Kainic acid (1) is a neuroexcitatory amino acid, isolated by Takemoto and co-workers in 1953 from the seaweed Digenea simplex.' Thereafter, a number of structurally related compounds have been identified, including domoic acid (2), acromelic acid (3), and isodomoic acid (4), all of which share a common trisubstituted proline motif. Their unique biological activities have inspired widespread interest in establishing chemical access to this class of natural amino acids. Herein, we report the total synthesis of (±)-kainic acid (1), in which a novel photochemical sp^3C-H carbamoylation of cis-fused azabicyclo[4.3.0]nonane 10 has been devised to construct the highly substituted amino acid motif. 1. Photochemical sp^3C-H Carbamovlation of Tertiary Amine Photolysis of tertiary amines in the presence of a photosensitizer serves as a powerful means for cleaving the nitrogen-substituted sp^3C-H bonds. Evaluation of the photolysis conditions led to the discovery that cyclic amine 10 (1.0 equiv) underwent sp^3C-H carbamoylation with phenyl isocyanate (1.5 equiv) in the presence of 4,4'-dimethoxybenzophenone (0.2 equiv) to afford anilide 9 along with biscarbamoylated compound 11. This is, as far as we know, the first successful example of the direct production of an amino acid anilide from a tertiary amine via intermolecular addition of photochemically generated a-amino alkyl radical to phenyl isocyanate.2. Total Synthesis of (+)-Kainic Acid With suitably functionalized anilide 9 available, further synthetic manipulations were made to yield kainic acid (1). By common deprotection-protection protocols, anilide 9 was successfully converted to tetracyclic motif 12. Acidic hydrolysis of 12 followed by regioselective silylation of the resultant diol afforded silyl ether 13 regioselectively. Dehydration of 13 with Martin sulfurane successfully afforded alkene 14, which, by acid treatment followed by Dess-Martin oxidation, provided enone 15 in high yield. Enone 15 was then transformed into α,β-unsaturated enone 16 through Me_2CuLi-mediated methylation followed by silylation with TMSC1 and Pd(OAc)_2-mediated oxidation of the resultant silyl enol ether. Convex face selective 1,4-silylation of enone 16 produced quaternized compound 17 as a single detectable isomer. We envisioned that the silylated ketone 17 would exhibit a high degree of regiocontrol in the Baeyer-Villiger oxidation due to the steric demand caused by the hindered substituent. To our delight, the oxidative ring expansion of compound 17 with mCPBA was found to yield desired seven-membered lactone 18a. Furthermore, this transformation led us to discover an unusual silyl-migration reaction that produced 18b. It is likely that the stabilization of the cationic 0-carbon through anchimeric assistance of the silyl group enables the unique migration. Then, compounds 18a and 18b were each subjected to the desilylative olefination with HF. Py to deliver olefin 19, respectively, as a single product. Hydrolysis of compound 19 with 3N NaOH took place smoothly to eventually furnish kainic acid (1) as the sole product. The spectroscopic and analytical data of the synthesized kainic acid (1) exactly matched those reported in the literature.

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In vivo molecular imaging enables non-invasive observation of molecule of interest in organisms has been attracting much attention and has been widely used in life science. In particular, imaging technique utilizing near-IR bioluminescence has been developed recently. Coelenterazine (CTZ, 1) is known as a luciferin of several marine-derived luciferases such as Renilla, Oplophorus, and Gaussia, as well as a light emitting substrate for same Ca^<2+>-binding photoproteins. So far, more than fifty CTZ analogs have been synthesized and their luminescent properties were examined. Among them, v-coelenterazine (v-CTZ, 2), having a fused consecutive tetracyclic core structure shows red-shifted light emitting character favorable for in vivo molecular imaging. In fact, in vivo molecular imaging of mice was achieved by using v-CTZ in combination with a mutant Renilla luciferase. Although Kishi and Shimomura et al. reported the first and only synthesis of v-CTZ in 1988, the experimental details including procedures, reagents, yields and intermediates were not mentioned. Because more, efficient substrate with further red-shifted emitting character and increased stability was desired from practical viewpoint, we embarked on the synthetic study of v-CrZ and its analogs. Herein, we disclose a concise synthetic method of v-CTZ, which can be readily applied to the synthesis of a diverse array of analogs. We developed an efficient, synthetic route of v-coelenteramine (v-CTM), the precursor of v-CTZ. The route is based on the use of three continuous regioselective cross幼oupling reactions, namely, Negishi, Suzuki柚iyaura, and Stille coupling, followed by ring closing metathesis. This strategy allows facile preparation of broad range of analogs by replacing the coupling partners. The 1H NMR spectrum of synthesized v-CTZ was fully consistent with that of the reported one. The synthetic v-CTZ showed similar emission characters with previous reports when it was used as a substrate of Renilla luciferase and its mutant. In the previous study, we found that trifluoromethyl group placed instead of hydroxy group on the C2-phenyl group of CTZ contributes to improving the stability of CTZ without (detriment of light emitting properties. Thus, we also synthesized the trifluoromethyl-congener of v-CTZ, cf3-v-CTZ (22), which was also found to work as a substrate of Renilla luciferases.

