A new method of ring transformation has been developed. As shown in Table 1, treatment of 3-(3-oxoalkyl)cyclopentanones with BF_3-Et_2O and ethylene glycol afforded the ring transformed products. Cyclopentanones with carbonyl function at the α-side chain underwent a facile ring expansion under the same reaction conditions (Table 2). The ring-transformation reaction of hydropentalenes provided us a new strategy for construction of bridgehead, spiro, and hydroazulene skeletons (Table 3). The process of this "one-pot" ring transformation is tentatively proposed to involve three steps of aldol condensation, acetalization, and Grob fragmentation. This method has been applied to the syntheses of (dl)-trichodiene and (dl)-acorenone B. By using a similar ring fragmentation reaction to the ring-enlarged lactone (28) from intramolecular acetal (27b), synthesis of (R)-(-)-phoracantholide I has been successfully achieved.
Juvenile Hormones (JH's) have attracted much attention of synthetic chemists since their discovery in 1960's. Only few enantioselective syntheses, however, have been reported because the construction of the epoxide moiety in enantiomerically pure state was difficult. We developed several biochemical conversions to obtain chiral building blocks, and thought that JH's could also be synthesized by utilizing those methods. Herein we describe the syntheses of all known JH's in enantiomerically pure state. As the precursor of the epoxide moiety was chosen the 1,2-diol system, which could be constructed from E by means of ring opening. The alcohol 2a, which could be obtained by baker's yeast reduction of the corresponding diketone, was the starting material of JH III synthesis. The Baeyer-Villiger oxidation of the acetate derived from 2a afforded 3 bearing a hidden 1,2-diol moiety. After the ring opening of 3, its carbon-chain elongation was executed to afford 7. The final step was the formation of the epoxide ring. The use of methanesulfonic anhydride as a mesylating reagent successfully excluded the participation of nucleophilic chloride ion in the reaction mixture, resulting in no racemization at the chiral center to give pure (+)-JH III. The unnatural (-)-JH III could also synthesized from 7. As for other JH's, (+)-2b was required as the common starting material. After screening some yeast strains, Pichia terricola KI 0117 was found to be a suitable one for the selective reduction of 8. By employing the similar procedure as for JH III, (+)-JH 0, I and II were synthesized. The alcohol (+)-2b was successfully converted into (-)-2b, and the synthesis of the unnatural (-)-JH I was also attained. The remaining JH to be synthesized was 4-Me JH I (1e). The additional chiral center was introduced by diastereoselective alkylation of 13 with 11 to afford 14. After several functional group modification, the desired 1e was synthesized. The present samples of both the enantiomers of JH I and JH III were employed for the bioassay, and the results showed that the natural enantiomers show 5,000 to 10,000 times stronger activities than those of unnatural ones.
Grayanotoxins (1-4), toxic principles isolated from leaves of various plants of family Ericaceae, have been shown to increase specifically membrane permeability to sodium cation in sodium-dependent excitable membranes. These diterpenes are characterized by the A-nor-B-homo-kaurane skeleton, unique tetracyclic carbon framework, and by the dense arrangement of hydroxyl groups. Effective synthetic routes to the CD-, A-, and B-rings of grayanotoxins has been successfully developed. Construction of CD-Ring. A reliable synthetic scheme to produce the CD-ring, a diol-γ-lactone 17, in an optically active form was explored. Stereoselective formation of the C-ring was performed through enantioselective Diels-Alder reaction of an α, β-unsaturated ester 10, prepared from L-ethyl lactate, stereocontrolled alkylation of a β-ketoester 13, and regio- and stereoselective reduction of a keto-γ-lactone 14. The D-ring was constructed via radical cyclization of a hydroxy-γ-lactone 9 and stereoselective iodohydrin formation of an olefine-γ-lactone 16. Construction of A-Ring. Connection of the CD- and A-rings was examined. It turned out that cross Aldol reaction of the acyclic precursor of the A-ring, aldehyde 7 and the CD-ring, methylketone 8 took place cleanly, giving an α, β-unsaturated ketone 18. Thus, elaboration of the A-ring was studied using model compounds. Stereocontrolled cyclization of the A-ring meditated by samarium(II) iodide was achieved by employing an allylsulfide 19 as a starting material to afford an alcohol 20. Construction of B-Ring. The tertiary hydroxyl group of the B-ring was introduced by stereocontrolled epoxidation of a homoallylalcohol 24, synthesized from grayanotoxin II (2), followed by reduction, giving rise to a diol 25. Ring closure reaction that lead directly to the vicinal cis-diol moiety of the B-ring was also investigated. Samarium(II) iodide induced pinacol coupling reaction of ketoaldehyde 5, prepared from grayanotoxin III (3), was found to occur in a stereoselective manner to afford a triol 26.
Macrocycles have the π-orbitals of olefins oriented in the plain of the ring to minimize the transannular nonbonded repulsions. Therefore in a macrocyclic system, the inter- and intramolecular reactions should proceed exclusively from one side (Fig. 1). For example, intermolecular reaction proceeds from the outside of the ring, and intramolecular reaction takes place only through the interior side of π-orbitals. There are extensive studies on the stereocontrol of enolate reactions in normal five, six membered ring and acyclic systems. However, it is quite difficult to predict the stereoselectivity of the macrocyclic enolate reactions because of their many conformational possibility. It would be an important advance if these problems could be solved. Here we report the efficient total synthesis of sarcophytol A, a simple cembranoid that has been claimed to have potent anticancer activity, and the construction of steroid skeleton, based on the macrocyclically controlled reactions of enolates. We also describe the conformational analysis of the large membered enolates for the prediction of the stereoselectivity of the enolate reactions. The syntheses of sarcophytol A and steroid skeleton feature noteworthy methods including the following: 1) Conjugate addition of dimethylcuprate with the exo-enone 14 followed by β-elimination of MOMO group providing the E,Z-endo-dienone system of sarcophytol A, stereoselectively. 2) Conformational analysis of macrocyclic systems by Multiconformer and Monte Carlo method to predict the stereoselectivity of the β-elimination. 3) Development of dianion method for the construction of large memberd ring system.
Antheridiogen-An (A-An, 2) is a plant hormone which stimulates sex-organ development and spore germination in fern. The gibberellin-related structure was elucidated by Nakanishi et al. in 1971, and later the configuration at the C(3) position was corrected by the total synthesis of A-An by Corey et al. Here, we wish to report the total synthesis of A-An in a highly stereocontrolled manner. Hydrofluorene lactone 5 was prepared from diene 6 via acid anhydride 7 and keto acid 8 (Scheme 1). Lactone 5 was then converted into δ-lactone 28 (A/B cis) (Scheme 4). Saponification of 28 gave the carboxylate, which was subjected to Birch reduction followed by successive thioketalization and MCPBA oxidation giving sulfoxide 31. Thermolysis of 31 in the presence of diisopropylethylamine followed by Diels-Alder reaction with 2-chloroacrylonitrile gave bicyclo[2.2.2]octane derivative 32. Exo-olefin 34 having a carbon skeleton of A-An was synthesized from 32 by following sequence: i) stepwise reduction of the cyano group; ii) acetylation, iii) Li-liq.NH_3 reduction to give 33, iv) acetylation; and v) Li-liq.NH_3 reduction. The secondary hydroxyl group at C(1) in 34 was removed via 35 having C(1)-α-OH to give 36, whose acetal was easily hydrolyzed to afford aldehyde 37. Synthesis of (±)-antheridiogen-An was accomplished by elaborative adjustment of functionality of A ring in 37 (Scheme 5).
