A wide variety of natural products are formed by the so-called polyketide pathway. The difficulties in achieving the cell-free system of polyketides syntheses have retarded their enzymological investigation. To date, only two polyketide synthases have been purified, 6-methylsalicylic acid synthase and chalcone synthase. Orsellinic acid synthase was chosen as our target enzyme because orsellinic acid (1) is the simplest aromatic tetraketide. We found the orsellinic acid synthase activity in the cell-free extract of Penicillium cyclopium which produces penicillic acid. The enzymatic formation of orsellinic acid (1) was confirmed by carrier dilution experiment. The enzyme was unstable and partially stabilized by the addition of glycerol, DTT, and EDTA to the buffer. By preparative centrifugation (210,000xg for 1hr), the enzyme was pelleted and solubilized by Tween 80. The solubilized enzyme was partially purified by DEAE-cellulose column chromatography. Questions about the stereochemistry of orsellinic acid synthase reaction was approached by,using chiral malonate (2). (2R,3S)-[2,3-^<13>C_2,3-^2H_1]Malate and (2R,3R)-[2,3-^<13>C_2,2,3-^2H_2]malate, which are configurationally stable precursors of S- and R-malonate, respectively, were synthesized. The chiral malonates were prepared by KmnO_4 oxidation and their chiralities were confirmed by CoA transferase and fatty acid synthase system. Then, chiral malonates were reacted with CoA transferase and orsellinic acid synthase system. Mass spectroscopic analyses of the orsellinic acids formed from chiral malonates suggested that elimination of methylene hydrogen in the enolization (or aromatization) occurs in non-stereospecific.

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Feeding experiments with chirally deuterated glycerol and deuterated glucose to the culture of an extreme halophile Halobacterium halobium and ^1H- and ^2H-nmr analyses of the deuterium enriched 2,3-di-O-phytanyl glycerol were undertaken to study the biosynthesis of the membrane unit lipid of archaebacteria from stereochemical and metabolic standpoints. The results that the C-6 of glucose and the sn-C-3 of glycerol were stereospecifically incorporated without loss of any methylene hydrogens into the sn-C-1 of the lipid which carries a polar head group strongly imply that the carbohydrate metabolism of H. halobium is identical with that of evolutionary diverged eubacteria and eukaryotes which contain 1,2-di-O-acyl glycerol in the membrane and that stereochemical inversion apparently takes place at the C-2 position of glycerol to form 2,3-di-O-alkylated glycerol lipids of archaebacteria. Also observed was the loss of the C-2 hydrogen of glycerol, which may suggest involvement of oxido-reduction during the stereochemical inversion of the glycerol moiety in the lipid biosynthesis. A possible mechanism involving sn-1-O-alkyl dihydroxyacetone phosphate is discussed.

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We have demostrated that "Green Odour" of green leaves consists of six volatile compounds of C_6-aldehydes and C_6-alcohols including leaf aldehyde, (2E)-hexenal, and leaf alcohol, (3Z)-hexenol. These volatile compounds are biogenerated from linolenic acid and linoleic acid via their respective hydroperoxides in leaves. The biogeneration involves four enzymes. Among these enzymes, lipoxygenase and hydroperoxide lyase are especially interesting. The two enzymes are found to bind to the lamella membrane of chloroplasts in green leaves. The lipoxygenase catalyzes a stereoselective oxygenation of unsaturated fatty acids having a (1Z,4Z)-pentadiene system to produce 13-(S)-hydroperoxides, whereas, the hydroperoxide lyase cleaves the bond between C-12 and C-13 of these hydroperoxides into C_6-aldehydes. We will present the enzymic cleavage mechanism of 13-(S)-hydroperoxides to C_6-aldehydes and C_<12>-oxo-acids and substrate specificities for the enzymic oxygenation of the unsaturated fatty acids to 13-(S)-hydroperoxides in tea chloroplasts, using an entire series of synthetic (ω6Z,ω9Z)-C_<13>-C_<20>-dienoic acids and dienols.

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Recently, the reduced polyketide compounds, which are possibly biosynthesized via intramolecular Diels-Alder reaction, have been found in the metabolites of fungi and Streptomyces. Those possess decalin moiety,and a double bond and two ajacent substituents in one ring of decalin. To investigate this possibility, the biosynthetic pathway of two phytotoxins, betaenoe B(1) and solanapyrone A(2) were studied. 1. Betaenone B(1) The biosynthetic origin of oxygen atoms in 1 was established by feeding experiment of [1-^<13>C,^<18>O_2]acetate. The result was supported by the accumulation of the intermediate, probetaenoe I(5) in the cytochrome P-450 inhibitor treatment of P. betae. The radioactive (5) was efficiently converted to 1 (6.02%) in P. betae. 2. Solanapyrone A(2) The biosynthtic building block of 2 were examined by feeding experiments with ^<13>C-labelled precursors. The results showed 2 was octaketide with two C_1 units. Participation of Diels-Alder reaction in the biosynthesis of 2, was suggested by the isolation of solanapyrone D(9), which was a diastereomeric isomer of 2. The absolute configulations of 2 and 9 imply the enzyme recoginizes loosely the diene moiety.