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Iminosugars have emerged as potent inhibitors of glucosidases and glucosyltransferases, due to their transition state analogues in the enzymatic reactions. Therefore, many enantioselective syntheses of iminosugars have been reported in recent years. However, up to now, much attention has been focused on the synthesis of their D-forms. There were few reports of systematic studies of the biological properties of the L-forms of iminosugars. Herein, we report both catalytic enantioselective synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranose derivatives 2. We prepared iodoalkane 8 as the key intermediate for the synthesis of desired iminofuranose derivatives via asymmetric allylic aminations and ring-closing metathesis. Ni-catalyzed Negishi cross-coupling of 8 with many alkyl zinc halides proceed to give the desired products 9 in moderate yields. With 9 in hand, we have converted from coupling products into various 1-C-alkyl L-arabino-iminofuranose derivatives 2 in 3 steps (Scheme 2). Some of the synthesized iminofuranoses were found to be potent inhibitors of a-glucosidases, and their inhibitions were comparable to those of commercially available drugs such as acarbose, voglibose, and miglitol for the treatment of type 2 diabetes. Especially, 1-C-butyl-L-arabinoiminofuranose 2c showed much powerful inhibitory activity for rat intestinal sucrase. Additionally, we prepared iminosugar 12 having 1-hydroxybutyl group as 1-C-alkyl units and their inhibitory activities toward a-glucosidase were measured.

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2-Substituted tetrahydroquinoline moieties are frequently found in biologically active molecules. Several of these compounds are naturally occurring and many relatively simple synthetic 2-substituted tetrahydoroquinolines are already used or have been tested as potential drugs. Consequently, 2-substituted tetrahydroquinolines have been a significant subject of synthetic studies of biologically active compounds. Herein, we described a new efficient synthesis of 2-substituted tetrahydroquinolines achieved by the domino reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an alcohol, rearrangement of an aryl group, and addition of an organolithium or magnesium reagent. The synthetic utility of this approach is demonstrated by the syntheses of (±)-galipinine and (±)-martinellic acid. The domino reaction of N-indanyl(methoxy)amine (5) with various organometallic reagents proceeded smoothly to afford 2-substituted tetrahydroquinolines 6a-e in very short reaction time. We next investigated the domino reaction of substituted N-indanyl(methoxy)amines 7a-d. As shown in Table 2, these reactions also proceeded effectively to give 8a-h in good yields. In order to demonstrate the synthetic potential of this methodology, we performed syntheses of (±)-galipinine (16) and (±)-martinellic acid (17). The domino reaction of 5 with allylmagnesium bromide and N-methylation proceeded to give tetrahydroquinoline 11 in good yield. Then, olefin isomerization of 11 followed by cross metathesis with 14 and subsequently hydrogenation provided (±)-galipinine (16). We next applied the methodology to a formal synthesis of (±)-martinellic acid (17). The tricyclic methoxyamine 22 for the domino reaction was prepared from commercially available acetal 19. With the substrate for key reaction in hand, we next investigated the domino reaction of 22 with allylmagnesium bromide. The reaction, proceeded smoothly and stereoselectively to give the desired pyrroloquinoline. 23 in 94% yield as a sole product The brornination of 23 followed by hydroboration-oxidation of the resulting 'bromide 24 aftrded pyrrolot3,2-clquinoline 25, which is a. key intermediate used in the synthesis of (±)martinellic acid (17).

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We have isolated cortistatins, novel steroidal alkaloids having anti-angiogenic property, from the marine sponge Corticium simplex in 2006. Among them, we found that cortistatin A (1) showed highly selective anti-proliferative activity against human umbilical vein endothelial cells (HUVECs). The characteristic structure and intriguing biological activity of 1 attracted synthetic chemists, and many synthetic studies have been reported. We also engaged in synthetic study of 1 for overcoming the scarcity of natural supply. Here we present a new synthetic approach toward 1 using intramolecular Heck cyclization as a key step, and synthesis of some readily accessible analogs of 1. 1. Synthetic study toward total synthesis First, an A-ring fragment 17 was synthesized in 9 steps from 2-cyclohexen- 1 -one. Coupling reaction between the A-ring fragment 17 and a CD-ring fragment 16, which was obtained in 2 steps from readily available (+)-Hajos-Parrish ketone, afforded 21 and subsequent manipulations gave an enol triflate 25. The intramolecular Heck cyclization of 25 proceeded through 7 -endo manner to give compound 26b. After conversion of 26b into an enone 13, oxy-Michael reaction furnished a carbocyclic core structure of 1. Further study toward total synthesis of 1 is now under investigating. 2. Design and synthesis of active lead compounds Although many synthetic reports of cortistatin A (1) have been appeared, there have been no report about the in vivo anti-tumor properties of cortistatins by using the synthesized compounds. Then we are engaging in synthetic study of the structurally simplified and readily available analogs of cortistatins, based on the 3-D structure of 1 and the structure-activity relationship of the isolated eleven minor cortistatins. We found that a synthesized compound 37 having isoquinoline moiety and tetracyclic planar core structure showed potent and selective anti-proliferative activity against HUVECs. The compound 37 also exhibited in vivo anti-tumor activity in a mouse model inoculated sarcoma S180 cells.

