Destomycin C, a pseudo-trisaccaride antibiotic having an interglycosidic spiro-orthoester linkage, was synthesized. Stereoselective formation of orthoester linkage in the previously developed method, where glyconolactone and diol were coupled in the presence of TMSOTf, was studied using various derivatives of the diol, and achieved by the reaction of the diols having monosilyl or two different silyl groups. Anomerization of β-mannopyranoside was observed on the formation of orthoester in CH_2Cl_2 but depressed in ether. The total synthesis of destomycin C was performed in the following sequence: (1) formation of β-glycosidic linkage between D-mannopyranose and deoxystreptamine derivatives, (2) 2',3'-O-glycosylidenation of the pseudo-disaccharide with destomic acid derivative, which was derived from destomycin A, (3) inversion of configuration at C-4 of the mannopyranosyl moiety and (4) deprotection. Synthetic compound was proved to be identical with natural destomycin C by comparison of ^1H-NMR spectra at 500 MHz.
One of the most remarkable characteristic of heparin is the high ability as a blood-anticoagulant, which is ascribed to the specific affinity of this mucosaccharide for antithrombin III (AT-III), an inhibitory protein against a series of blood-clotting enzymes. The complex pentasaccharide (1) is the AT-III-binding sequence of heparin recently proposed. This paper describes the synthesis of 1, utilizing cellobiose (6) as a main starting material. The synthetic strategy was built upon the methodology, established by us, for completely regioselective modification of cellobiose (6). Thus, two different disaccharide segment (4 and 5) were prepared from 6, and coupled each oter. The resulting tetrasaccharide (39) was elongated by condensation with the known monosaccharide derivative (3), giving the expected pentasaccharide (2). These syntheses included several key steps such as the configurational inversion from D-gluco to L-ido in the nonreducing end of a disaccharide derivative.
Recentrly we have found prominent 1,2- and 1,3-asymmetric induction in the intramolecular Michael addition of y- and δ-carbamoyloxy-α,β-unsaturated esters. High complementary stereoselection was observed by changing the site of carbamoyl group in the reactions of ethyl erythro-4,5-dihydroxy-2 (E)-hexenoate, and it was applied to the highly stereoselective syntheses of N-acyl (±)-acosamine (2b) and (±)-ristosamine (3b). Contrary to the erythro derivative (1,3-syn), relatively low 1,3-anti stereoselection (up to 5:1) was found in the reaction of ethyl threo-5-carbamoyloxy-4-trialkylsilyloxy-2 (E)-hexenoate. The reversal of diastereofacial selectivity in these reactions suggested that the factor governing such stereoselection might be the antiperiplanar effect due to the group at 4-position. Dramatic improvement of the 1,3-anti selectivity in the reaction of threo-diol derivatives, however, has been realized by changing the geometry of the double bond from E to Z, as expected by the mechanistic consideration of the reaction transition state based on the anti-periplanar effect. Thus, the optically active 17 was produced in ratio of >100:1 by the base-catalyzed cyclization of 11, synthesized from t-butyldimethyl-silyl (S)-lactaldehyde (13) and methyl propiolate via the stereoselective reduction of methyl 5-t-butyldimethylsilyloxy-4-oxo-2-hexynoate (15) with L-selectride, culminating in a stereoselective synthesis of N-benzoyl L-daunosamine (1b). New diastereoselective syntheses of optically active 2b and 3b will also be described.
Lipid A, a biologically active constituent of LPS of Gram-negative bacteria, was found recently to contain a β-1,6-linked D-glucosamine disaccharide substituted by two phosphates and four ester- and amide-bonded fatty acids. On the basis of these results, we report here new syntheses of Lipid X,Y and Salmonella mutant Lipid A. 1) Synthesis of Lipid X Our methodology includes new development of selective removal of the N-acyl group from the acid-unstable 4,6-isopropylidene compound (3) leading to the novel key-compound (4), whose one amino and four hydroxyl groups can be chemically distinguishable from each other and easily convertible into the required substituents for Lipid A and the related compounds. Successful conversion of 4 into Lipid X was realized as shown in Scheme 1. 2) Synthesis of Lipid Y A new chemoselective debenzylation of the glycosidic benzyl group of the glucosamine derivative (13) was developed and applied to the synthesis of Lipid Y as described in Scheme 2. 3) Synthesis of Salmonella mutant Lipid A New development of the common key disaccharide intermediate (26) bearing chemoselected two amino and six hydroxyl groups which is capable of direct conversion into several Lipids A and a formal synthesis of Salmonella mutant Lipid A from 26 were realized as indicated in Scheme 3.