Triterpene or steroidal oligosaccharides so called saponin is an important group of natural product on the basis of a variety of biological activities. However little total synthesis have achieved probably due to the interruption between sugar chemistry and terpenoid synthesis. We have recently reported the total synthesis of sweet tasting diterpene glycosides, baiyunoside and analogs, by means of a biomimetic olefin cyclization followed by glycosylations. Then we have developed a very simple thermal glycosylation procedure, which is particularly useful for the synthesis of O-α-rhamnose linkage. Now we wish to disclose herein the novel synthetic study of an intensely sweet tasting saponin, osladin (1) isolated from rhizomes of Polypodium vulgare (Polypodiaceae) by Sorm and co-workers in 1971, as the extension of our series of synthetic program. However the stereochemistry of osladin was not yet fully established. Although the stereochemistry of aglycon are confirmed by partial synthesis, stereochemistry at C-26 is unknown and two kinds of O-rhamnoside bonds are only deduced to be α. Thus we have to confirm the stereochemistry throughout this synthetic study. Points of the synthetic ideas are 1) sugar residues are regarded as protecting groups of C-3 and 26 oxygen functionalities and are introduced at relatively earlier stage of synthesis, 2) stereochemistry of C-5, 22, 25, and 26 must be controlled by stereoselective reactions and other asymmetric centers will be able to derive from starting material, stigmasterol, 3) the difficulty of glycosylation into the hemiacetal hydroxyl at C-26 have to be overcome by a stereoselective manner. Synthesis were started from easily available aldehyde 2 as a degradation product of stigmasterol. To the lactone alcohol 5, a novel β-selective glycosylation to give 7 was achieved by using triflic acid catalyzed reaction with 2-hydroxy chloro sugar 6. Condensation of 7 with rhamnosyl chloride 8 was accomplished by our original thermal glycosylation procedure in very high α-selectivity. Hemiacetal 12 was coupled with 8 by means of AgOTf catalyzed Koenigs-Knorr type reaction. Trisaccharide 14, a possible structure of osladin, was derived from 12 in four steps. However the aqueous solution of 14 did not show any sweet taste at all. Thus we have to continue the investigation to find the real structure of osladin by means of synthetic as well as isolation study.
Glycosyl-phosphatidylinositol (GPI) anchor, which attaches many surface proteins to cell membrane is a novel glycolipid composed of phosphatidylinositol, non-acetylated glucosamine, oligosaccharide, and ethanolamine linked by a phosphodiester bond. Recently, it was suggested that GPI anchor was involved in signal transduction of insulin as well as Qa-2 mediated T-cell activation. We will present here a first total synthesis of GPI anchor present on a variant surface glyco-protein (VSG) of the parasitic protozoan Trypanosoma brucei. Glycoheptaosyl core 2 of the target molecule 1 was designed to be constructed from glycotriosyl acceptor 5, galactobiosyl donor 6, and two mannosyl donors 7 and 8. The key intermediate 5, which was prepared from optically active inositol synthon 9, glycosamine synthon 10, and mannose synthon 11 was coupled with 6 in the presence of Cp2ZrCl2-AgClO4 to yield 24. Glycopentaoside 24 was converted into glycoheptaoside 28, which was reacted with 29 to give 2. Finally, introduction of two phosphodiester functions into 2 was achieved by employing H-phosphonate method to afford GPI anchor 1.
Carbohydrates are important sources of chirality in organic synthesis. We recently became aware of possible stereocontrol elements in which the intrinsic molecular architecture of a carbohydrate may serve as a template for chirality transcription irrespective of individual chiral carbons. Oxidation of diacetone-D-glucose affords 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexos-3-ulose 1. The molecular architecture of 1 can be regarded as a sort of C_2 symmetric cyclopentanone, having an α-oriented bulky 1,2-O-isopropylidene protecting group and a β-oriented large substituent at C-4 in the five-membered furanose ring. Thus, α- and β-substituents introduced into the C-3 carbonyl group must sterically interact with these two bulky substituents. These steric interactions may be promising elements for stereochemical control for the reactions on the chiral template 1. In the present studies, the β-substituents were substituted vinyl groups introduced into the C-3 carbonyl group of 1, and the derived hydroxyl group was modified into the suitable α-substituent. Diastereoselective reaction due to the single steric interaction between the β-oriented vinyl group and the bulky substituent at C-4 was demonstrated in the OsO_4 oxidation of 13 and 16, from which all four diastereoisomers of monodeuterated glycerol were synthesized. The inherent antiparallel double repulsion as illustrated in the introductory figure can fix the conformation between the β-substituent and the α-substituent at C-3. Thus, the intramolecular reaction such as Claisen-type rearrangement and [2,3]-Wittig rearrangement between these substituents may well proceed highly diastereoselectively in such a way that one particular face of the double bond is involved. Usefulness of this stereocontrol elements was demonstrated in the enantioselective syntheses of D- and L-alanine 24 and 25, chiral glycines 26 and 27 as well as 3-isopropylmalic acid 32. This approach was applied to the stereochemical studies on the decarboxylation reaction of 3-isopropylmalate dehydrogenase from thermophilic bacteria Thermus thermophilus HB-8.
Stereoselective hydrogenolysis of alkenyloxiranes to homoallylic alcohols was carried out using formic acid in the presence of palldium-phosphine catalyst. The stereoselectivity of hydride attack, which induces the ring opening of alkenyloxiranes, can be controlled by the olefin geometry of alkenyloxiranes. Thus, inversion of configuration at the oxirane carbon by the hydride attack was observed in the reaction of (E)-alkenyloxiranes, whereas configuration at the oxirane carbon was retained with (Z)-alkenyloxiranes owing to the anti-syn isomerization of the π-allylpalladium system prior to the hydride attack. On the basis of these observations, syntheses of optically active natural products, (-)-serricornin, (-)-nupharamine, dendrobatid alkaloids 235B, 205A, invictolide, endo-1,3-dimethyl-2,9-dioxabicyclo[3,3,1]nonane, and yashabushitriol were performed.
Novel isotactic polymethoxy-1-alkenes 1-8 were isolated from tolytoxin-producing Blue-Green algae belonging to the family Scytone-mataceae. Polymethoxy-1-alkenes 3-5 were first found in a field-collected sample of Tolypothrix conglutinata. Scytonema mirabile produced 1 and 2, whereas 3 and 4 were isolated from S. burmanicum. Tolytoxin-producing S. ocellatum elaborates different isotactic polymethoxy-1-alkenes (6-8). The gross structures and relative stereo-chemistries were determined by mass and NMR spectral analyses. The absolute configurations of 1-8 were established by direct comparison with optically active synthetic samples. Synthesis of 1-8 were carried out in a convergent method, where a common synthetic intermediate 13 was used. The epoxide 13 was prepared by the 1,3-polyol synthesis using a C_4-chiral building block 14 developed by us. Coupling of 13 with lithiodithianes 15, 16, 12, and 49 followed by high syn-1,3-stereoselective reduction gave polymethoxy-1-alkenes 1-8. S. mirabile has also been found to contain six novel isonitriles, viz. mirabilene isonitriles A-F, which are mildly cytotoxic and antimicrobial. The relative and absolute stereochemistry of A(9) and B(10) were solved by chemical degradation and direct comparison of degradation products with synthetic samples: mirabilene isonitrile-A(9), for example, was degradated to (3R, 5R, 7S, 9S)-3, 5, 7, 9-tetramethoxy-10-oxoundecanal (38) and isopropyl (S)-3-trifluoroacetamidobutyrate. which indicated the absolute configurations in 9 to be all S.