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(+)-PD 128907 is a potent and selective agonist for human dopamine subtype D3 receptor and its structure is a simple trans-tetrahydrobenzopyran-1,4-oxadine framework. Although its supply by chemical synthesis is required, there are only two reports on the synthesis PD 128907; one is the synthesis of the racemate and the other is asymmetric synthesis via resolution. 3-Amino-6-methoxy-3,4-dihydro-2H-l-benzopyran-4-ol derivatives (1a,b) are key intermediates for these syntheses. We expected that compounds la,b could be readily prepared by the intramolecular cyclization of N-protected 2-(2-hydroxy-5-methoxybenzoyl)aziridine 4, which could be obtained by aziridination of 2-hydroxy-5-methoxyphenyl vinyl ketone 3. We discovered that Ru(CO)-salen complex 5, which is an efficient catalyst for the asymmetric aziridination of simple olefins with N-SES* azide, also catalyzes the aziridination of various vinyl ketones (Table 1). The aziridination of vinyl ketone 3 was found to proceed with almost complete enantioselectivity (>99% ee), and the treatment of the resulting 4 with Hiinig's base gave 3-SES-6-methoxy- 1 -benzopyran-4-one 8 (96% ee), which was recrystallized form hexane/CH2C12 to organic purity. Then, compound 8 was converted into (4aR,10bR)-3,4,4a,10b- tetrahydro-9-methoxy-4-propy1-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazine (trans-2) via i) NaBH_4 reduction, ii) Aggarwal's 1,4-oxadine formation, iii) deprotection of SES group, and iv) N-propylation. Since demethylation of trans-2 has been reported by Wise et al., we could achieve formal total synthesis of (+)-PD 128907 using highly enantioselective aziridination of vinyl ketone as the key step, in eight steps. * SES= 2-trimethylsilyethanesulfony, a readily removable N-protecting group

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Welwitindolinone A isonitrile (1), isolated from the cyanobacteria Hapalosiphon welwitschii by Moore in 1994, has a unique structure in which an oxindole is spiro-fused to a functionalized bicyclo[4.2.0]octene core, and Baran and Wood have reported total synthesis of 1, independently . We recently demonstrated ruthenium(II)-catalyzed [2+2] cyclization of 1,7-allenynes leading to a bicyclo[4.2.0]octadiene skeleton. Here, we report synthetic study of Wood's synthetic intermediate 8 by using the ruthenium-catalyzed [2+2] cyclization as a key step. Allenynes 15a and 15b, which is a diastereomer of 15a with respect to propargylic hydroxy group, were prepared through coupling of diethyl malonate derivative 18 and allenylacetate 16 as a racemic form. Cyclization reactions of 15a and 15b were carried out in the presence of 10 mol% of Cp*RuCl(cod) in methanol at 50℃, and the corresponding bicyclic compounds 31a and 31b were obtained in good yields, respectively. After protection of propargylic hydroxy group of 31a and 31b, allylic oxidation of 32a and 32b under various conditions was investigated. However, no desired enone derivative 33 was obtained. Next, we examined hydroboration of 32a and 32b. As a result, reaction of 32b and BH_3.THF gave the alcohol derivative 37a, which had desired stereochemistry at the ring junction, along with its stereoisomer 37b. The alcohol 37a was oxidized by TPAP to give the corresponding ketone 34, from which transformation into the target compound 8 is currently in progress.

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Diaporthichalasin (1), isolated from an endophytic fungus Diaporthe sp., was reported by Pornpakakul and co-workers in 2007. This natural product exhibited significantly potent inhibition against the enzyme CYP3A4. Its gross structure and relative stereochemistry were established based on spectroscopic analysis. The structure of 1 is characterized by a pentacyclic core framework, which consists of a tetrahydroisoindolone and a decahydrocyclopentanaphthalene substructure. We have involved in a total synthesis of 1 by featuring a sequential Diels-Alder (IMDA) approach. We synthesized first the substrate 5 for an intramolecular Diels-Alder (IMDA) reaction for constructing the upper-half octahydronaphthalene substructure. The Suzuki-Miyaura cross-coupling of (E,E,E)-trienyl boronate 10, prepared from tiglic aldehyde, and (E)-alkenyl iodide 14, prepared from (S)-citronellol, provided an all-trans conjugated tetraenyl allylic alcohol 15 which was converted to unsatureated aldehyde 5. The BF_3-0Et_2-promoted IMDA reaction of 5 provided an endo-adduct 4 as a sole product. After unsuccessful results for installing a lower-half equivalent (a functionalized pyrrolidinone ring) into the bicyclic intermediate 4, we explored the Diels-Alder reaction of 20 derived from 4 and N-protected maleimide 18 for constructing the tetrahydroisoindolone substructure in 1. The DA reaction proceeded in the presence of Me_2A1C1 at -78 ℃ to produce a tetracyclic D-A adduct 21 as a sole product (its stereochemistry is tentatively assigned). Further synthetic endeavor toward the total synthesis of 1 is under exploration, and the results will be presented.

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Recently, we developed a palladium-catalyzed cycloalkenylation (Scheme 1, eq 1), and this protocol has been successfully adapted to the stereoselective syntheses of polycyclic natural products. In our efforts to expand the utility of this palladium-catalyzed cycloalkenylation, we undertook a concise synthesis of 6-oxatricyclo[6.3.0.0^<1'5>]undecane. Although ketene silyl acetal 3 gave rise to desired tricyclic compound 4 under palladium-catalyzed cycloalkenylation conditions, the yield was less than 9% probably due to the instability of ketene silyl acetal 3 (Scheme 1, eq 2). To solve this problem, we recently developed a palladium-catalyzed oxidative cyclization of olefinic keto and lactone esters (2^<nd> generation palladium-catalyzed cycloalkenylation) as an alternative method of the original palladium-catalyzed cycloalkenylation for the construction of polycyclic compounds (Scheme 1, eq 3). In this presentation, we will describe the total synthesis of iridolactones and alkaloids shown in schemes 2-4, employing the 2nd generation palladium-catalyzed cycloalkenylation.