Starting from simple chiral synthons, several biologically active natural products were synthesized. All four stereoisomers of 16-heptadecene-1,2,4-triol (1), an antimicrobial component of avocado fruit, were synthesized from a single starting material, (S)-2,2-dimethyl-1,3-dioxolane-4-ethanal, which was derived from L-malic acid. Natural triol was proved to have 2R, 4R configuration. 9,10-Epoxy-16-heptadecene-4,6-diyn-8-ol, a nematicidal constituent of Cirsium japonicum, was synthesized from 2,3-O-isopropylidene-D-glyceraldehyde. The absolute stereochemistry of natural epoxy-alcohol was determined to be 8R, 9R, 10S. Monilidiol (22) and dechloromonilidiol (23), phytotoxic metabolites of Monilinia fructicola , were synthesized from glyceraldehyde derivatives (12 and 46). The absolute configuration of their glycol part on the side chain was confirmed as 3'R, 4'S. A facile and efficient synthetic methods of 1,2: 5,6-di-O-cyclohexylidene-D-mannitol (44) and 2,3-O-cyclohexylidene-D-glyceraldehyde (46) were developed. Syntheses of pyriculariol, osmunda lactone derivative and phomalactone will be presented.
Four possible stereoisomers of vicinal diol derivatives were synthesized stereoselectively by nucleophililc addition to optically activeα-alkoxy-β-trimethylsilyl-β,γ-unsaturated carbonyl compounds. Thus, (R)- and (S)-2-alkoxy-3-trimethylsilylalk-3-enals 4 react with Grignard reagents to afford syn-5 with >93% selectivity, and syn-4 thus prepared can be readily converted to >99% pure anti-5 via oxidation and subsequent reduction of the resulting ketones 6 with L-Selectride (Scheme 1). Both (R)- and (S)-2-alkoxy-3-trimethylsilylalk-3-enals 4 were selectively synthesized starting with (R)-O-isopropylidene glyceraldehyde 7. The utility of the present reaction is also demonstrated by the preparation of exo- and endo-brevicomin.
Lardolure is the aggregation pheromone of acarid mite, Lardoglyphus konoi (Sasa et Asanuma) (Acarina: Acaridae). Its relative stereochemistry was determined by GLC comparison of the natural pheromone with the synthetic pheromones prepared in stereocontrolled manners. Both the enantiomers of lardolure were synthesized in 100% e.e. (2R,4R,6R,8R)-Enantiomer 20 showed the same ORD spectrum as the natural pheromone. Therefore, the natural pheromone is the formate of (2R,4R,6R,8R)-4,6,8-trimethylundecan-2-ol.
Four geometical isomers of 5,7-, 6,8-, 7,9- and 8,10-dodecadien-1-ols were systematically synthesized by two routes. One involved the Wittig reaction between (E)-2-alkenal and a phosphorane with an appropriate carbon chain, and yielded a mixture of (E,Z)- and (E,E)-isomers in a ratio of ca. 3:2. The other route comprised of the Wittig reaction of a 2-alkynal and the stereoselective reduction of the triple bond to a (Z)-double bond via hydroboration with dicyclohexylborane to give a mixture of (Z,Z)- and (Z,E)-isomers in a ratio of 6:1〜10:1. Both the mixtures were separately chromatographed on a silica gel column impregnated with silver nitrate to give four geometically pure isomers. With 9,11-diene they were analysed by GC on a capillary column, HPLC, silver nitrate impregnated TLC, ^1H and ^<13>C NMR, and GC-MS. By the ^<13>C NMR analysis of all the isomers a new method for assigning ^<13>C signals of a conjugated system was proposed. The method is based on two empirical rules. The first involves the ^<13>C shift differences of olefinic carbons induced by a substitutional change at an end of the conjugated diene system. The second rule concerns the chemical shift changes of allylic and olefinic carbons by converting the geometry of conjugated diene systems. On the electron impact mass spectrometry, every dienic compound showed typical series of C_nH_<2n-2>^+〜C_nH_<2n_5>^+ with abundance maxima around C_4, C_5, C_6 or C_7. Each double bond positional isomer characteristically yielded different ion peaks in the series, which were useful for its distinction from other isomers. The process of formation of some of the ions can be speculated by the comparison with the mass spectra of deuterated compounds.