Recently, we have developed a novel and efficient method for the synthesis of β-alkoxy cyclic ethers. This methodology is based on the intramolecular reaction of the group 14 organometallics with acetals or aldehydes. Thus, treatment of γ-alkoxyallylsilane 1 with TiCl_4-PPh_3 afforded 6-membered cyclic ether 2a as a major product along with small amounts of its cis isomer 2b (95% total yield, trans:cis=98:2). Furthermore, this cyclization reaction was applicable for the synthesis of 7- and 8- membered cyclic ethers (Table II, Scheme 1). As a next stage, we carried out the construction of 6-7-7-6 fuzed ring system 16 which is the CDEF ring skeleton of brevetoxin B(Scheme 2, 3, 4). The BF_3・OEt_2 promoted reaction of 23 derived from optically active diol 17 gave 24 in 99% yield without accompaning the formation of any other stereoisomers. The most attractive aspect of the present procedure was iterative ring construction; the repeated use of the allic tin based cyclization gave 16 in good yield.
Twenty thousand of people in subtropical and tropical regions have suffered annually from ciguatera caused by poisonous fishes dwelling in coral reefs. In 1989 Yasumoto et al. established the whole structures including relative stereochemistry of the causative principle, ciguatoxin (CTX, 1), isolated from moray eel, Gymnothorax javanicus, and its congener, gambiertoxin 4B (GT4B, 2), from epiphytic dinoflagellate, Gambierdiscus toxicus (Fig. 1). Extremely low accessibility of these toxins, however, hampers further studies on their absolute configuration, pharmacological studies at the molecular level and development of immunoassay for differentiating poisonous fishes. Therefore, determination of the absolute stereochemistry and the chemical syntheses are critical and of great interest. The AB ring framework of gambiertoxin 4B (3) which has a butadienyl substituent on the tetrahydrooxepin ring A has been synthesized stereoselectively (Scheme 2) and its CD spectrum (Fig. 2) suggests that gambiertoxin 4B (2) and ciguatoxin (1) have 5R configuration.
Unprecedented high enantiospecific epoxidation of alkenylethylene glycol substrates under the Katsuki-Sharpless asymmetric conditions has been first recognized. Both dissymmetric and symmetric (C_2 and Cs) substrates underwent facile epoxidation in highly enantio- and diastereo-specific manners with inversed selection modes established in the conventional allylic alcohol substrates. Thus, dissymmetric and C_2-symmetric substrates afforded the corresponding epoxides in inversed enantio- and diastereo-selection modes, while C_2 (meso)-symmetric substrate afforded the epoxide in inversed enantioselection mode. Moreover, complete enantio- and diastereo-selective discrimination of two chemically equivalent vinyl groups in 2,2-bis-vinylethylene glycol substrate has also been observed under the epoxidation conditions. The observed stereochemical outcome, especially, that observed with the C_2 (meso) and the 2,2-bis-divinyl substrates, seemed to support that the monomer mechanism rather than the dimer mechanism is involved in the reaction of the 2-alkenyl-1,2-ethyleneglycol substrates. As a practical application of the present finding, a new enantiocontrolled synthesis of L-erythro- and D-threo-sphingosines has been established using the epoxides obtained from the C_2- and the Cs-symmetric substrates, respectively.
I. Glycosphingolipid: Soya-cerebrosides I and II Soya-cerebrosides I and II, two new glycosphingolipids, were isolated from the seeds of Glycine max and their chemical structures including the fatty acid compositions (major: 2R-hydroxypalmitoyl-type) were elucidated on the basis of their physical data and chemical derivatizations. By using the apparatus W-08, it has been found that soya-cerebrosides I and II exhibit ion-binding activity for Ca^<++> ions. Further, by the method for measuring ion-permeability, it has been revealed that soya-cerebroside II exhibits activity to increase internal Ca^<++> ions of human erythrocytes. So that, we have synthesized 2R-hydroxypalmitoyl and palmitoyl analogs of soya-cerebroside II from a chiral C4-epoxide, the synthon of our synthetic study of complex lipids. The 2R-hydroxypalmitoyl analog has been shown to exhibit ion-binding and membrane-permeable activities for Ca^<++> ions, while the palmitoyl analog to show very little activities. II. Coronand Epoxides derived from Geraniol and E, E-Farnesol Each two coronand-type epoxides (GL_2E_2, GL_2E_4 and FL_1E_2, FL_2E_4) were synthesized respectively from geraniol and E,E-farnesol. GL_2E_4 exhibited ion-transport activity for Ca^<++> ion and ion-permeability for K^+ and Ca^<++> ions while FL_2E_4 exhibited ion-transport activity and permeability for K^+ ions. Each six diastereomers of GL_2E_4 and FL_2E_4 were separated by HPLC and their activities were shown as affected by the epoxide configurations. III. Podand Epoxides derived from Geraniol and E,E-Farnesol Totally 16 podand-type epoxides (GE-1〜GE-8 and FE-1-FE-8) were synthesized from geraniol and E,E-farnesol. GE-8, ω-hydroxy methyl ester diepoxide, exhibited ion-binding, ion-transport and ion permeable activities for Ca^<++> ions. Four optically active GE-8 (13,14,15,16) were then synthesized by employing Sharpless asymmetric epoxidation. As for ion-binding activity for Ca^<++> ions, syn-type GE-8 (13,15) exhibited more higher activity than anti-type GE-8 (14,16), and further one of syn-type GE-8 (15) showed quite stronger ion-permeability than another syn-type GE-8 (13). These findings indicate that human erythrocyte membranes clearly distinguish between two enantiomers, 13 and 15.
Dolastatin 10, a potent antineoplastic substance, was isolated from an Indian Ocean sea hare, Dolabella auricularia. The absolute stereostructure of dolastatin 10, four constituents of which are unusual amino acids, was unambiguously determined by its total synthesis to be 1. Since the reported synthesis lacks stereo-selectivity, we have developed a more efficient route to dolastatin 10, a medicinally interesting peptide. Z-(S)-Dolaphenine was prepared by the Hantzsch method using Z-L-Phe-NH_2 as a starting material. (2R, 3R, 4S)-Dolaproine was prepared from Boc-(S)-prolinal (5) and N-propionyloxazolidinone 4 by the Evans aldol methodology. The unexpected threo aldol adduct 7 was produced as the major product with a small amount of the expected erythro adduct 6 when di-n-butylboron triflate was used in excess (Table 1). Stereochemistries of these aldol adducts were determined on the basis of ^1H-NMR analyses of their corresponding cyclic derivatives 18. Further investigation about this reversal of selectivity was carried out with a variety of aldehydes including amino aldehydes under the above reaction conditions (Table 2). (3R, 4S, 5S)-Dolaisoleuine, an isostatine analogue, was prepared from Boc-L-isoleucine via the β-ketoester 22, and (S)-dolavaline was prepared from L-valine according to the literature. Assembling each constituent obtained above was efficiently carried out in a stepwise manner from the C-terminal. DEPC was mainly used for the coupling, and the attachment of Boc-L-valine with the tripeptide fragment was accomplished by use of Bop-Cl. Dolastatin 10 (1) thus synthesized was identical with the natural one in every respect.