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The biotransformation of the foreign substrate using the living cells is interested in medical, pharmaceutical and organic synthesis fields. In such a status we had studied the biotransformation of foreign substrate using plant cultured cells and it was found that the plant cells have the conversion ability such as stereoselective reduction, enantioselective oxidation, regioselective hydroxylation and glycosylation. the saponine is accumulated in plants as secondary metabolites and it's ability in high functionally and draw an international attention as functional material. Also glycosylation was useful primarily for enhancement of water-solubility and thermal stability. We had investigated the production of saponines in one step and at reasonably low cost by using plant cultured cells. In this way, we have studied the biotransformation of using plant cultured cells. Recently we extract glucose transferase (PaGT3) derived from plant cells. To synthesize of the high functional saponines using PaGT3 we study the biotransformation of substrate using PaGT3 enzyme. To produce the glycoconjugates efficiently, we could use not only the purified enzyme but also the recombinant E.coli cells containing the PaGT3 gene. At this time we use trans-resveratrol as a substrate.The enzyme reaction trans-resveratrol→trans-resveratrol 4'-0-13-D-glucoside (yield 2.5%) The recombinant E.coli cell cultures reaction trans-resveratrol→trans-resveratrol 4'-0-13-D-glucoside (yield 11.7%) From this result it was found that the plant cultured cells and PaGT3 glycosylate the hydroxyl group of phenols in a good yield.

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l -0-cis-Cinnamoyl-β-D-glucopyranose, an allelochemical isolated from Spiraea thunbergii, exhibits potent plant growth inhibitory activity. cis-Cinnamic acid is the essential portion structure of 1-0-cis-cinnamoyl-β-D-glucopyranose responsible for the growth inhibitory activity. cis-Cinnamic acid exhibited potent inhibitory activity against the elongation of lettuce roots, and the half maximal effective concentration (EC_<50>) of cis-cinnamic acid was 2.2 μM. In this project we adopted cis-cinnamic acid as a novel lead compound, and examined the structure-activity relationship of cis-cinnamic acid to develop the environmentally friendly agrochemical. Moreover, we synthesized the fluorescent probes of cis-cinnamic acid aiming at the clarification of the mechanism of the activity expression. At first, we synthesized 1-0-cis-cinnamoyl-β-D-glucopyranose by the Hanessian protocol, and the synthetic compound showed similar inhibitory activity (EC_<50> 6.4 μg/mL) with that of the natural product (EC_<50> 4.0 μg/rnL). Next, we synthesized the cis-cinnamic acid analogues, and evaluated the inhibitory activities on the elongation of lettuce roots. Some analogues were found to be more potent than cis-cinnamic acid. Moreover, we found that the analogues having an oxime ether substituent at the meta position on the aromatic ring maintained strong inhibitory activity even if a sterically bulky substituent was on the ether moiety. This result is very important for the probe design because the direct substitution on the aromatic ring with the bulky ether group resulted in loss of the activity. The synthesis of the fluorescent probes, in which the core cis-cinnamic acid was connected with a fluorescent group with the oxime linkage, was achieved, and some probes exhibited potent inhibitory activity comparable to cis-cinnamic acid.

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Manzamine A and B were isolated from a marine sponge Haliclona sp. by Higa and co-workers in 1986 and 1987, respectively. It is well known that manzamine A has many interesting biological activities including strong antimalarial activity and has been synthesized by several groups including us. On the other hand, the biological activity of manzamine B has not been studied well due to its poor availability from natural sources. We have been studying total synthesis of manzamine B in order to provide enough amount of material for investigation of biological activity. We initially developed the asymmetric Diels-Alder reaction of aminodiene 2d and dienophile 1 using Cr-salen-F complex 3e as a promoter, which was originally reported by Rawal. After the reaction, the adduct 4d was triturated in hexane/AcOEt and enantiomerically pure 4d was obtained in 20 g scale. The adduct 4d was converted into oxabicyclo[2.2.2]octane 6 to control stereoselectivity of next alkylation. As expected, the Grignard reagent attacked from 13 face to avoid acetoamide moiety and gave desired compound 8 selectively. Aldol reaction of ketone 9 enabled introduction of Cl unit. However, the product was dehydrated enone 10 which was converted to thiophenyl ether 11. Pummerer reaction of 11 gave aldehyde 12. In this reaction, aminoalcohol group was converted into 2-CF3-oxazoline group, which is easily hydrolyzed under mild conditions. From compound 13, butenyl chain was successfully introduced for construction of C-ring by RCM. Hydrolysis of TFA amide and introduction of hexenoyl side chain are in progress.

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Pyripyropene A (PPPA, 1), isolated from the culture broth of Aspergillus fumigatus FO-1289, was found to strongly and selectively inhibit the isozyme of acyl-CoA:cholesterol acyltransferase 2 (ACAT2; IC_<50> >80 1.1M for ACAT1 vs. 70 nM for ACAT2). Moreover, 1 is orally active in mouse models of atherosclerosis. To assist the development of new cholesterol-lowering or anti-atherosclerotic agents, we investigated the structure-activity relationship of 1. Benzoyl and benzoyl 1,11-benzylidene acetal derivatives with different substituents at the 7-position were synthesized from natural 1 in two-to-three steps. Some of the derivatives strongly inhibited ACAT2 with picomolar IC50 values and exhibited higher isozyme selectivity than 1. We achieved a stereocontrolled total synthesis of pyripyropene A (1). Key features of the synthetic strategy included an intramolecular Ti(III)-mediated radical cyclization for construction of the A-ring, stereoselective 13-epoxide formation/Peterson olefmation for preparation of the functional groups on the B-ring, and stereoselective intramolecular cyclization for C-ring formation. The total synthesis provided 1 in 5.3 % overall yield in 17 steps. Extension of this chemistry to the synthesis of structural analogs of 1 for evaluation of the structure-activity relationship is currently under way and will be reported in due course.