Though [2,3]-Wittig rearrangement has recently been shown by Nakai et al, to be a useful method of stereocontrol, the same rearrangement of allyloxyacetic acid has been reported to proceed with rather poor selectivity. In the course of the studies directed to new stereocontrolled synthesis of hydroxy acids, we found that amides or esters of allyloxyacetic acids underwent the rearrangement in highly stereo-selective manner through zirconium mediation. Thus, the amides (5) bearing a chiral auxiliary rearranged to 3'-alkyl-2'-hydroxy amides (7) with high syn-diastereo and diastereoface selection, and the esters (10) to 11 with high syn-diastereo-selection. It is noteworthy that in the rearrangement of optically active 1'-alkyl-2'-butenyloxyacetic acids (12), exclusive (Z)-selection has been observed along with excellent syn-diastereo-selection and chirality transfer. The methods have been further applied to the synthesis of an alcohol (19) related to tedanolide, and to the synthesis of bombykol.
The chiral lactonic acid 5, which is a versatile building block for the synthesis of natural products, was prepared from 4-hydroxypimelate 4 by asymmetric protonation. Thus, treatment of 4 with (1S)-(+)-10-camphorsulfonic acid in ethanol afforded (S)-(-)-lactone 5 with 94% ee in quantitative yield. Asymmetric induction was greatly affected by the concentration of the substrate, water contents in the solvent, and the reaction temperature. Since 4 is obtained by the hydrolysis of racemic 5 or the corresponding ethyl ester, allover process constitutes the enantioconvergent transformation of a racemic mixture into a single enantiomer. Simple optically active natural products were synthesyzed from chiral lactonic acid 5.
(+)-Pederin (1) is a potent insect poison isolated from Paederus fuscipes. The unique stereostructure of 1 having nine chiral centers has attracted the attention of synthetic organic chemists. We recently reported the stereoselective reduction of acyclic ketones with Zn(BH_4)_2 and the general methods for the syntheses of both 1,3-syn- and 1,3-anti-polyols. We now report the total synthesis of (+)-pederin (1) based on these newly developed methods. 1) Stereoselective Synthesis of (+)-Benzoylselenopederic Acid (+)-Benzoylselenopederic acid (4), the left half of pederin, was synthesized stereoselectively using Zn(BH_4)_2 reduction twice. 2) Stereoselective Synthesis of (+)-Benzoylpedamide (+)-Benzoylpedamide (5), the right half of pederin, was synthesized under virtually complete stereoselection using the method for the synthesis of 1,3-syn- and 1,3-anti-polyols effectively. 3) Total Synthesis of (+)-Pederin (+)-Pederin (1) was synthesized via the coupling of the left half 4 and the right half 5, followed by the NaBH_4 reduction.
Current progress toward a stereoselective total synhtesis of okadaic acid (1) will be presented. 1 was retrosynthesized into three segments A, B and C (Fig 1). Key features of our synthesis are i) synhtesis of each of the segment in optically active form, ii) acyclic stereoselection at C-2, 13, 27 and 29 in which heteroconjugate addition was employed for the preparation of both the syn and anti diastereoisomers, and iii) coupling of the segment C with the segment B and then with the segment A.
(+)-Diplodiatoxin (1) is a mycotoxin isolated from maize infected with Diplodia maydis, causal fungus of the disease "dry not". Since only planar structure for the mycotoxin was suggested on the basis of spectroscopic data and chemical reaction, the relative configuration of 1 has been elucidated by extensive comparison of ^1H NMR spectra of 1 with those of betaenone B (2). In order to confirm the absolute configuration, total synthesis of chiral diplodiatoxin has been undertaken by using highly stereocontrolled strategy, in which the intramolecular Diels-Alder reaction of a(E, E, E)-trienone 3 involves. The trienone is devided by three segments A, B and C. Segment B containing two chiral carbons was derived from a known compound 4 which was prepared from D-glucose. Two succesive Wittig-Horner reaction of segment B with segments A and C gave a mixture of the trienone 30 and other isomers in a ratio of 4:1. The intramolecular Diels-Alder reaction of the trienone mixture heating at 140℃ afforded single product 31 in quantitative yield. Removal of protective group of 31 yielded a product which is identical with natural (+)-diplodiatoxin in all respects. Therefore stereochemistry of this mycotoxin has been unequivocally confirmed to be 1.