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A number of terpenoid dialdehydes have been isolated from both terrestrial and marine plants, animals, insects and microorganisms. Nearly all kinds of dialdehydes are biologically active and some of them were found to show remarkable antifungal and antitumor activities. Our research projects are to develop the useful synthetic methods generally applicable to the synthesis of terpenoid dialdehydes and to elucidate the structure activity relationship. In this paper, we deal with following topics: 1. the synthesis of penstemide and didrovaltrate, 2. the synthesis of allamandicin and plumericin1,2,3, 3. the synthesis of secologanin4, 4. the synthesis of secoiridoids and 5. the synthesis of optically active petiodial and determination of its absolute structure5.

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Intramolecular cycloadditions of Allenes constitute the versatile methods for the stereocontrolled synthesis of variously functionalized polycyclic compounds. Especially, intramoleclar Diels-Alder reactions using allenic dienophiles can full enjoy the merits of the unique structure of allens and proceed with extraordinary ease. On the basis of this strategy, several new synthtic methodologies were developed; (1) the intramolecular Diels-Alder reaction of allenyl ethers followed by hydration andoxidation provided a new polycyclic lactone synthesis (Scheme 1). This method was successfully applied to the total synthesis of platyphyllide 30(Scheme 5). (2) The allenyl ether bearing a substituent at C-2 position (ex.,1c,1d) underwent the tandem [2+2] cycloaddition and [3,3] sigmatropic rearrangement to produce the novel product having an bicyclo [n.3.11 carbon ring system (ex., 5c, 5d) (Scheme 2).

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Among many bioactive compounds derived from family Euphorbiaceae, breynin A and B, isolated from Breynia officinalis HEMSL in Taiwan, showed a significant hypocholesterolemic activity in rats. On the basis of X-ray crystallographical study on breynolide (1), an acid-hydrolysis product of breynin A, it was determined that breynins have a glycosidic structure carrying breynogenin (2) as an aglycon which involves a novel tetrahydrothiophene and spiroketal moieties. In connection with our synthetic investigation concerning bioactive natural products, synthetic process toward 1 would be presented. Retrosynthetic analysis suggested that coupling reaction of a sulfur-contained bicyclic segment with a pyranose derivative, followed by formation of the spiroketal might be an effective route to the target (1). The above-mentioned two segments were successfully synthesized from L-(-)-carvone and L-(+)-tartaric acid. Sufone-mediated coupling reaction of 11 with 16, followed by several manipurations afforded an oxygenated breynolide (22) sulfone derivative of 1. Final step to breynolide (1) is still going on.

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The total syntheses of hymenolin (50) and and parthenin (52) have been established starting from 4-methyltropolone (2). The synthetic strategy is shown in Scheme 1. The regioselective tosylation of 2 and successive condensation of the resulting tosylate (5) with diethylmalonate gave 2H-cycloheptatblfuran-2-one derivative (7). The catalytic hydrogenation of 7 gave the desired saturated lactone (12) in which C_6-Me and Y-lactone ring were situated in cis. Various attempts of alkylation or functionalization at C_7-position of ketone 10 were unsuccessful. The attempt of the syntheses of intermediates 20 and 21 via cycloaddition of dichloroketene to the olefin 15 was also unsuccessful because of their poor yields as shown in Scheme 3. The 1,4-addition of Grignard reagent (33) to the α,β-unsaturated ketone (29) which was derived from 15 and successive methylation of the resulting 30 gave a mixture of α- and β-methyl derivatives, 31 and 32. Acid catalyzed aldol condensation of benzoate 36, which was derived from 32, gave the desired product (38) in a moderate yield. Reduction of 38 with LiAl(OMe)_3H gave a β-alcohol (40) as major product. Platinum catalyzed air oxidation of 40 and successive Jones oxidation gave a cyclopentanone derivative (42). The conversion of 42 to hymenolin (50) was achieved by the analogous procedure reported by Heathcock and his coworkers in their synthesis of parthenin. Successive treatmnt of 50 with LDA and CBr_4 gave an α-bromolactone (51) as the sole product. Treatment of 51 with DBU gave parthenin (52), which was identical with natural product.

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Bicyclohumulenone (1), sesquiterpene ketone isolated from a species of liverworts, Plagiochila acanthophlla subsp. japonica, is an attractive synthetic target because of its challenging structural features as well as its high level of aroma composition. The stereoselective synthesis of bicyclohumulenone was achieved in which the crucial 10-membered intermediate 2 was constructed by the intramolecular alkylation of the protected cyanohydrin 3. The E-cyclopropane ring at C(9) and C(10) was introduced stereoselectively by the 1,4-addition of dimethyloxosulfonium methylide to the enone 2. The stereoselectivity of this cyclopropanation was discussed based on MM2 calculations. The new structure of Periplanone A (17), the sex excitant pheromone of the American cockroach, has been proposed by Hauptmann based on its isolation and his synthesis. In his synthetic approach, the 1,4-relative stereochemistry between C(1) and C(8) in 17 was constructed by the highly stereoselective epoxidation (99:1) of the enone 21 using ^tBUOOH/KH. Our reexamination in this epoxidation based on MM2 calculations and experimental results showed that the epoxidation of 21 proceeded with nonstereoselectivity to give a mixture of 17 and 18 in a ratio of 1.3:1.