(-)-Physostigmine (1), a principal alkaloid of the Calabar bean, has been used clinically for glaucoma and myasthenia gravis. Recently, selected analogues of 1 have shown promise as Alzheimer's disease therapeutic agents. Here we report chiral total syntheses of 1 via asymmetric nitroolefination. 1. Synthesis starting with the lactone 4. Reaction of zinc-enolate 3 with chiral nitroenamine 2 afforded the nitroolefin 4 of 86% ee (99% yield). Diels-Alder reaction of 4 with Danishefsky diene furnished the adduct 6, which was then converted into (-)-eserethole (15) in ten steps. Transformation of 15 to 1 has already been known. 2. Synthesis starting with the lactam 18. Asymmetric nitroolefination of 17 was achieved with chiral nitroolefin 16, where chiral sulfoxide functions as a leaving group. Thus, 18 was obtained in 84% ee and 91% yield, which was converted into (-)-esermethole (24) in seven steps. Transformation of 24 to 1 has already been known. 3. Synthesis starting with the oxindole 26. To develop the most straightforward synthetic route to 1, 25 was selected as a starting material. Asymmetric nitroolefination of 25 with 2 afforded 26 of only 38% ee. On the other hand, use of the novel chiral nitroenamine 28 furnished 26 of 95% ee (83% yield). Transformation of 26 into 24 was achieved in four steps.
1.1 Asymmetric Syntheses of Tertiary Chiral Building Blocks from Ethylmalonic Acid Synthesis of chiral building blocks was carried out via chiral half esters of monoalkylmalonic acids. The menthyl half-ester of ethylmalonic acid afforded a single diastereoisomer (1a) through crystallization-induced asymmetric transformation. 1a was reduced to chiral building blocks without epimerization via acid chloride. 1.2 Asymmetric Syntheses of Alkaloids Using the Tertiary Chiral Building Block Diastereoselective synthesis of the acetal (12) was achieved starting from the chiral building block via 1,2-asymmetric induction by radical cyclization. The compound (12) was converted into (-)-protoemetinol, (-)-protoemetine, (-)-dihydrocorynantheol, and (+)-dihydroantirhine. The compound (12) was further transformed to the cis-substituted lactam (20), the potential intermediate of quinine alkaloids 2.1 Asymmetric Syntheses of Quaternary Chiral Building Blocks from Malonic acids Substitutions of the chiral half-esters of monosubstituted malonic acids with alkyl halides were examined. Alkylation of methylmalonic acid derivative gave (R)-isomers (23) as major diastereoisomers. Interestingly, the same stereoisomers were produced by methylation of monosubstituted malonic acids. 2.2 Asymmetric Syntheses of Alkaloids Using the Quaternary Chiral Building Block from Ethylmalonic Acid The major product (25), obtained by allylation of the (-)-phenylmenthyl half ester (24, R=Et) of ethylmalonic acid, was converted into two lactones (31) and (33), the key intermediates for indole alkaloids of Hunteria- and Aspidosperma-types.
We have accomplished a novel and efficient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-alkylated alkaloids. And (±)-ambinine, a B/C-hexahydro benzo[c]phenanthridine alkaloid possessing a unique substitution pattern on the aromatic rings was totally synthesized from the corresponding 13-alkylberbine. Condensation of the bromophenethylamine (7) with the benzaldehyde (8), followed by reduction afforded the secondary amine (9), which was converted into the N-phenethylisoquinolone (10) on treatment with α-chloro-α-methylthioacetyl chloride (2). The isoquinolone (10) was conveniently transformed into 2,3,9,10-tetraoxygenated protoberberine alkaloids, (±)-canadine, (±)-tetrahydropalmatine, (±)-stylopine, and (±)-sinactine. On the other hand, 10 gave the 4-alkylated isoquinolone (13) which was converted into the 13-alkylprotoberberine alkaloids, (±)-thalictricavine, (±)-corydaline, (±)-tetrahydrocorysamine, and (±)-13-ethyltetrahydropalmatine. Convenient transformation of 13-methylberbine (21), prepared according to the above method, into (±)-ambinine (24) was successfully achieved by our biomimetic method.
A first total synthesis of montanine-type alkaloids, (±)-montanine(1), (±)-coccinine(2), and (±)-pancracine(3) was accomplished as follows. Olefin diacetate (11) was prepared in several steps starting from anhydride(6) via tosylamide(10a). Stereoselective hydroboration-oxidation of 11 gave an alcohol(12) in a sole product, which was converted to 18 in several steps. Treatment of 18 with vitride^[○!R] in boilig xylene gave 5,11-methanomorphanthridine(19) in good yield. DIBAL reduction of 19 afforded 20a, which would be a potential key compound for synthesis of montanine-type alkaloids. Actually, 20a was converted to (±)-coccinine(2) in 5 steps. On the other hand, (±)-montanine(1) and (±)-pancracine(3) were synthesized through 27a, obtained by stereoselective chlorophenylselenylation of 26a under ultrasonication, which was derived from 20a in two steps.
Neuraminidase and sialyltransferase, respectively hydrolysing and transferring N-acetylneuraminic acid in the non-reducing end of carbohydrate chains of glycoproteins and glycolipids, are involved in various biological functions such as immune response, oncogenesis, metastasis of tumors, sperm penetration, viral infection, etc. Siastatin B (1), an inhibitor of neuraminidase, was isolated by H. Umezawa et al. in 1974 from a Streptomyces culture. The total synthesis of siastatin B was achieved in a totally stereospecific fashion based on a chiron strategy, and consequently its absolute configuration elucidated as 2R-acetamido-3R,4S-dihydroxypiperidine-5S-carboxylic acid. Recent experiences in totally synthetic as well as chemically modified analogues (more than 60 compounds), rationally designed species able to mimic N-acetylneuraminic acid in glycoprotein or glycolipid, will be discussed, especially those types which represent an improvement over siastatin B.
We reported that the Diels-Alder adduct (2) was transformed into the chiral lactam (4) by regioselective reduction and samarium-induced desulfinylation. Easy availability of the chiral hydroxy-lactam (4) enabled us to exploit stereoselective nucleophilic addition to the acyliminium ion generated in situ from the lactam. We now describe the stereoselective intra- and intermolecular addition to the acyliminium ion derived from the chiral hydroxy-lactam by stereocontrol due to the bicyclo[2.2.1]heptane moiety.  Intramoleculer Nucleophilic Addition N-butynyl sulfinylmaleimide (9) was synthesized, and the Diels-Alder adduct (10) was transformed into the chiral lactam (5). The N-butenyl derivative (12), which was obtained by selective hydrogenation of (5), was subjected to N-acyliminocyclization to give the product (13) as the single diastereoisomer. The tetracyclic formate (13) was further converted into (+)-δ-coniceine. Alternatively, (5) was protected as the methyl ether (17), which upon treatment with (PhS)_2 and LDA afforded (18). Exposure of (18) to formic acid produced tetracyclic ester (19) as the single product. Reduction and subsequent flash vacuum pyrolysis afforded the bicyclic amide (21) which was transformed into (+)-trachelanthamidine.  Intermolecular Nucleophilic Addition Reaction of (4) with allyltrimethylsilane and with alkylcopper in the presence of a Lewis acid took place in a diastereoselective manner (d.e. 〜100%) to give the product (26). The heptyl derivative (26)(R=heptyl) was converted into (29), which was a precursor in the synthesis of a venom alkaloid analogue (30).