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A yeast strain, Torulaspora delbrueckii NBRC10921 catalyzes the regio- and enantio-selective reduction of triketone 1 to give stereochemically pure form of bicyclic hemiacetal (+)-2 in excellent enantiomeric excess. Hemiacetal (+)-2 was converted to β-acetoxyketone (+)-3 via radical fragmentation using hypervalent iodine reagent. The resulting β-acetoxy-cc,a-disubstituted cyclopentanone would be useful for syntheses of various bioactive compounds because of its multifunctionalized structure. Madindorines A and B were isolated from the culture of Streptomyces nitrosporeus K93-0711 by Omura group in 1996 as a selective inhibitor of IL-6 activity. Madindolines were expected as a treatment of osteoporosis and the chronic rheumatism, and have quaternary chiral centers and a sterically congested cyclopentendiones. Acetyl group of 3 was removed under acidic condition and the subsequent tosylation followed by inversion of the hydroxyl group with KNO_2 gave hydroxyketone 14 (d.r.=25:1). Hydroxyketone 14 was protected as TBS ether and subsequent Saegusa oxidation produced enone 11. The introduction of the two alkyl groups was successful to provide enone 17. The final stage of the synthesis was the selective cleavage of the double bond in side chain. Ozonolysis of alkene 17 in Me0H followed by treatment with Ac_20-Et_3N in CH2C12 afforded the desired methyl ester 10, the key intermediate to (+)-madindoline A.

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Sandramycin (1), which was isolated from the culture broth of Norcardioides sp. (ATCC 39419), constitutes one of the members of class of C2-symmetric cyclic decadepsipeptide. It binds to the minor groove of double-strand DNA (dsDNA) with bisintercalation. Sandramycin (1) has exceptionally potent activity against L1210 cell in vitro with IC_<50> values of 0.02 nM. Total synthesis of 1 has accomplished by Boger's group via a sequential peptide coupling approach. The macrocycle moiety of 1 binds to the minor groove of dsDNA and greatly contributes to the sequence selectivity. We planned to synthesize 1 and its analogues of the macrocycle moiety considering to develop more convergent synthesic route, which can be applicable to study the structure-activity relationship of the macrocycle moiety. Our retro-synthetic analysis of sandramycin (1) is depicted in Scheme 1. First, the cyclic imine 6 was obtained by the Staudinger/aza-Wittig reaction sequence, and it was subsequently reacted with the isonitrile 5 and the carboxylic acid 7 in toluene at 70℃ as the Ugi three component reaction. As a result, the desired pentadepsipeptide 4 was obtained in 59% yield in a diastereoselective manner. This synthesis allows us to construct the pentapeptide 4 with simultaneous construction of the unnatural L-Pip residue and its linking to the two dipeptides at both C- and N- terminus. Next, deprotection of either the Boc group or the Tce group of 4 gave the amine 19 and the carboxylic acid 20, respectively. The [5+5] assemblage of 19 and 20 was conducted by the peptide coupling with the formation of the additional N-methylamide moiety to afford the liner decapeptide 21 (DEPBT, NaHCO_3, CH_2C1_2-DMF, 74%). Deprotection of the Boc and the Tce group of 21 with the same conditions used for the preparation of 19 and 20 gave the free liner peptide 3, which was then cyclized by DPPA in CH_2Cl_2-DMF to afford the cyclic decadepsipeptide 2 in 46% yield over three steps from 21. This synthetic approach is advantageous because sarcosine has no substituent at the a-position and the peptide coupling is free from a racemization, which is usually problematic in the peptide coupling chemistry.

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Omaezallene (1) was isolated from Laurencia sp. by Okino and showed strong antifouling activity against the larvae of the barnacle amphitrite. Although organotin compounds, such as tributyltin (TBT), had been widely used as a fouling inhibitor, the use of TBT was prohibited by IMO in 2008 due to its toxicity. Therefore, the development of the potent nontoxic fouling inhibitor is desired strongly, and 1 is expected to be a lead compound as the fouling inhibitor. Although the relative and absolute structure of 1 was assumed using 1D-and 2D-NMR experiments, the relative configurations have not been determined completely. To determine the relative configurations as well as the absolute configuration, the synthetic study toward 1 was started. The synthesis commenced with the known aldehyde 5, derived from D-glucose in 5 steps, which was transformed into the unsaturated ester 12 with E geometry. The ester 12 was next converted to the hemiacetal 14 in 3 steps. The treatment of ethynylmagnesium bromide to 14 afforded the desired propargy alcohol 6 as a major diastereomer. Cyclization of 6 with NBS furnished the construction of the two contiguous stereocenters to give the bromoether 15 in a highly stereoselective manner, which was then derived to the aldehyde 8 in 4 steps. Coupling reaction between 8 and the tribromoolefin 10 synthesized from E-olefin 9 afforded the propargyl alcohol 24. Final two steps successfully furnished the diol 25, of which 11-1-NMR spectrum was almost corresponding to that of natural 1.