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Synthetic studies on anisatin (1), a toxic sesquiterpenoid having a novel B-lactone are described. In order to determine the absolute stereochemistry of anisatin (1) unambiguously, optically active noranisatin (2), an oxidation product of anisatin (1) was synthesized from a bicyclic enone (4) prepared from (R)-(+)-pulegone (3). Spiroalkylation of (4) provided a compound (6), from which a triol (15) was synthesized stereoselectively. The triol (15) was converted into a hydroxy acid (17). Lactonization of (17) followed by oxidation with RuO_4 afforded noranisatin acetonide (19), chiroptical and spectral properties of which were identical with those of the authentic specimen derived from natural anisatin (1) in all respects. Thus, the absolute stereochemistry of anisatin was determined to be depicted as the formula (1). Deprotection of (19) accomplished the synthesis of optically active noranisatin (2). For the synthesis of the natural enantiomer of anisatin (1), an olefin (8) obtained from (4) was transformed into a crossconjugated dienone (25), and subsequently converted into an unsaturated lactone (26), whose structure was established by an X-ray crystallographic analysis. The lactone (26) was further converted into a diacetate (27), from which a triol (28), a key intermediate for the synthesis of optically active anisatin (1) was obtained.

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In our first total synthesis of cycloaraneosene (1), the structure of its hydroxyderivative has been reviced from 9α-(12) to 8β-hydroxycycloaraneosene (4) by physical data comparisons of synthetic 12 with the natural substance. To obtain a concrete proof for this conclusion, both stereoisomers of 8-hydroxycycloaraneosene have been synthesized via an improved 8-membered ring formation, a Lewis acid-catalized intramolecular enereaction, and a [2,3]-rearrangement of an allylselenoxido derivative. The 4 and 19, thus obtained, were identical with natural hydroxycycloaraneosene and its epimer, respectively. The stereochemistries of the hydroxyls of these compounds were deduced as had been expected by a differential NOE experiment on compound 4. The framework of Sordaricin (5), which is believed to be biosynthesized from 1 via 4, has been constructed by an intramolecular Diels-Alder reaction of a B-seco-derivative of 1.

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Total synthesis of (±)-gibberellin A_3 (GA_3) by a new route was described. Hydrofluorene lactone 7 was synthesized from 1 according to the previously established method,3) involving Diels-Alder reaction of diene 1 with dienophile 2, intramolecular Friedel-Crafts reaction of 4, and stereoselective introduction of formyl group into C(6) position of 6 (Scheme I). Lactone 7 was successfully converted into enone 16 with desired C(9)-H configuration via 15b. Prior to dearomatization of the aromatic ring in 7, transformation of 7 into 15b (A/B trans) was carried out. Birch reduction of 15b followed by successive acid treatment and base treatment gave 16 (Scheme II). While similar reactions for 10 (A/B cis) resulted in formation of 11 with the undesired C(9)-H configuration. Photo reaction of 16 with allene, subsequent oxidative cleavage of cyclobutane ring in 17, reductive intramolecular cyclization of keto ester 19, and introduction of exo-methylene group provided 23 having a gibbane skeleton (Scheme III). Synthesis of (±)-GA_3 was accomplished by elaborative adjustment of functionality of A ring in 23 (Scheme IV). GA_5, GA_<20> and GA_<60> were also synthesized from (+)-23 (Scheme V).

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Recently, we have developed a new method for the construction of chiral quaternary carbon centers using the chiral nitroenamine 1, which has a SMP group as a chiral leaving group. The reactions of the chiral nitroenamines with zinc enolate of α-alkylated-δ-lactones afforded optical active nitroolefinlactones 3 in high yields with high enantiomeric excess. This reaction proceeds through the addition-elimination process. Addition of enolates to 1 occurs through the six-membered ring transition state including metal cation under kinetic control (Scheme 1). As an application to the total syntheses of naturally occuring terpenoids, the synthesis of (+)-podocarpic acid (5) was accomplished in nine steps starting from (S)-nitroolefinlactone 3a. The conjugate addition of the Grignard reagent to nitroolefin, ring A construction by the intramolecular alkylation of nitroalkane, and stereoselective ring B construction are included as key reactions. This synthesis constitutes the formal asymmetric syntheses of six diterpenoids (taxodione, nagilactone, callitricic acid, hinokino methylether, trachiloban-19-oic acid, and lambertianic acid), which have been transformed from (+)-podocarpic acid. Starting from (R)-nitroolefinlactone, an optically active tricyclic compound 6 was synthesized by the same synthetic method. This synthesis also constitute the formal asymmetric syntheses of three diterpenes okaurenoic acid, steviol. and monogynol) and three diterpene alkaloids (acisine, veachine, and garryine).