Stereocontrolled construction of the adjacent tertiary carbons was examined using the Michael addition of ester and amide enolates to α,β-unsaturated esters. It was applied to the stereoselective synthesis of natural products possessing acyclic or extracyclic chiral centers. Reaction of lithiated propionates with crotonates in THF-HMPA at -78℃ gave erythro-2,3-dimethylglutarates highly selectively. Threo-isomers were synthesized by using t-butyl propionate (1b) in THF. A formal synthesis of faranal (6), the trail pheromone of monomorium pharaonis, was performed. When ω-halo-2-alkenoates (10) were treated with the enolate in the presence of t-BuOK, the Michael-induced intramolecular alkylation occurred smoothly. And cycloalkanes were obtained as a single isomer concerning three chiral centers containing an extracyclic center. (+)-Dehydroiridodiol (12), isolated from Actinidia polygama Miq. as an attractant for members of the Chrysopidae, and (+)-isodehydroiridodiol (13) were synthesized stereoselectively. The enolate of N-propionylpyrrolidine (18a) reacted with the unsaturated esters in ether to give threo-adducts. The other isomer was synthesized by using 2,5-trans-disubstituted pyrrolidine amide 18b. The asymmetric Michael addition was performed with (L)-N-methyl-N-propionylvalinol (18c), and, after the hydrolysis of ester and amide group, (2R,3R)-2,3-dimethylglutaric acid (erythro-22) was obtained. (L)-N-Propionyl-prolinol (18d) afforded (2R,3S)-acid (threo-22). The synthesis of (+)-12 and (-)-13 was achieved utilizing this methodology.
In the synthesis of natural products consisting of the basic structure of cyclopentane ring, variously functionalized cyclopentanones are required as starting materials. Previously, we succeeded in a simple, highly stereospecific synthesis of the cis-3,4-disubstituted cyclopentanones by the mild reaction with RhCl(PPh_3)_3. By the application of this newer cyclization reaction, we have succeeded in the synthesis of cis,cis-dihydronepetalactone, prostanoic acid, 8-isoprostanoic acid, (+)-brefeldin A and carbacyclin in the optically active form from limonene or Corey lactone. These compounds were synthesized via the following key steps. 1) 3-(3-Oxobutyl)cyclopentanone was easily converted to the deconjugated bicyclic enone (3→4). 2) The regioselective alkylation of limonene was performed by using s-BuLi-TMEDA (1→8). 3) The cis-3,4-disubstituted cyclopentanone from limonen-10-ol could be converted to the trans-3,4-disubstituted cyclo-pentanone by the epimerization (15→16, 22→23).
As one of continuous synthetic studies on naturally occurring spiro compounds, we describe stereoselective total synthesis of the hydroxylated spirovetivane-type phytoalxins, lubiminol (2) and oxylubimin (4) in racemic form. 1. Total Synthesis of (±)-Lubiminol (2) The previously reported spiro-enone (8) was transformed into 14 via 13 by a several-steps sequence. The three-carbon unit introduction at C-2 in 14 was followed by catalytic hydrogenation to give 9 as a single diastereoiosmer, which was converted into (±)-lubiminol (2). 2. A New Method for α'-Hydroxylation of α,β-Unsaturated Ketones We have developed a novel method for introduction of hydroxyl group to the α'-position of α,β-unsaturated ketones by means of TPPO oxidation of their silyl enol ethers. 3. Total Synthesis of (±)-Oxylubimin (±)-Oxylubimin (4), the highest oxidized spirovetivane-type phytoalexin, was also totally synthesized with high stereoselectivity usig the above mentioned hydroxylation method as a crucial step starting the enone (8).
Synthetic studies of ptaquiloside (1), a carcinogen of bracken fern, Pteridium aquilinum var. latiusculum are described. α-Allyl-δ-valerolactone (6) was converted by six-step sequence into a bromo ketone (4b), the intramolecular alkylation of which afforded a cis-hydrindane compound (5). A cyclopropyl unit was constructed in the compound (5) to give a ketone (11a). Introduction of an oxygen function into a cyclopentane moiety of the ketone (11a) has been performed by the following sequence: 11a→12→16→17.
