformate and DMAP in acetonitrile leads to the 10-phenyloxy(thi0car-bonyl) derivatives 2c/3c. Free-radical reduction with tri-nbutyltin hydride and ap'-azobis(isobutyronitri1e) (AIBN) in toluene leads to 1Cepiginkgolide (2d) and ginkgolide (3d) 20

Chemistry of Ginkgolides, IV1). – Synthesis of Ginkgolide B from Ginkgolide C The reaction of ginkgolide C (3) with tert‐butylchlorodiphenylsilane results exclusively in the formation of the 1‐O‐tert‐butyldiphenylsilyl ether 5, which when treated with O‐phenylchlorothioformate leads to the 7‐phenyloxythiocarbonyl derivative 6. The reduction of 6 with tributyltin hydride/AIBN yields the 1‐O‐tert‐butyldiphenylsilyl ether 7 of ginkgolide B (2). Removal of the silyl protective group with tetrabutylammonium fluoride gives pure ginkgolide B (2). The structures of the reaction products were confirmed by analytical and spectroscopic methods.

Aus dem sodaalkalischen Extrakt von Picrorhiza kurrooa wurden zehn Verbindungen als Acetate kristallin isoliert. Während das Pentaacetyl‐6′‐cinnamoylcatalpol, Hexaacetyl‐6‐vanilloylcatalpol und Hexaacetylcatalpol direkt mit authentischen Proben identifiziert werden konnten, wurden die Strukturen der Verbindungen 1–6 und 8 durch Röntgenstrukturanalyse bzw. spektroskopisch ermittelt. Die acetylierten Cucurbitacin‐glucoside 3–5 weisen gegenüber den natürlichen Cucurbitacinen eine verkürzte Seitenkette auf. Da sie im Neutralextrakt chromatographisch nicht nachgewiesen werden konnten, müssen 3–5 erst bei Extraktion bzw. Aufarbeitung entstehen und Artefakte darstellen. Als einziges acetyliertes C30‐Cucurbitacin‐glucosid konnte (20R)‐3β,16α,20,25‐Tetrahydroxy‐2β‐(β‐D‐tetraacetylglucopyranosyloxy)‐10α‐cucurbit‐5‐en‐22‐on (8a) kristallin erhalten werden.

By hydrogenation of 3,14-didehydro-l0-hydroxyginkgolide into its MOM derivative 2b. Ozonolysis of 2b gave a stable (3,14-anhydroginkgolide A, 1) the 3,14-didehydro-lO-hydro-secondary ozonide 3 and 10-methoxymethoxy-3-0x0-xyginkgolide-15-acid (2) was obtained. Reaction with diazo-14,15,16-trinorginkgolide (4). methane led to the methyl ester 2a, which was transformed Besides bilobalide and some flavanoid glycosides, the diterpenoid ginkgolides A-C are present in certain medicines such as Tebonin@, Roekana and Tanakan@, which are used for the therapy of peripheral arterial blood-flow disturbances and cerebrovascularSince their metabolism is still unknown, we set out to prepare 14C-labelled ginkgolides in order to enable appropriate investigations to be made. For this purpose, we prepared the ketone 4 and obtained thereby besides this ketone a stable secondary ozonide with a ginkgolide structure. Its biological effects may be of special interest and are currently being investigated.As starting compound we used ginkgolide A, from which the 3,14-didehydro-10-hydroxyginkgolide ("3,14-anhydroginkgolide A", 1) was prepared by treatment with P0Cl3 in dry pyridine, as we have described previously [3]. Hydrogenation of 1 in glacial acetic acid with Pt as catalyst led to the formation of ca. 40% of 3,14-didehydro-1 O-hydroxyginkgolide-15-acid (2), ca. 15% of the corresponding hydrogenated acid and ca. 40% of the 10-hydroxy-14-epiginkgolide. It is noteworthy that the hydrogenation was complete after consumption of 1.2 mol of H2 and that the three products were almost invariably formed in essentially the same ratio. The acidsL41 were converted into their methyl esters and separated by column chromatography on silica gel (toluene/acetone, 95 : 5). The pure 3,14-didehydroginkgolide-15-acid methyl ester (2a) was quantitatively converted into its 10-MOM derivative 2b by adding P4Ol0 to a solution of the compound in a large excess of dimethoxymethane. In this way, use of the carcinogenic methoxychloromethane, which had been formerly used for such purposes, was avoided. When a solution of 2b in dry acetonitrile was treated with ozone for ca. 1 h at -40°C and then stirred with 2 N acetic acid at room temp., the secondary ozonide 3 and the ketone 4 were formed. These could be isolated by subjecting the reaction mixture to column chromatography on silica gel (toluene/acetone, 95: 5). The first indication of the existence of the secondary ozonide 3 was given by the comparison of its 13C-NMR spectrum with those of the other compounds (see Table 1). The signals of C-3 and C-4 appeared in the region where the acetal signals are normally found. Conclusive evidence for the constitution and configuration of compound 3 was obtained from its crystal structure analysis. The molecular structure shows the normal framework of ginkgolide but without the five-membered ring at C2 and C3, which is replaced by the ozonide at C3 (Figure 1).