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Glycinoeclepin A (1) is a degraded triterpenoid isolated from kidney bean roots as a hatching stimulus for soybean cyst nematode. Its unusual structure as well as its strong activity made us to attempt its synthesis. Two (S)-hydroxyketones (E and F) readily available by reducing the corresponding symmetrical 1,3-diketones (G and H) with baker's yeast were employed as chiral starting materials. One of the key intermediates (C&equiv;7) possessing the bridged-ether ring was synthesized from E in 14 steps and the other (D&equiv;15) was obtained from F after 12 step-conversion including the introduction of the methyl groups and the methylene insertion. Aldol condensation of 15 with 7 gave 17 as a sole product, which has all chiral centers of glycinoeclepin A correctly. The aldol product 17 was converted to the key-intermediate, diketo lactone 24, via the intramolecular Horner-Wittig reaction to introduce a two-carbon unit and the following transformation. Reductive C-ring formation was accomplished by treatment of 24 with Me_2CuLi to give 31 in high yield after esterification. Finally, dehydration and deprotection yielded glycinoeclepin A (1). The overall yield of 1 was 3.0% in 32 steps from E or 2.6% in 31 steps from F.

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Among a large number of quassinoids, bruceantin (1) and related compounds possess significant in vivo antileukemic activity. These quassinoids have also many contiguous chiral centers and highly oxygenated carbon frameworks. We have studied total syntheses of bruceantin (1) and its analogues to obtain detailed informations on the structure-activity relationships. Herein, the first total synthesis of bruceantin (1) was reported. Natural brusatol (6) was converted to 15-deoxybruceolide derivative (2) in 5 steps in order to (a) supply advanced intermediate for a total synthesis of bruceantin itself and (b) establish the stereostructure of synthetic intermediates. The pentacyclic lactone (3) was converted to 2, identical with the authentic sample in the spectroscopic manner, via 5 in 8 steps. Final stage of our synthesis toward bruceantin (1), transformation of 2 into 1, requires the regio- and stereoselective oxidation at C-15. We solved this problem by the following sequences: (1) selective reduction of lactone carbonyl group of 2 in the presence of C-2 conjugated ketone; (2) dehydration of 13 to give 14; (3) regio- and stereoselective oxidation of 14 to give 15; and (4) chemoselective oxidation of hemiacetal group of 15 giving the bruceolide derivative (16). Finally, DCC mediated esterification of 16 with (E)-3,4-dimethy1-2-pentenoic acid and subsequent deprotection by acid hydrolysis gave bruceantin (1), identical with the authentic sample, along with bruceantin 11-acetate (19).

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The 2-oxazolone moiety has proved of synthetic potential as an excellent leaving group in carboxyl- and phosphoryl-activating processes. This work deals with another synthetic aspects of the heterocycle as a building block for vic-amino・alcohol structures, which are structural units found in a substantial number of bioactive compounds such as enzyme inhibitors, antibiotics and sympathomimetic amines. The synthetic strategy shown in Fig.1 offers versatile routes to a wide variety of vic-amino alcohols in which the key step is regio- and stereoselective introductions of easily replaceable groups (X,Y) to the olefinic moiety of the 2-oxazolone (1), followed by stereospecific and stepwise substitutions with appropriate groups (R^2and R^3). This methodology would be expected to result in predominant formation of threo-derivatives (5), which could be readily converted, if needed, to erythro-configurations (6) by inversion of the hydroxy group via oxazoline intermediates (8 and 10). Enantiomerically pure type 2 synthons were readily obtained by bromo-methoxylation of (+)/(-)-3-ketopiny1-2-oxazolones with new reagent system, Br_2/MeC(OMe)_3/TMSOTf. The reactions were smoothly proceeded to result in highly diastereoelective formation of trans-5-bromo-4-methoxy adducts (2,90%de) which served as common intermediates for biologically significant vic-amino alcohols such as (16), (21) and (24).

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Recently, we are systimatically developing new asymmetric reactions which should be available for the syntheses of drugs and natural products. We describe asymmetric alkylations onto cyclic acyl iminium species 22 and 29 (Schemes 2 and 3) and 5-hydroxy-2(5H)-furanone 35 (Scheme 4) based on new design (Figs. 2-5) for diversification of asymmetric synthesis utilizing C4-chiral thiazolidines 6 and 7. Herein, their application to an asymmetric total synthesis of (-)-spinidine (4) (Scheme 3) and formal syntheses of (-)-retro- necine (2) (Schemes 5-7) was also documented.