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Micronesian marine sponge Lendenfeldia chondrodes contains structurally diverse neuroactive metabolites such as dysiherbaine, neodysiherbaine, dysibetaine, dysibetaine CPa and CPb, and cribronic acid, which have received significant attention from the synthetic community as structural motifs for developing novel neuroactive compounds. It is also of our considerable interest to use these metabolites as a probe for investigating functions of synaptic receptors. In the present study, we established a synthetic route to dysibetaine CPa (1) in racemic form, which is amenable to the analog synthesis, to study the biological function as well as the structure-activity relationships. Dysibetaine CPa (1) is a betaine consists of a quaternary ammonium group and two carboxyl groups, located on a novel 1,2,3-trisubstituted cyclopropane ring. From the synthetic point of view, differentiation of the functional groups on the cyclopropane ring is essential for the total synthesis but proved to be challenging during our study because of the instability of the synthetic intermediates. Upon considerable experimentation, we discovered that the cyclopropane ring was readily constructed by the reaction of N-(4-nitrophenyl)maleimide with sulfonium ylide 3. Reductive opening of the cyclopropane-fused imide 22 with NaBH_4 proceeded chemoselectively, giving rise to hydroxyamide 23. The amide was converted to ethyl ester over two steps, and then quaternary ammonium group was introduced by way of bromide 6'. Finally, acidic hydrolysis of two esters was effected by hydrochloric acid to achieve the total synthesis of dysibetaine CPa ((±ア)-1). Total yield was 4.5% for 12 steps. Furthermore, synthesis of five analogs was performed in the present study. Our route for the racemates, thus established here, will be also expanded to the asymmetric synthesis to determine the absolute stereochemistry of 1. Preliminary study indicated that all synthetic compounds did not induce noticeable behavioral change when 20 μg was administrated in mice intracerebroventricularly, as was observed with natural product.

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Tamulamide B (1), a new family of marine polycyclic ethers, was isolated from the Florida red tide dinoflagellate Karenia brevis by Baden and co-workers in 2010. This compound inhibits the binding of tritiated dihydrobrebetoxin B to the voltage-sensitive sodium channels in a concentration dependent manner and acts as a brevetoxin antagonist. As well as the novel biological activities, the unique structural features have attracted attention of synthetic chemists. In this paper, we wish to report the recent results and our efforts on the synthetic study of tamulamide B (1). Synthesis of the ABC ring segment 3 was started from the known lactone 5. The Kumada-Tamao-Corriu coupling of the triflate 6, prepared from 5, with vinylmagnesium bromide gave the diene 7, which was converted to the acrylate 9. Reductive cyclization of 9 with SmI2 efforted 10 in highly stereoselective manner. Compound 10 was converted to the ABC ring segment 3 by several steps. The FG ring segment 4, prepared from the furan 14 via the Achmatowicz reaction and Et3SiH reduction, was connected with the ABC ring fragment 3 leading to the a-acetoxy ether 28. Intramolecular allylation of 28 followed by ring-closing metathesis using the Grubbs catalyst 30 to furnish the heptacyclic ether 2. The right hand diene was introduced by Wittig reaction, and the construction of the left hand side chain was archieved by Curtius rearrangement to afford the acetamide 38. Further studies towards the total synthesis of tamulamide B (1) is in progress.

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The asymmetric cationic cyclization reaction is the key reaction in the biosynthesis of the natural products such as terpenoids and steroids, and recognized as one of the important research issues in synthetic organic chemistry. During the course of our recent studies regarding the reactions of an α-silyl cation, which is presumed to be a short-lived reactive species, we found that an acidic treatment of an α-alkenyl-α-hydroxysilane afforded the intramolecular Friedel-Crafts type cyclization product via a generation of the putative a-silyl cation. In this report, our recent efforts toward the chirality transferring Friedel-Crafts cyclization of an optically active α-alkenyl-α-hydroxysilane and its silyl ether are described. The treatment of the optically active α-alkenyl-α-hydroxysilane 11a with TMSOTf (1 equiv) underwent the cyclization reaction at the γ carbon attached to the silicon in a highly regioselective manner to give the vinylsilane-containing cyclized product 12. Despite the cationic reaction conditions, the chirality of the starting lla was significantly transferred to the product 12. The corresponding tent-butyl substituted analog 14 underwent the cyclization reaction to give the racemic product 15. These results indicated that the silyl group played a crucial role in the chirality transfer of the present cyclization. After several attempts, the use of a catalytic amount of TMSOTf or TfOH was found to be quite effective for the chirality transfer to produce the cyclized product 12 with a small loss of their starting optical purity. The catalytic reaction pathway of the present intramolecular Friedel-Crafts cyclization is underway.