Thermal Claisen rearrangement of an aryl propargyl ether has been recognized as a general method for the preparation of arylpyrans. In the course of synthetic studies on benzo[c]phenanthridine alkaloids we occasionally found that isomeric 2-methylarylfurans, instead of desired arylpyrans, were formed in excellent yield when the ethers were subjected to the rearrangement in the presence of cesium fluoride (CsF). The precise examination of the CsF-mediated Claisen rearrangement using 2-naphthyl propargyl ether (3) is described. Satisfactory transformation of the 2-methylarylfuran to the salicylaldehyde derivative was achieved by stepwise oxidation using osmium tetroxide and sodium periodate. Combination of the CsF-mediated Claisen rearrangement and the oxidation serves as a useful method for regioselective introduction of a C_1 unit to ortho position of phenol group. Chelerythrine (1) (II: R=Me) has four sequentially substituted benzene ring (ring A) in its molecule. Application of this strategy to the phenol amide (12) led to total synthsis of 1, which could be prepared from the 2-methylbenzofuran (20) derived through the CsF-mediated Claisen rearrangement of isovanillin (17). The furan (20) was also available to synthesis of lemaireocereine (2) belonging to simple isoquinoline alkaloid. Thus the furan ring in 2-methylfuran can act as not only a source of C_1 unit but also a protecting group for phenol, in other words as a masked salicylaldehyde.
The first total syntheses of (+)-paspalicine (2) and (+)-paspalinine (3) have been achieved, respectively, exploiting a unified strategy which earlier afforded (-)-paspaline. In constrast with the paspaline venture, wherein the indole nucleus was incorporated late in the synthesis, our point of departure for paspalicin and paspalinine entailed the conversion of common intermediate (10) to (13) via the Gassman indole protocol. With the ABCDE-ring system of the simple tremogens, we envisioned installation of ring F and G via alkylation of the thermodynamic enolate derived from (13) with epoxide (20). Coupling of enone (13) and epoxide (20) proceeded the Stork metalloenamine protocol (i.e, conversion of (13) to the corresponding dimethylhydrazone, deprotonation [LDA(1.9 equiv), THF, 65℃, 15h], and alkylation with (20). Best results required rigorous exclusion of oxygen. Workup with benzoic acid to provide (35). Acetylation of secondary hydroxyl, hydrazone hydrolysis, acid-promoted deketalization with concomitant cyclization, and acetal removal then afforded (39). Moffat oxidation provided β,γ-unsaturated enone (40), along with a minor amount of (+)-paspalicine (2) (ca. 4:1). Grieco's rhodium chloride protocol effected complete conversion from (40) to (+)-paspalicine (2). Furthermore, oxidation of (+)-2 with selenium dioxide then provided (+)-paspalinine (3). Synthetic (+)-2 and (+)-3 were identical in all respects with authentic samples.
We have been studying natural product synthesis starting with (+)-nopinone (1) as a chiral source. In this presentation, we report our recent synthetic study. (a) A general and convenient synthetic route to 4,4-dialkyl nopinones 16a-d from phenylthio enone 9 derived from 1 was developed using repetition of the two-step sequence of reactions, Pummerer rearrangement and Michael reaction, as the key steps followed by reductive desulfurization of the resulting sulfone 15a-d. (b) BF_3 OEt_2-promoted cleavage of cyclobutane ring in 16 provided enol acetates 17 with little loss of optical integrity. (c) Chemical transformation starting from compounds possessing nopinone skeleton, 25a and 33, as well as cyclobutane opened compounds, 26a and 27b, was carried out, giving chiral building blocks, 29a, 30a, 31, 37, and 38, suitable for natural product synthesis. (d) Alkylation of phenylsufonyl enone 6 with a variety of alkyl halides under the conditions of K_2CO_3 in MeCN proceeded at the γ position to the conjugated enone system in regio- and dia-stereoselective mode to give 44a-d in good yields. (e) Starting with 44a, the first and highly stereoselective total synthesis of a nardosinan sesquiterpene, (-)-kanshon A (8) was accomplished.
Mediterraneols A,B 1,2, isolated from Cystoseira mediterranea, inhibit the mitotic cell division fertilized urchin eggs and exhibit antitumor activity against P388 leukemia. The central structural feature of these novel diterpenoids is the bicyclo[4.2.1]nonane framework with three contiguous quarternary carbon centers. On the basis of the new method for efficient construction of bicyclo[4.2.1]nonane skeleton by skeletal rearrangement of 6-4 fused ring system, which has been developed by us, we studied the total synthesis of Mediterraneols. Our convergent synthetic plan derived from a retrosynthetic analysis, was designed to assemble two segments, the hydroquinone side-chain 7 and the bicyclo[4.2.1]nonane moiety 8. Thus, the left-wing 7 was synthesized readily from 1-bromo-2,5-dimethoxy-3-methylbenzene 33 as a starting material. Synthesis of the key component, right-wing 8 was undertaken starting from tert-butylcyclohexenone 11. Utilizing our method, bicyclo[4.2.1]nonanone 16 was synthesized successfully from allene-photoadduct 13 by acid-catalyzed rearrangement with TiCl_4 and BCl_3. The ketone 16 was transformed to the aldehyde 32 through introduction of the methyl and allyl groups at C(7) of the ketone 12. As a model study, bicyclo[4.2.1]nonane-2,4-dione 41 was also synthesized from bicyclo[4.2.1]nonanone 6 derived by skeletal rearrangement of the 6-4 ketone 5.
Protein kinase C (PKC), a serine and threonine phosphorylating enzyme, plays crucial roles in signal transduction. The enzyme is usually physiologically activated by diacylglycerol but it is also activated by structurally diverse tumor promoters like phorbol myristate acetate (PMA), ingenols, teleocidins, and bryostatins. The tumor promoting activities of these compounds were found incidentally so that the structures would not be necessarily the best ones to bind with PKC. Although, the precise structural requirements for the biological activities exhibited by these compounds have not been established, we have thought that computer assisted design of an advanced analog of PMA which is structurally simpler and has more potent activity can be possible. Taking synthetic route into consideration, compound 1 and 4 were selected as candidates for this purpose based on computer graphics by comparison with the stable conformer of PMA and a lot of its computationaly designed analogs. It is now clear that PKC is a family of more than ten subspecies with distinct structures and individual enzymological properties. So, the designed analogs 1 and 4 may specifically activate certain PKC subspecies and they may become useful tools for biochemical studies. Starting from the optically active (+)-3-carene, common synthetic intermediate 11 for 1 and 4 was synthesized highly stereoselectively using intramolecular nitrile oxide cycloaddition of 17 as a key step. Instead of the acyloxy group at C-12 position, PhMe_2Si group was introduced to 12 as a hydroxy group equivalent to avoid β-elimination. In order to confirm the effectivity of seven membered B-ring annulation to synthesis of 1, compound 10 was used as a model for the further transformation. After 10 being converted into the nitro derivative 21, 21 was treated with p-ClC_6H_4NCO and Et_3N to give desired 23 as a sole product in good yield. Although attempt to construct the A-ring moiety via McMurry coupling of 30 resulted in giving 4-epi derivative 31, nucleophilic addition of cerium trimethylsilylacetilide to 34 utilizing neighboring-group assistance gave a desired adduct 36 in 76% yield. Analogously, skeletal synthetic study of 4 is in progress via the functionalized derivative 43 as an intermediate.
Sarcophytol-A (1), a cembrane type diterpenoid isolated from an Okinawan soft coral, has been shown to be a potent antitumor promoter in a two-stage carcinogenesis model, and to exhibit antitumor activity. The first total synthesis of 1 was accomplished in a highly stereo- and enantioselective manner, starting from commercially available (E,E)-Farnesol (5) or Geraniol(20). The synthesis involved 1) the newly developed, highly stereoselective Horner-Emmons condensation (Z:E>35:1) of 6 with phosphonatenitrile (16), 2) the modified macrocyclization based on intramolecular alkylation of cyanohydrin trimethylsilyl ether (18), 3) the highly enantioselective reduction (93% e.e.) of macrocyclic ketone (2) with chiral lithium aluminum hydride, and 4) the highly stereoselective mercury-free Claisen sequence (E>99%) using acetal(26).