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Recently we have been Involved in the development of a new carbon-carbon bond forming reaction via the rearrangement of sulfur ylide intermediates which were easily prepared by the preferential interaction of a carbene or carbenoid with divalent sulfur. This synthetic strategy was applied to the synthesis of pyrrolizidine alkaloids as follows. Intramolecular treatment of 5-phenylthiopyrrolidone derivative having organodiazo function in the presence of rhodium (II) acetate brought about the carbon-carbon bond formation at the position previously occupied by sulfur atom to give the bicyclic compounds which were then converted to (±)-isoretronecanol, (±)-trachelanthamidene, and (±)-supinidine. Whereas the intermolectlar reaction of an opticaly active 4-hydroxy-5-phenylthlopyrrolidone derivative with α-diazo-malonate yielded the carbon introduced product stereoselec-tively at the a-position to nitrogen atom, and this product was successfully transformed into (+)-heliotridine and (+)-retronecine. Moreover, the construction of carbapenem and penem ring skeleton was achieved through its 2,3-bond formation by application of the oxalimide cyclization with thioacetal group. This results supports the reaction mechanism involving a carbene species.

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6-Methoxy-5-methylbenzo[h]pyrrolo[4,3,2-de]quinolin-4(51-)-one (eupolauramine) (1) is a structually unusual azaphenanthrene alkaloid isolated from Eupomatia laurina. In this paper we have described the 9-steps total synthesis of 1 in 34% overall yield using new methods recently developed in our laboratory. The key steps are involving (1) the first example of new application of an intramolecular aromatic substitution with a N-methoxy-N-acylnitrenium ion to the synthesis of a natural product bearing nitrogen heterocyclic rings (step d), (2) the direct regiospecific introduction of a methoxy group into the para-position of N-methoxy function (step e), (3) the aromatization of dihydrocarbostyril moiety in the presence of other functional groups to quinoline moiety via thiolactam formation followed by the desulfurization and simultaneously occurring dehydrogenation with Raney Ni (step f and g), and (4) nitration of the compound (26) labile to oxidation by using Cu(NO_3)_2・2H_2O in the presence of ascorbic acid (step h). This methodology will be useful not only for the synthesis of azaphenanthrene skeleton but also other nitrogen heterocyclic rings, which will offer a new route for the synthesis of natural products bearing nitrogen heterocyclic rings.

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Benzo[c]phenanthridine alkaloids have been shown to be biosynthesized from the corresponding alkaloids through an oxidative C_6-N bond cleavage followed by recyclization between C_6 and C_<13> position of the latter alkaloids via the hypothetical aldehydeemamines. And a hexa-oxygenated fully aromatized alkaloid has been found to be biosynthesized from a 2,3,7,8-tetra-oxygenated one through a penta-oxygenated one. According to the above biosynthetic process, we have accomplished a novel and efficient synthesis of penta-oxygenated benzo[c]phenanthridine alkaloids, chelirubine (7), chelilutine (13a) and sanguilutine (13b), and macarpine (20), a hexaoxygenated one, and B/C-hexahydrobenzo[c]phenanthridine alkaloids, (±)-corynoline (27), (±)-11-epicorynoline (28), (±)-isocorynoline (29), and (±)-11-epiioscorynoline (30). Dihydrofagaridine (10a) and its analogue (10b), derived from palmatine (8b) were converted to chelilutine (13a) and sanguilutine (13b), respectively, through salcomine-catalyzed oxidation and reductive methylation. Oxychelirubine (5) was converted to oxymacarpine (18) through regioselective iodination followed by methoxylation with NaOMe in the presence of CuI and CuO. Oxymacarpine was derived to dihydromacarpine (19) and macarpine (20). Sequential treatment of the Hofmann degradation product (23), devived from corysamine (21), with Tl(NO_3)_3, NaBH_4, 15% HCl, and NaBH_3CN afforded (±)-corynoline (27) along with (±)-11-epicorynoline (28). Reduction with zinc instead of NaBH_3CN in the above reaction gave (±)-isocorynoline (29) accompanied with (±)-11-epiisocorynoline (30), 27, and 28.

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Theory and theoretically obtained results themselves naturally want to be proved in an experimental way. Recently Kitagawa and we have theoretically determined the absolute configuration of a series of novel pentacyclic polyketides, halenaquinol (1) and halenaquinone (2), isolated from tropical marine sponges, to be 12bS by the application of the x-electron SCE-CI-dipole velocity MO method to the calculation of CD spectra. Here we report the experimental proof of their absolute stereostructures theoretically determined, by describing the first total synthesis of (+)-halenaquinol 1 and (+)-halenaquinone 2. Optically pure (8aR)-(-)-Wieland-Miescher ketone (4) was converted to enone (+)-(12). The Diels-Alder reaction of 3,6-dimethoxybenzocyclobutene (18) and (+)-12 gave compound (+)-(19) of a tetracyclic skeleton, which was converted to halenaquinol dimethyl ether (12bS)-(+)-(3). All of the spectroscopic data of the synthetic sample of 3, including the chiroptical data of [α]_D and CD spectra, were completely identical with those of the authentic sample derived from natural halenaquinol. Dimethyl ether (12bS)-(+)-3 was converted to halenaquinone (12bS)-2 and finally to halenaquinol (12bS)-1. We have thus succeeded in the experimental verification of their absolute configurations theoretically determined. The present results have established the reliability of the x-electron SCF-CI-DV MO method which is useful for the theoretical determination of the absolute stereochemistry of twisted x-electron systems.