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Rice blast disease, caused by infection of rice blast fungus Magnaporthe grisea (Hebert) Barr. (perfect stage of Pyricularia oryzae Cabara), has been the most serious pest for rice. The fungus mainly produces several phytotoxic compounds according to fermentation method, i. e., dihydropyriculol (1), pyriculol (2), and pyriculone (3) by a shaking culture; dihydropyriculariol (5) and pyriculariol (6) by an aeration and agitation culture; and tenuazonic acid by a stationary culture in a soy sauce-sucrose medium. Pyricuol (4) together with 2 were produced by a shaking culture with a potato dextrose medium. These salicylaldehyde-type phytotoxins are common metabolites of blast fungi of various host plants except a ginger. To develop novel methods to control the blast disease a better knowledge of the biosynthesis is necessary. Synthesis of both enantiomers of pyricuol (4) from (R)- and (8-lactates was achieved using [2,31-Wittig rearrangement and Stille coupling reactions as the key steps. This revealed that the natural 4 has an R-configuration. Racemic synthesis is also reported. On the other hand, optically active pyriculariol (6) was synthesized from L-rhamnose using microwave assisted Stille coupling reaction of the unprotected substrates as the key step. A comparison of the CD spectra and 1H NMR spectra of the corresponding MTPA esters found that natural pyriculariol (6) existed as a racemate. Biotransformation of the plausible biosynthetic intermediates 7-d2 and 8-d in deuterio forms was also examined. Not diol 7-d2 but aldehyde 8-d was converted by the fungus M. grisea into dihydropyriculariol (1-d) in soy sauce-sucrose medium under a shaking culture. Foliar application test of the synthetic compounds on rice leaves revealed that both a salicylaldehyde and a side chain fragments are necessary for the necrotic activity. In conclusion, the blast fungus M. grisea produced 1, 2, and 4 in optically active forms and 5 and 6 as racemates depending on the culture conditions. Additionally, it is interesting that both oxidation and reduction would be coexist at the later stage of biosynthesis of these phytotoxins.

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MA026, a novel lipocyclodepsipeptide, exhibits selective antiviral activity against enveloped viruses such as influenza and herpes. An antiviral compound with complex depsipeptide structure like MA026 is scarce, and MA026 has the potential to inhibit viral infections with a novel mechanism. However, the availability of MA026 from natural resources is limited, therefore, the chemical synthesis is essential to accomplish the biological investigation. Here, we present synthetic studies to establish an efficient synthetic pathway to MA026. MA026 consists of (3R)-hydroxydecanoic acid, linear peptide six amino acids and cyclodepsipeptide eight amino acids. Nine of the amino acids posses the D-configuration. The retrosynthetic analysis of MA026 (1) is shown in Figure 2. MA026 was devided into three key segments to maximize the convergency : branched cyclic depsipeptide 2, tripeptide 3 and fatty acid moiety 4. Key to the total synsthesis of MA026 is the macrocyclization of depsipeptide, so we chose two macrocyclization sites, (A) D-Val - D-Leu and (B) L-Leu - D-Gln. Protected amino acids were condensed to gave tripeptide 3. Fatty acid moiety 4 was synthesized from n-octylaldehyde through samarium mediated Reformatsky reaction. The macrocyclization substrate 5 was prepared by the condensation of peptide fragments. Then, 5 was cyclized and the formation of branched cyclic peptide 2 was confirmed by mass spectorometry, however, the 2 was not obtained as a single compound. Five dipeptides were condensed to gave the macrocyclization substrate 6. Attempts to cyclize the precursor 6 is in progress.

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Lactimidomycin (1) is a highly unsaturated 12-membered macrolide possessing a biosynthetically rare glutarimide side chain, isolated from the fermentation broth of Streptomyces amphibiosporus R310-104 by Sugawara and co-workers. It displays strong in vitro cytotoxicity against a number of cancer cell lines including the highly invasive MDA-MB-231 human breast adenocarcinoma, in vivo antitumor activity in mice, and potent antifungal activity. It also inhibits both DNA and protein syntheses by blocking the translation-elongation phase through binding to the 60S ribosome. Its attractive biological activity and intriguing structure prompted our synthetic efforts toward lactimidomycin. Synthesis of 23 has been achieved from acetaldehyde and known oxazolidinone derivative 6 in 13 steps through vinylogous Mukaiyama aldol reaction (VMAR), chiral diamine-catalyzed asymmetric aldol reaction, Stile coupling, Yamaguchi macrolactonization, and E-selective double bond installation. Since a three-step conversion of 23 into 1 is known, the present synthesis constitutes a formal total synthesis of 1. In our effort toward the total synthesis of 1, we set known glutarimide-carboxylic acid 24 as our starting material. This compound was converted to aldehyde 30 in 6 steps via thiol esterification, TMSE protection of the nitrogen of the imide group under Mitsunobu conditions, Fukuyama reduction, Maruoka asymmetric allylation, and ozonolysis. The VMAR of 30 with 6 and subsequent protection and reductive removal of the chiral auxiliary of the resulting product 31 gave olefinic aldehyde 32. The aldehyde was subjected to asymmetric aldol reaction, reduction and Wittig olefination to furnish vinyl iodide 33 as a single isomer. After coupling of 33 with vinyl stannane 12, the resulting ester 34 was hydrolyzed and then exposed to Yamaguchi macrolactonization conditions to give 36 in moderate yield. Finally, NaIO_4-oxidation of 36 afforded key intermediate 37 bearing the complete carbon skeleton of 1, in good yield and geometrical selectivity.