The stereocontrolled introduction of side chains into steroids has been widely investigated due to the discovery of physiologically active steroids, such as ecdysone, brassinolide, and withanolide, which have highly oxygenated side chains. Synthesis and structure elucidation of two novel ecdysteroids, abutasterone and gerardiasterone, are described. 1. Synthesis and Structure Elucidation of Abutasterone Side Chain Abutasterone, isolated from the Amazonian plant Abuts velutina, is a novel ecdysteroid and its structure elucidated by spectral means except the stereochemistry at C-24. Both (24R)- and (24S)-tetraols(3,4) were prepared employing hydroxylation of the lactone (7) with MoOPH. Since the NMR spectrum of 3 was close to that of abutasterone, the stereochemistry of the 24-position was deduced to be R cofiguration. 2. Synthesis and Structure Elucidation of Gerardiasterone Gerardiasterone is a new ecdysteroid with a 20,22,23,25-tetra-hydroxylated side chain from the Mediterranean zoanthid Gerardia savaglia. The configurations on the side chain have not been established. Preparation of four model compounds(14-17) among eight possible diastereomers suggested that the stereochemistry on the side chain could be 20R, 22R, 23S configurations. Thus, synthesis of (20R,22R,23S)-gerardiasterone(35) was achieved by stereoselective hydroxylation of 22E-olefin(34) as a key step. The NMR spectrum of 35 was identical with that of natural gerardiasterone.
Development of a novel and flexible method for the construction of 2,3-disubstituted, 2,3,4- and 2,3,5-trisubstiruted, and 2,3,4,5-tetrasubstituted fused furans and its application to the synthesis of furanoterpenoids have been demonstrated. The key strategic element of the method involves the intramolecular [3+2] dipolar cycloaddition reaction of the nitrite oxide (1) to furnish the isoxazoline (2), which is exposed to the conditions for reductive hydrolysis followed by treatment of the crude reaction product with p-toluenesulfonic acid. The reaction leads to the formation of a variety of fused furans (4) and their regioisomers in moderate or good yields. Employing this methodology, total syntheses of (+)-pallescensin A (16) and (+)-menthofuran (58) have been accomplished. Furthermore, the left half segment (30), containing fused furan and diene moieties, of hippospongin (okinonellin A) (20) has been synthesized by using the Yamamoto rearrangement for an elaboration of the chiral quaternary carbon center presented. The construction of BCD ring system (47) of the tanshinones has also been demonstrated.
Manoalide isolated from the marine sponge significantly reduces chemically induced inflammation in vivo and irreversibly inhibits phospholipase A_2 (PLA2) directly. PLA_2 is an enzyme hydrolyzing the ester linkage at C-2 position of phospholipid, and is found in several neurotoxic venoms, pancreas of animals, and various cells. We have studied independently to elucidate the mechanism of inhibition of PLA_2 by synthesized manoalide and its analogues. PLA_2 used in our study was isolated from bovine pancreas, and the activity was measured toward the mixed micell of di-dodecanoylphosphatidylcholine with sodium cholate. Our study is focused the following three points. 1. Development of simple analogue for manoalide which possesses the equal ability to inhibit PLA_2 comparing to that of dl-manoalide. 2. Elucidation of the necessary functional groups in manoalide to inhibit PLA_2. 3. Understanding the inhibition mechanism of PLA_2 by manoalide; 1)identification and characterization of the amino acid residues which are modified by manoalide selectively, and 2)understanding the mechanism of the reaction of manoalide with those amino acids residues. We have found that compound 1a is an excellent analogue of manoalide and the two aldehyde groups of manoalide is essentially necessary for the inhibition of PLA_2. Furthermore, it was strongly suggested that analogue 1a reacted selectively with Lys^<53> and Lys^<56> in bovine pancreatic PLA_2, and resulted that the hydrolytic ability of bovine pancreatic PLA_2 toward the mixed micell of phosphatidylcholine with sodium cholate was inhibited. These results suggest that Lys^<53> and Lys^<56> are probably concerned with the binding of mixed micell forming from phospholids and anionic surface-active agents.
Dactylyne (1) and its isomer, isodactylyne (2), isolated from the sea hare Aplysia dactylomela, are characterized structurally by the common tetrahydropyran ring with all α-oriented, four substituents, (2E)-3-bromo-2-pentenyl and pentenynyl groups at C-2 and C-6, and bromine and chlorine atoms at C-3 and C-5, and possess central nervous system depressent activity, as evidenced by the potentiation of pentobarbital hypnosis. In view of the structural features and the biological activity, these are attractive synthetic targets. We commenced the total synthesis of these natural products on the basis of two new reactions concerning the regioselective opening of 2,3-epoxy-l-ols and their derivatives with halogeno nucleophiles at the 3-positions (Table 1). Starting with the coupling reaction of compounds 6 and 7, we derived the optically pure epoxy alcohol (15), which was intramolecularly cyclized on treatment with zinc triflate to give the synthetic key intermediate (16) as a sole product (Schemes 2 and 3). Compound 16 was smoothly transformed into (-)-1 and (-)-2, involving the two elongation reactions at the substituents of the C-2 and C-6 positions (Scheme 4). These results constitute the first total synthesis of these natural products.
The structures of many interesting Sphingoglycolipids from marine organisms have been determined. Although their biological functions are still not clear, these compounds are assumed to participate in various processes associated with recognition phenomena. We report here the stereoselective syntheses of the sphingosine 3 of 1, isolated from a marine snail Turbo cornutus, and the ceramide parts 12 and 21 of 2, isolated from a marine sponge Halichondria japonica. D-Erythro-C_<18>-sphingosine 3 was prepared from 3,4,6-tribenzyloxygalactal 4 in nine steps in 26% overall yield. Highly optically pure long-chain (R)- and (S)-α-hydroxy acids 20a and 20b were prepared via nucleophilic ring opening of chiral epoxy diols 15 and 16, respectively, which are derived from L-ascorbic acid. The attempt towards the total synthesis of phytosphyngosine part 21 of 2 from the same key intermediate 15 is described.
Ti(IV) chloride mediated reaction of allenylmethyltrimethylsilane (2) with various aldehydes and acetals has been examined establishing an efficient method for the preparation of racemic dienol derivatives rac-4. Application of this method to chiral acetals 6 led to chiral dienols 4 with high optical purity (≥90% ee) which were alternatively synthesized by the Sharpless kinetic resolution of rac-4. The synthetic utility of the methods described above has been demonstrated, at first, in the enantiocontrolled syntheses of branched-chain sugars, L-arcanose (24) and L-olivomycose (29) starting from Lewis acid mediated reaction of 2 with (S)-2-benzyloxy-propanol (16). Furthermore, concise enantioselective synthesis of the key synthetic intermediate 34 for anticancer anthracyclines has been accomplished starting from Lewis acid mediated reaction of 2 with the chiral acetal 35.