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The semi-synthetic podophyllotoxin glycosides, VP-16-213 (1) and VM-26 (2) showing a marked clinical efficacy and the intriguing mechanisms of action have stimulated interest in the synthesis of new active analogues of the podophyllotoxin glycoside. The systematic chemical modification of podophyllotoxins was studied. 1) Aminoglycosidic lignan variants (6, 7, etc.) of 4'-O-demethy1-1-epipodophyllotoxin were synthesized by a stereoselective BF_3-catalyzed coupling of 5 with the corresponding aminosugar derivatives. N-Alkylaminoglycosyl analogues (8, etc.) of 1 were also derived from 6. 2) Syntheses of all possible diastereomers (1, 6, 8, and 15-23) of 1, 6 and 8 were achieved via optical resolution of (±)-podophyllotoxin by glycosidation with D- and L-sugars. 3) Glycosidic variants of 1-β-hydroxy-α-peltatin and 1-β-hydroxy-8-O-methyl-a-peltatin (24-26) were synthesized by glycosidation of 28 and 29 with the corresponding sugar derivatives. 4) The syntheses of carbocyclic lignan variants (34-37) of 4'-O-demethyl-1-epipodophyllotoxin were achieved by coupling of 5 with chiral aminocyclitols. 5) 1-O-(2-Aminoethyl) ethers of 4'-O-demethyl-1-epipodophyllotoxin (38-42, etc.) were synthesized by coupling of 5 with the corresponding 2-aminoethanol derivatives, and with ethylene glycol followed by reductive amination of its aldehyde. Among all derivatives synthesized, 6 and 8 were found to have superior antitumor activity to 1.

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The carbapenem antibiotics represented by 1, 2, and 3, have been the focus of current synthetic endeavor due to their potent antibacterial activities and broad spectra. We wish to report here novel and efficient synthetic routes to the optically active carbapenem key intermediates 4, 5, and 6. Thus, it was found that the [2+2]-cycloaddition reaction of the chiral aliphatic imine 9 prepared from (S)-7, could proceed in a highly stereoselective manner to afford the 3,4-trans-β-lactam 10 as a major product (Scheme II). The β-lactam (10) was readily elaborated to 5 (Scheme III). The similar methodology could be applied to the syntheses of the other key intermediates 4 and 6. Thus, the addition reaction of diketene to the chiral imine prepared from (S)-13, was found to produce 17 in a highly stereoselective manner (Scheme IV). 6 and 4 could be readily prepared from 17 (Scheme V and VI). Taking into account high stereoselectivity in the β-lactam formation and uses of commercially available inexpensive (S)-7 and (S)-13 as starting materials, the overall processes may hold promise as the practical synthetic methods of 5 and 6. As the second method for preparing 5, the Reformatsky reaction of 6 was studied. It was found that the reactions of sterically crowded achiral 2-oxazolidone derivatives (24b,f)in the presence of zinc dust in refluxing THF gave rise to 25β as major products (at most, 95:5) in excellent yield (Scheme VII). Trans-formation of 25β to 5 could be successfully accomplished (Scheme VIII). This latter process is also anticipated to be one of the most practical synthetic methods of 5 because of high β-diastereoselectivity, high overall yield, mild reaction conditions, and use of inexpensive reagents.

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Extremely high enantioface selection was achieved in cisdihydroxylation of olefins with osmium tetroxide using chiral diamine 1. Enantioface selection in this reaction is shown by the general presentation 4. Since both (+)- and (-)-1 are readily available in optically pure forms, this method allows the synthesis of both enantiomers of diols with predictable absolute configuration. This efficient synthetic method was effective in the enantioselective synthesis of aglycons of anticancer antibiotics anthracyclins. Asymmetric oxidation of 13 followed by silane reduction afforded 17 in 85% ee. Friedel-Crafts reaction followed by recrystallization afforded optically pure 18, which was then converted into 4-demethoxy-9-deacetyl-7-dehydroxy-9-hydroxymethyldaunomycinone (22). Oxidation product (23) of 14 was also converted into 25 through two steps in 82% ee. Friedel-Crafts reaction followed by recrystallization afforded optically pure 26, which was then converted into 4-demethoxydaunomycinone (27) with conventional method. This is the shortest-step approach to the asymmetric synthesis of anthracyclins.

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For recent years, we have been studying on the stereoselective total synthesis of naturally occuring products having complex chemical structures and improtant biological activities, such as macrolide and polyether antibiotics. Erythromycin A (1) is a well known macrolide antibiotic and we have already reported the total synthesis of (9S)-9-dihydroerythronolide A (3), however some problems, for example lactonization, remain unsolved. We would like to report here an improved synthetic approach to (2) starting from D-glucose. Construction of the chiral centers were carried out by the methods which were previously deveroped in our laboratory, and synthesis of the sulfone (9) and the aldehyde (16) were accomplished. Coupling of (9) and (16) (n-BuLi, Et_2O, -60℃) proceeded smoothly and after desulfonylation with sodium amalgam in Me0H-AcOEt at ?10℃, (18) was isolated in 63% yield. Remaining chiral centers at C_5 and C_6 were easily introduced by a base catalized epimerizatoin (K_2CO_3, MeOH, r.t.) and a non-chelation controlled alkylation of the ketone (MeLi, THF, -78℃). Thus obtained (22) was converted to the seco-acid (26). Cyclization of (26) by modified Corey's method in the presence of DMAP, which improved the yield remarkably, afforded the lactone (27) in 60% yield. Lactonization using other methods and transformation of (27) into (2) are now under investigation.