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Ladder-shaped polyether marine toxins produced by marine dinoflagellates are known to have diverse biological activities, such as neurotoxicity, cytotoxicity, and antifungal activity. The distinguishing structures of trans-fused cyclic ethers of sizes ranging from five- to nine-membered rings have attracted the attention of a number of synthetic chemists. However, the stepwise synthesis of more than ten rings is practically impossible due to the large number of transformations required. It is therefore important to develop an efficient method for the construction of large toxins. We herein report a new convergent strategy for the synthesis of this class of molecules. Our synthetic strategy is based on the alkylation of an oxiranyl anion generated from epoxy sulfone I with triflate II followed by 6-endo cyclization of III. The six-membered ketone IV could serve as a precursor of the seven-membered ring VI by a ring expansion reaction. After a reductive etherification reaction of ketones IV and VI, a second six-membered ether ring would be generated. Through the use of this strategy, two new six-six-membered and six-seven-membered ring systems V and VII were constructed. Application of our convergent approach was demonstrated by the synthesis of pentacyclic polyethers 21 and 23 starting from the monocyclic triflate 16 and the bicyclic epoxysulfone 17. The polyether 23 corresponds to the framework of the FGHIJ ring system of gymnocin-A. The present method features a flexible approach toward polycyclic arrays consisting of six- and seven-membered ether rings starting from the same starting materials.

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We recently reported the intramolecular substitution of an allyl alcohol by a heteroatom using a palladium (II) catalyst without activation of the allylic alcohol. We report here highly stereoselective intramolecular cyclization of dihydroxyketone using palladium (II) catalyst via unstable hemiacetal, in which cyclization occurs without activation of the allylic alcohol to afford spiroketal structures.1) Cascade type cyclization via hemiacetal inermediate using Pd(II) catalyst. Treatment of 1 , 11 -tetrahydropyranyloxyun dec-9-en-5-one derivatives 1 and 3 with 10 mol% palladium (II) bis(benzonitrile) dichloride in THE afforded 6,6-membered spiroketal in good yield and good stereoselecitivity.2) Synthetic studies of spirofungin A and B Spirofungin A is a polyketide-type antibiotic isolated from Streptomyces violaceusniger Tu 4113. Now we show a synthesis of spirofungin A using the cascade cyclization of ketone 12 as a key reaction. Retrosynthetic fragmentation of spirofungin A affords three segments. Firstly, we synthesized the aldehyde segment 9 from 1,3-propanediol and the sulfone segment 10 was prepared from methyl (R)-3-hydroxy-2-methylpropionate. The cyclization precursor 12 was prepared by using Julia coupling reaction between the aldehyde segment 9 and the sulfone segment 10 (Scheme 2). The key cascade cyclization of 12 was achieved successfully by treatment with PdCl_2(PhCN)_2 and Me0H at room temperature to give the spiroketal 7 and 13 (Scheme 4). Studies on the connection of the segment B and the segment A and C to construct the whole structure of spirofungin A are now underway.

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We identified two glycosyltransferases that contribute to the structural diversification of flavonol glycosides in grapevine ( Vitis vinifera)-glycosyltransferase 5 (VvGT5) and VvGT6. Biochemical analyses showed that VvGT5 is a UDP-glucuronic acid: flavono1-3-0- glucuronosyltransferase (GAT), and VvGT6 is a bifunctional UDP-glucose/UDP-galactose:flavono1-3- O-glucosyltransferase/galactosyltransferase. The VvGT5 and VvGT6 genes have very high sequence similarity (91%) and are located in tandem on chromosome 11, suggesting that one of these genes arose from the other by gene duplication. Both of these enzymes were expressed in accordance with flavonol synthase gene expression and flavonoid distribution patterns in this plant, corroborating their significance in flavonol glycoside biosynthesis. The determinant of the specificity of VvGT5 for UDP-glucuronic acid was found to be Arg140. We also analyzed the determinants of the sugar donor specificity of VvGT6. G1n373 and Prol9 were found to play important roles in the bifunctional specificity of the enzyme. The results presented here suggest that the sugar donor specificities of these VvGTs could be determined by a limited number of amino acid substitutions in the primary structures of protein duplicates, illustrating the plasticity of plant glycosyltransferases in acquiring new sugar donor specificities.

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The objective of our research is to establish an innovative methodology for biosynthesizing bioactive molecules using a combination of two approaches. First, when mRNA synthesis is absent from the target secondary metabolite biosynthetic gene cluster, fungal molecular genetics is used to enable expression of transcriptional regulator in the target gene cluster to activate its natural product biosynthesis. Second, once mRNA can be transcribed from the target gene cluster, cDNA can be synthesized to allow transfer of the cluster into yeast and achieve heterologous production of the new compounds. Polyketides (PKs) and nonribosomal peptides (NRPs) have been isolated from Streptomyces and many other source organisms. In recent years, gene clusters encoding PK synthases (PKSs) and NRP synthetases (NRPSs) have been discovered through fungal genome sequencing. While on average 50 gene clusters are identified in a single fungal genome, fewer fungal PK and NRP products can be isolated from a fungal culture grown under a typical growth condition. Thus, simple artificial reactivation of the cryptic gene cluster may be insufficient for an efficient natural product biosynthesis. To circumvent these obstacles, we examined upregulation of 60 gene clusters encoded in chromosomal DNA of four fungal species, Aspergillus fumigatus, A. flavus, A. oryzae and Chaetomium globosum, using the aforementioned fungal molecular genetics. Thus far, we have isolated seven new PK and NRP compounds successfully. Subsequently, we used our recombination cloning-based yeast expression system to reconstitute these biosynthetic gene clusters quickly and efficiently. Our preliminary results clearly demonstrate successful expression of seven C. globosum PKS gene clusters in Saccharomyces cerevisiae, three of which led to the production of new natural products whose identities have been characterized spectroscopically. Our methodology will facilitate the efforts in isolating novel natural products and rationally engineering in the biosynthetic pathways for production of analogs possessing comparable if not more potent bioactivity.

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