In recent years, we have systematically investigated the possibility of using bakers' yeast and lipases as a practical reagent in organic synthesis. As a continuing effort toward the chemoenzymatic synthesis of optically active natural products, we here present the synthesis of chiral pheromones through enzyme-catalyzed transformation using lipase P (Pseudomonas fluorescens lipase). (2R,6S,10S)-Trimethyl-2-pentadecanol [(2R,6S,10S)-15], one of the stereoisomers of the sex pheromone of Corcyra cephalonica Stainton, was synthesized in highly optically pure form by the two-step hydrolysis of the 2,2,2-trichloroethyl carbonate derivative (2RS,6S,10S)-15a with lipase P. The same resolution method led to stereochemically pure (2R,8R)-8-methyl-2-decanol propionate [(2R,8R)-24], which is a component of the sex pheromone of Diabrotica species. (3R,6E)-7-Methyl-6-nonen-3-ol acetate [(R)-quadrilure, (R)-32], the aggregation pheromone of Cathartus quadricollis, was synthesized in enantiomerically and geometrically pure form by the enzyme-catalyzed hydrolysis of racemic 32 with lipase P, followed by enzyme-catalyzed transesterification with PPL. A similar procedure for the preparation of (S)-32 will also be described.
A new and potentially useful synthetic method for the polypropionate chains has been developed by using the stereospecific methylation of γ,δ-epoxy acrylates with (CH_3)_3Al. The reaction of (CH_3)_3Al (10 equiv) on trans-γ,δ-epoxy acrylic esters in dichloroethane in the presence of water (6 equiv) at -30℃ gave anti-δ-hydroxy-γ-methylacrylates in a highly stereoselective manner and high yields. On the other hand, cis-γ,δ-epoxy acrylates exclusively produced syn-δ-hydroxy-γ-methylacrylates under the same conditions. In these reactions, addition of water was indispensable. For example, treatment of the epoxyacrylate 1 (optically active) with (CH_3)_3Al gave only the anti compound 2 in 96% yield, while the cis-congeners 3 and 4 produced exclusively the syn-compounds 5 and 6, respectively. The method allows its iterative use. Thus the repeated application of the reaction on the trans-epoxy acrylate 1 gave 27 having four consecutive asymmetric centers in high yield. Synthetic potential of the new method has been demonstrated by the syntheses of (+)-Prelog-Djerassi lactone and (+)-Protomycinolide IV.
myo-Inositol (1) and L-quebrachitol (2) are representative cyclitols found abundantly in nature. In this paper, syntheses of some natural products in optically active forms utilizing 1 and 2 as the starting materials are described. 1. Total Synthesis of (+)- and (-)-Nojirimycin (17a and 17b) from myo-Inositol (1): The racemic diol (4), readily obtained from 1 in 3 steps, was converted into its L-O-acetyl mandelate derivatives (5a and 5b) and resolved. The cyclohexane ring of 5a was cleaved oxidatively in a regioselective manner by way of Baeyer-Villiger oxidation of ketone (7a), followed by acid treatment to give 9a. Introduction of the amino function into 12a with Mitsunobu reaction and deprotection gave 15a, which was converted into 16a. Treatment of 16a with basic resin afforded 17a. From 5b, compound 16b and 17b were also synthesized. Compound 16b was found to possess high inhibitory activity against β-glucosidase. 2. Formal Total Syntheses of (-)-Isoavenaciolide (31) and (-)-Ethisolide (37) from L-quebrachitol (2): The structurally interesting antifungal mold metabolite, (-)-isoavenaciolide and its homolog, (-)-ethisolide were synthesized from 2. Wittig olefination of the ketone (23), obtained from 2 in 9 steps, gave 24. Stereoselective hydrogenation of 24, followed by treatment with BBr_3 afforded the lactone 26. Periodate oxidation of 26 gave 27, which was converted into the known intermediate (30) for a synthesis of 31. Compound 27 was also converted into 36, which is a known synthetic precursor for 37. 3. Total Synthesis of Bengamide E (51) from L-Quebrachitol (2): Bengamide E (51) is a novel sponge-derived natural product and possesses a unique structure. The polyhydroxyl carboxylic acid moiety (48) of bengamide E was prepared stereoselectively from 2. Wittig reaction of L-mannofuranose derivative (41), obtained 4 steps from 2, gave 42. Inversion of the stereochemistry of the allyl alcohol and oxidation of the primary alcohol provided 49, which was condensed with cyclo-L-lysine to give 50. Deprotection afforded 51. This first synthesis of 51 fully confirmed the absolute configuration of this novel natural product.
Nephritogenoside, isolated from the basement membrane of rats, is a nephritogenic glycopeptide whose structure 1 was determined by S. Shibata et al. in 1988. In the molecule of nephritogenoside, the trisaccharide containing three glucose moieties is linked with the peptide composed of 21 amino acids via N-glycoside bond on the asparagine residue. We planned the synthetic study of this glycopeptide in order to confirm the proposed structure and to elucidate the structure-activity relationship. In our synthetic strategy, allyloxycarbonyl group which is removable by palladium complex under neutral conditions was chosen as the final protecting group, taking account of general unstability of glycopeptide under acidic and basic conditions. Trisaccharide 4 was synthesized from heptaacetylisomaltosyl fluoride and 2,3,4-triacetylglucopyranosyl azide. The compound 4 was reduced followed by acylation with Aloc-Asp(OH)-O^tBu to give N-glycoside 5. After replacement of acetyl group with Aloe group, the coupling with the eicosapeptide (2-21) was attempted. However, N-hydroxysuccinimide active ester (7) did not react with the peptide but cyclized itself to give the succinimide derivative of 7. Therefore, we then tried a coupling of the active ester of glycosyldipeptide (1-2) (10) with nonadecapeptide (3-21). This reaction gave us a desirable protected nephritogenoside. After deprotection of all Aloc group by palladium complex, the crude product was purified by HPLC to give free nephritogenoside. In this study, we established the synthetic strategy for glycopeptide with relatively long peptide chain. The glycodipeptide was coupled with an appropriate peptide using Aloc group as the final protecting group and an active ester method for the coupling.
Neocarzinostatine chromophore (1), an active component of antitumor antibiotic neocarzinostatine produced by Strepromyces Carzinostsaticus, has been reported to possess novel bicyclo[7.3.0]dodecadienediyne system, which has been proposed to relate deeply with its biological activities. In our project aiming at the synthesis of stable but still active analogues of 1, we could develop a novel synthetic scheme toward the cyclic dienediyne system. Thus, palladium-catalyzed coupling reaction of (Z)-enol triflate (8) and optically active acetylenediol (22) prepared from D-xylose afforded dienediynediol (23) in a good yield. Tosylation and desilylative epoxide formation gave dienediyneepoxide (24). Upon treatment of 24 with lithium bistrimethylsilylamide in THF at ?-78℃ followed by boron trifluoride etherate complex, smooth cyclization was observed to produce 10-membered cyclic dienediyne (2), whose structure was confirmed by measuring the long-range coupling between C_6H-C_9H in the ^1H-NMR spectra of acetate (3). Attempt to obtain 9-membered cyclic analogue from either epoxide (27) or aldehyde (28) were unsuccessful.
The enantioselective total synthesis of neooxazolomycin (1), structurally novel antitumor agent, was achieved by utilizing newly developed several synthetic methods. For the construction of the fused bicyclic lactam-lactone terminus of (1), a novel dianion cyclocondensation was found. Thus, the reaction of the dianion 3 with the ester 6 furnished the β-hydroxylactams 7 and 7 in a 1:1.4 ratio. Treatment of 7 with acidic condition brought about diastereoselective lactonization to give 8, which was converted into 15 via selective reduction of its ester group. Next, the four-carbon homologation of the aldehyde 15 to E,E-dienamine 18 could be achieved efficiently under mild conditions by iodomethylenation with CrCl_2 -CHI_3, with subsequent Pd-catalyzed coupling to the vinylstannane 12 followed by mild cleavage of the FMOC group. Finally, the synthetic problem inherent to the construction of the chiral α, α-dimethyl-β-hydroxycarboxylic acid subunit was successfully solved. The diastereoselective aldol reaction of the conjugated Z-enal 23 with tin(II) enolate derived from chiral oxazolidinone 21 gave R,S-oxazinedione 24 as a single isomer, which was converted into the left half acid portion 33 via Pd-catalyzed coupling between 27 and 31. Final amide formation of 18 and 33 followed by deprotection gave the synthetic (1), which was identical with an authentic sample by NMR, IR, HPLC, and FAB mass spectrometric comparisons.