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The polyene macrolide antibiotics have attracted much attention for their potent antifungal activity and unique structure. The characteristic structural feature of the antibiotics is that they involve 1,3-polyol and all-trans-polyene moieties. However, in most cases even a relative configuration of these 1,3-polyols remains unknown. Convergent synthesis of 1,3-polyols: We have already reported a stereoselective and stepwise method for the synthesis of 1,3-syn and anti-polyols. Recently, an effective and stereocontrolled convergent method for the synthesis of 1,3-polyols has been developed in this laboratory. Using this new method, the first total syntheses of two natural products 3 and 4 having 1,3-synpolyol moiety have been accomplished. Determination of the stereostructure of 1,3-polyols: We have recently developed a reliable strategy for determining the relative and absolute configuration of 1,3-polyols based on the structurespecific ^1H NMR splitting patterns observed in lactones B and C. Based on this new method, the absolute configuration of pantamycin, a polyene macrolide antibiotic, has been determined as shown in structure 51. Furthermore, fungichromin, lagosin, and cogomycin were proved to be the same compound as pentamycin. Thus, their absolute stereostructures should also be shown as 51.

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Bleomycins (BLMs) are a group of antitumor antibiotics of unusual glycopeptide structure. The potent activity of BLM is attributed to the oxygen activation and the DNA cleavage by the iron-chelate of the linear sequence of unique amino acids. The aldol reaction of (R)-3-bromoacetyl-4-isopropyl-1,3-oxazolidin-2-one 8 with 1-triphenylmehtylimidazole-4-carbaldehyde 9 proceeded highly enantioselectively to give bromohydrin 10 which was converted into erythro-β-hydroxy-L-histidine 2, a pivotal amino acid for the oxygen activation. (2S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid 3, a linker between the oxygen activating site and the DNA binding site, has been prepared in a good yield by aldol reaction of aldehyde 13 and chiral boron enolate of 12 with no isolable stereoisomers. The present synthesis of 2 and 3 allowed us to access artificial peptides with catalytic activity to activate oxygen, epoxidize olefin, and cleave DNA, namely, PYML-1, -4, -6, and PYML(6)-bleomycin.

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In order to establish an efficient route for the synthesis of a high-mannose type glycan chain, the target tetradecasaccharide (1) was divided into three blocks, (A), (B) and (C) by retrosynthetic consideration. Synthetic routes for these blocks were established as follows. Block (A) Trisaccharide (4), a synthetic equivalent of (A), was obtained by condensation of mannosyl donor (2) with chitobiosyl acceptor (3) in the presence of silver silicate. Block (B) and (D) In order to study model reactions, we designed a hexasaccharide (D) and three synthetic approaches were examined. i) A stepwise approach using monosaccharide donors (8), (10) and (12): The glycosyl donors (8) and (10) were reacted stercoselectively with glycosyl acceptors (7) and (9), respectively, in the presence of silver triflate to give only α-anomers. The condensation of nonreducing end donor (12) with (11) in the presence of mercuric cyanide proceeded only in low yield. ii) A block synthesis using a disaccharide donor (13): Mercuric cyanide promoted glycosylation of (13) with (9) gave an anomeric mixture of hexasaccharides (α:β ratio 2:1, at 6'-O) in 18%. iii) Block synthesis using pentasaccharide donors (15), (16), and (17): Condensation of peracetylated pentasaccharide donor (15) with (14) in the presence of silver triflate gave only orthoester (19). However, a 14% yield of hexasaccharide (20) was obtained by condensation of (16) with (14) in the presence of mercuric salts, although the product could not be purified from contaminated mercuric salts. Pentasaccharide donor (17) was also reacted with (14) in the presence of a mixture of mercuric salts and a 23% yield of hexasaccharide (21) was obtained. Block (C) A linear hexasaccharide (29), was synthesized using disaccharide synthons (22), (23), and (25). The reaction of (22) with (23) in the presence of silvertriflate in dichloroethane gave a 59% yield of (28) which was converted to peracetylated donor (24). A 56% yield of the desired hexasaccharide (29) was obtained by condensation of (24) with (25) in the presence of silver triflate in dichloroethane. Further experiments directed toward a total synthesis of (1) will be discussed.