A novel construction method for germacrene skeleton such as 3,7-dimethyl-10S^*-(1-methylethenyl)-2E,6E-cyclodecadien-1S^*-ol (18) by the stereoselective [2,3]-Wittig rearrangement of 3,6,10-trimethyl -1-oxa-2E,5E,9E-cyclotridecatriene (15) is presented. The stereoselectivity of this [2,3]-Wittig rearrangement is discussed based on the MM2 calculation. The stereoselective synthesis of(±) -4S^*-isopropyl-7R^*-(t-butyldiphenylsiloxy)methyl-9R^*,10R^*-epoxy-5-cyclodecen-1-one (43), as a precursor of Periplanone-B; the potent sex attractant and sex exitant pheromone of the American cockroach, is presented. In this synthesis,the 10-membered ring is constructed by the intramolecular alkylation of carbanion, generated from the protected cyanohydrin 41 and the stereoselective epoxydation of the enone 31 provides only the desired isomer 43. The stereoselectivity of the epoxydation is also discussed based on the MM2 calculation.
In a continuation of our synthetic studies on clerodane diterpenoids, we deal in the present paper with the asymmetric synthesis of (-)-kolavenic acid, which represent the first of its kind in the synthesis of clerodane diterpenoids, and the synthesis of agelasins, which are structurally featured by the presence of 9-methyl-7-adenylium moiety and biologically active. 1. Asymmetric synthesis of the octalon intermediate 1a. The octalon derivative 1a has been demonstrated to be a versatile intermediate in our syntheses of clerodane diterpenoids and we investgated first the chiral synthesis of 1a. This has been realized by the application Ender's asymmetric alkylation. 6-Methyl-2-cyclohexenone 5, thus obtained in 100% ee by a choice of the alkylating agent, was converted to (10R)-1a, [α]_D, +16°. (Scheme 1) 2. Total synthesis of (-)-kolavenic acid 2. The chiral 1a, prepared above, was transformed to kolavenal 10, [α]_D) 60°by 10 steps procedure (Scheme 2), which was confirmed to be identical in all respects, including the optical rotation, with the authentic specimen derived from natural 2. The conversion of 10 to 2 was also performed. 3. Synthesis of agelasins. The selective alkylation of the 9-methyl-adenine ring at 7 position was feasible by the application of Fujii's procedure, which make use of N^6-methoxy derivative. The demethoxylation of the alkylated products was performed with treatment of zinc/aqueous acetic acid. This method culiminated in the synthesis of agelasin B 3 from kolavenyl bromide 16. (Scheme 4)
The first achievement of total syntheses of two marine sesquiterpenes, (±)-Δ^<9(12)>-capnellene-8β,10α-diol(1) and (±)-Δ^<9(12)>-capnellene-3β,8β,10α-triol(3) will be disclosed. In the first place the efficient syntheses of the two key intermediate 16 and 21 corresponding to the AB-rings of the two sesquiterpenes will be presented. The synthesis utilized the common intermediate 12 easily produced from the silyl enol ether 10 by Saegusa-Ito reaction. Interestingly treatment of 12 with DBU in refluxing benzene gave 13 exclusively. In the second place the construction of the ABC-ring corresponding to 1 will be discussed. As expected, the aldol condensation of 23 under a variety of the reaction conditions provided only a trace amount of the desired product. However, this difficulty was nicely overcome by utilizing organosilicon chemistry. Namely treatment of 23 with TMSOTf-NEt_3 in refluxing benzene gave the desired product 24 in 40% yield together with the recovery of 23 30%. In the third place accomplishment of (±)-Δ^<9(12)>-capnellene-8β,10α-diol(1) via the triol 31 will be presented. In contrast to the triol route the allylsilane route shown in schemeV provided the stereoisomer 29, whose x-ray analysis is now under way. In the last place, according to the reaction sequence developed in the total synthesis of(±)-1, transformation of 21 to (±)-Δ^<9(12)>-capnellene-3β,8β,10α-triol(3) will be discussed.
The first total synthesis of antitumor diterpene spatol 1 is achieved in optically active form. The key step of this synthesis is the construction of tricyclo[5,3,0,0^<2.6>]decane nucleus. Intermolecular photocycloaddition of chiral butenolide 9 and olefin 10 gave the adduct 11 as a major product by the approach of 10 from the less hindered side. Transformation of the lactone ring of 11 into cyclopentenone ring gave 15, which was then successfully converted to β-bourbonene 3. For the construction of tricyclic nucleus of 1, the approach of 10 from the more hindered side of 9 is necessary, but was not the main course of the above intermolecular cycloaddition reaction. However this approach was realized by the intramolecular version of this cycloaddition. Thus, irradiation of 28 gave 29 and 30, having requisite configurations and functionalities. 29 and 30 were elaborated to 42, which possesses the common structure of all spatane diterpenes. Conversion of 42 into stoechospermol 2 was achieved by introducing the prenyl moiety to 42. Finally, conversion of 42 into sulfonium salt 45, generation of sulfur ylide, and addition to optically active aldehyde 47 gave the objective spatane diterpene (+)-spatol 1 in optically pure form having natural configuration.