The benzoquinoid ansamycin antibiotic herbimycin A (1) was isolated in 1979 from the fermentation broth of Streptomyces hygroscopicus strain AM-3672. It exhibits herbicidal, antitabacco mosaic virus, and antitumor activities. The structure of 1 was elucidated by spectroscopic and biosynthetic means and the relative configuration of 1 was established by X-ray crystallographic analysis. We now report the first total synthesis of herbimycin A (1) and elucidate the absolute stereochemisrty of 1. Herbimycin A (1) was divided into two portions, namely the ansa-chain aldehyde 2 and the aromatic chromophore 3. The epoxide 10, which was prepared from methyl α-D-mannopyranoside 4 according to our developed procedure, was transformed to the C7-C15 aldehyde 23 by using a regioselective epoxide-ring opening (disiamylborane-NaBH_4) and a stereoselective hydroboration (BH_3・Me_2S) as the key steps. This aldehyde 23 was subjected to the Brown's diastereo- and enantioselective allylation conditions [[(Z)-γ-methoxyallylidiisopinocampheylborane prepared from (-)-α-pinene] to afford the desired syn-type compound 24. After a three-step sequence, 24 was converted to the ansa-chain aldehyde 2. This ansa-chain aldehyde 2 was coupled with the lithiated aromatic chromophore (prepared from 3 and n-BuLi) to produce the coupling product 26, which was transformed to herbimycin A (1) through elongation of the C1〜C4 carbon unit and macrolactamization. All data (^1H NMR, IR, UV, [α]_D, and TLC mobilities) were identical with those of natural herbimycin A.
The macrolactonization of seco acid derivatives is a key step of the total synthesis of macrolide antibiotics such as erythronolide A(3), lankanolide (4) and oleandonolide (5) and the efficiency of lactonization depends upon the conformation of the seco acid derivatives. Therefore, in order to design the rational plan for the total synthesis of macrolide antibiotics, the conformational analysis of their seco acids is very important. We calculated stable comformations of the known seco acids 7 and 9 using the MM2-CONFLEX31 method recently developed by E. Osawa et al., and discussed the correlation of their reactivity to give lactone and their stable conformation calculated. The unknown seco acids 13, 14, 17 and 18 were also calculated to analyze their stable conformers and the prediction of their lactonization were discussed.
Antitumor antibiotics bleomycins (BLMs) induce G-C and G-T specific DNA cleavage owing to the functions of the following structural units; i) pyrimidine moiety to activate dioxygen by ironcomplexation, ii) disaccharide moiety to stabilize the iron-oxygen complex and facilitate membrane transport, iii) bithiazole region to interact with guanine base, and iv) linker moiety to combine each part of BLM at an appropriate distance and in a suitable orientation. Synthetic models for the metal-binding site of BLM with 4-methoxypyridine (PYML-6) and 4-dimethylaminopyridine (PYML-8) show dioxygen activation up to 97% and 125% of BLM, respectively. β-Methylstyrene is oxidized with the Fe(II)-O_2, Fe(III)-H_2O_2, or Fe(III)-PhIO complex systems of PYML-8 to give a set of products including optically active epoxide. The product composition suggests different active species generated from each complex system. Structure-function study on the 2,3-diaminopropionamide region, the fifth ligand moiety, was carried out by use of synthetic models based on PYML-6. Model compounds whose axial lignd moiety is replaced by 3-aminopropionic acid or 2,3-diaminopropionic acid (PYML-9, PYML-10) show pH-dependent oxygen activating power, i.e., 〜40% at physiological pH and 〜85% at alkaline pH. This accounts for the mechanism of the inactivation of BLM by an enzyme, BLM hydrolase, which hydrolyzes the carbamoyl group of 2,3-diaminopropionamide moiety to a carboxyl group. Model ligands having an axial imidazole ring instead of an amino group (PYML-13, PYML-14) show different property as metal complex although they can activate molecular oxygen relatively efficiently. These results demonstrate the significance of coordination of the axial amino group for efficient oxygen activation. The concerted mechanism of DNA cleavage by BLM, especially the role of the linker moiety, is studied by synthetic models, PYML(6)-(4R-APA)-distamycin, PYML(6)-(AHM)-distamycin, and PYML(6)-(4S-APA)-distamycin, in which the oxygen-activating PYML-6 moiety and the A,T-binding distamycin moiety are connected through (R)-4-aminopentanoic acid, (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid, and (S)-4-aminopentanoic acid, respectively. Efficiency and base sequence specificity in the DNA cleavage by PYML(6)-(AHM)-distamycin are virtually identical to those of PYML(6)-(4R-APA)-distamycin, indicating no influence of the removal of the 2-methyl and 3-hydroxyl groups of the linker amino acid. On the other hand, PYML(6)-(4S-APA)-distamycin shows markedly decreased DNA cleavage activity compared with PYML(6)-(4R-APA)-distamycin, suggesting that the efficiency of DNA cleavage largely depends on the stereochemistry of the linker moiety.
Teleocidins are potent tumor promoters produced by actinomycetes. (-)-Indolactam-Val (ILV), which has the fundamental structure of teleocidins and is the minimum unit for tumor-promoting activity, is useful as a lead compound for structure-activity studies and receptor analysis. Hitherto, total syntheses of ILV and its analogues have been intensively investigated. However, more convenient syntheses are desirable from the view point of synthesizing various indolactam congeners for structure-activity studies. We have demonstrated that ILV was biosynthesized from L-Trp, L-Val and L-Met via N-Me-L-Val-L-Trp-ol using Streptoverticillium blastmyceticum NA34-17. Since N-Me-L-Val-L-Trp-ol can be chemically synthesized without difficulty, utilization of the microbial cyclization enzyme would be a convenient synthetic method of various indolactam analogues for structure-activity studies. We have metabolized twelve synthetic seco-compounds and obtained ten ILV congeners with L-Ala, Abu, γ,δ-Δ-Nva, Nva, Nle, tert-Leu, Leu, Ile, allo-Ile, Phg, instead of L-Val in ILV. These indolactam congeners were examined for two biological tests related to tumor promotion. They were binding ability to the 12-O-tetradecanoylphorbol-13-acetate receptor and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. The results indicated that both the hydrophobicity and the bulkiness of the substituents at position 12 increased these activities, demonstrating the recent hypothesis that the isopropyl group at position 12 of ILV is involved in the hydrophobic interaction on the receptor site.
A pleasant fragrance was emanated from the motile female gametes of Scytosiphonales (Scytosiphon lomentaria and Colpomenia bullosa) and Chordariaceae (Analipus japonicus) when settled on a surface. The secretions were found to be the mixtures of hormosirene and ectocarpene, (95:5) for S. lomentaria and C. bullosa and (12:88) for A. japonicus. The abusolute configuration of hormosirene secreted from the temale gametes was determined to be (1R, 2R) for S. lomentaria and C. bullosa and (1S, 2S) for A. japonicus. The biosynthetic mechanism of (1R, 2R) and (1S, 2S)-hormosirene from a possible precursor, (3Z, 6Z, 9Z)-dodecatrienoic acid which was first detected in the female gametes was discussed.