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Starting from (S)-1,2-O-isopropylideneglycerol (5) as a sole chiral origin three five-carbon chiral building blocks 8, 10, and 11 were prepared efficiently in both enantiomeric forms via O-benzylglycidol (7). Namely, upon the reaction with acetylene in DMSO, 7 yielded the terminal acetylene-alcohol (8) in the presence of sodium hydride, while it afforded the internal acetylene-alcohol (9) with concomitant triple bond migration in the presence of potassium t. butcixide. The latter was further transformed into the (E)-allyl alcohol (10) by reduction with lithium aluminum hydride and the (Z)-ally1 alcohol (11) by reduction using Lindlar catalyst, respectively. The terminal acetylene (8), on sequential carboxylation and partial hydrogenation, afforded the α,β-unsaturated lactone (14) which furnished dehydrolavenderpyran (18) via stereoselective cuprate addition. On the Claisen-Johnson reaction only the (E)-alcohol (10) allowed diastereoselective rearrangement to give the homochiral ester (15) which was transformed to citronellal (19). On the other hand, on the Wittig rearrangement via the propargyl ether (13) only the (Z)-alcohol (11) allowed diastereoselective rearrangement to give the single acetylene-alcohol (16) which was transformed to elm bark beetle pheromone (21) and serricornine (23). Utilizing these building blocks jointly, we next attempted the synthesis of more complex polyketide maclorides, e. g., protomycinolide IV (1), milbemycin β_2 (2), amphotericin B (3), and mycoticin B (4). We have so far attained to protomycinolide IV (1) in formal sence, northern half (35) of milbemycin β_2 (2), C_<31>-C_<37> moiety (58) of amphotericin B (3), C_<27>-C_<34> moiety of mycoticin B (4), and key 1,3-glycol blocks, 50 and 51, of both 3 and 4.

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Under the influence of the (R)- or (S)-BINAP-based Ru(II) complexes (BINAP =2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), a wide range of functionalized ketones are hydrogenated in a highly enantioselective and predictable manner. The hydrogenation proceeds smoothly in alcoholic media at room temperature with initial hydrogen pressure of 40-100 atm. The substrate to catalyst mole ratio ranges from 230 to 2200. Ru complexes of the type RuX_2(binap) (X = halogen, empirical formula), Ru_2Cl_4(binap)_2N(C_2H_5)_3, or Ru(OCOR)_2(binap) are employable as catalysts, depending on the substrates. Various functionalities including dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc., can act as the efficient directive group. Neighboring halogen atoms also affect strongly the stereochemical outcome. This hydrogenation method is applicable to synthesis of physioligically and pharmacologically significant agents and their intermediates such as statine, carnitine, GABOB, compactin, etc.

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Leukotriene B_4 (1) is powerfully chemotactic for macrophages and neutrophiles and therefore relevent to allergic and inflammatory states. Herein we describe a highly stereocontrolled synthesis of 1 in which HPLC separation is not necessary to purify the final product 1 or any intermediates, thus, making it possible to prepare 1 in large quantity. Our synthesis is outlined in Scheme 1. The optically pure key intermediates 6 and 9 are synthesized according to the procedure (eq 1 and 2) in which the kinetic resolution of dl-4 (X = SiMe_3, SnBu_3, I) by the Sharpless asym metric epoxidation plays a central role. The conjugated triene unit of 1 is constructed stereospecifically from the cis enyne 7 (prepareed from 6) and the trans vinyl iodide 9 via vinyl borane 8 according to the procedure reported by Suzuki et al. We also report the synthesis of 5(S)-HETE (2) and 12(S)-HETE (3) as summarized in Scheme 5 and 6. The key intermediates 31 and 38 are prepared in an optically pure form by using eq 1 and 2.

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Chiral, highly functionalized cyclopentanes seem to be attractive synthons for the syntheses of natural products containing a five-membered ring. During a detailed examination on the cyclization of 1,4-diketones 1 to cyclopentenones 2, we have found that two oxygenated products (4,5) are formed when the purification by column chromatography on silica gel takes a long time. To prepare chiral 4a, microbial reduction was examined. On screening of microbial reduction of (±)-4a using 40 species of yeasts, Rodotorula rubra.was found to be effective for the kinetic resolution, and highly opticaly pure products (>99% ee) were obtained. The absolute stereochemistry was determined by using the exciton chirality method. As the application of the easily prepared chiral synthon (+)-4a, we have achieved the formal syntheses of (-)-α- and (+)- β-cuparenone (16,17). One of the structural features in cuparene family is vicinal quaternary carbons on five-membered ring. The quaternary carbon with p-tolyl function could be nicely constructed by stereoselective 1,4-addition of (p-Tol)_2Zn to (+)-4a. The key intermediate β-ketol 21 obtained from (+)-4a was successfully converted to the Meyers' intermediate (+)-25 and to the Greene's intermediate (+)-28, respectively. In a similar manner, PGE_1 methyl ester was prepared. The oxygenated product 7 as a starting material was reduced stereoselectively to 29. LiBH_4 reduction of 29 gave a desired tetraol 30, which was converted to the enone 31 via protection of 1,2-diol, chemoselective oxidation with RuCl_2(PPh_3)_3 and introduction of ω-chain. The major product, 32, in the reduction of 31 with TLBH was converted to PGE_1 methyl ester 34 by usual manners.

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