1. Synthesis of Polyfunctional Iridoids. 8,10-Dehydro-dehydrologanin was settled on as a versatile key intermediate for the synthesis of polyfunctional iridoids. Bicyclic β-ketoester derivative prepared from cis-1,2,3,6-tetrahydrophthalic anhydride was converted into α,β-unsaturated aldehyde by the following sequence: (1) acetalization, (2) OsO_4-NaIO_4oxidation (3) internal aldol condensation. α,β-Unsaturated aldehyde was successfully transformed into key intermediate by the sequence involving quantitative deconjugation of α,β-unsaturated ester followed by OsO_4-NMO-NaIO_4oxidation. Optically active key intermediate was synthesized from natural geniposide in high yield by the sequence involving Evans rearrangement of allyl phenyl sulfoxide derivative. Dehydrologanin aglycone was synthesized from key intermediate by treatment with phenyl thiolate followed by desulfurization. Sythesis of seco-loganin aglycone was achieved by the new method utilizing oxidative cleavage of γ-hydroxy alkylstannane prepared from key intermediate by stannylation followed by NaBH_4 reduction. Penstemide aglycone was synthesized from genipin in high yield. 2. Synthesis of Manoalides. Manoalide is a sesterterpene isolated from the sponge, Luffariella variabillis and was found not only to show remarkable gram positive activity but also to inactivate purified phospholipase A_2 which is an enzyme found in several neurotoxic venom and is also a rate limiting enzyme in phospholipid metabolism and prostaglandin synthesis. Manoalide and seco-manoalide were synthesized from methyl 7,8-dihydro-β-ionylidene acetate in high yield by the new method utilizing regioselective singlet oxygen oxidation of 3-alkenyl-5-trimethylsilyl furan to β-alkenyl-γ-hydroxybutenolide.
We recently reported the isolation and structure elucidation of glycinoeclepin A (1), which is a natural hatching stimulus for the soybean cyst nematode. The lack of a satisfactory natural amount and the highly biological importance of the compound as well as the unusual skeletal array have prompted us to investigate the chemical synthesis. The unstability of the compound seems to be attributed to the presence of a cross-conjugated moiety included in the C and D rings. Accordingly, we planned to disconnect the synthetic target molecule (1) into two fragments (2) and (3) corresponding to the A ring and C/D ring moieties, respectively, reconnect them, and finally construct the cross-conjugated system in question. We describe herein i) the stereoselective synthesis of the partial structure 2 in an optically pure form starting with readily available 2,2-dimethylcyclohexane-1,3-dione (4); ii) the substituent effects on intramolecular halocyclization reactions of 4-methylenecyclohexanols in connection with the construction of the A ring moiety of 1; iii) the stereoselective synthesis of the partial structure 3 (R=Ac, R^1=Me), starting with commercially available (R)-(-)-carvone (13), which involves stereoselective introduction of four successive assymmetric carbons; and finally iv) the demonstration of the effectiveness of our disconnection by the model experiment (28→29).
The stereocontrolled synthesis of steroid side chain has been developed. The major interest has been forcused on the synthesis of the side chain of ecdysone as well as crustecdysone from 20-oxosteroid via furan derivatives. Reduction of the olefin (21) over palladium-carbon afforded the (20S)-20-furylsteroid (22), stereoselectively, whose hydrogenation over rhodium-alumina, followed by ruthenium tetroxide oxidation and treatment with methylmagnesium bromide, gave the triols (28) and (29) having an ecdysone-type side chain, respectively. The stereoselective reduction of the lactone (33) as a key reaction to give the δ-lactone (35) and the γ-lactone (36), under various conditions has also been investigated. Grignard reaction of both lactones with methylmagnesium bromide led to the synthesis of the tetraol (37) possessing a crustecdysone side chain. The total synthesis of 2-deoxycrustecdysone (3) has also been achieved by application of the above method.
Using new synthetic strategy, intramolecular double Michael reaction, a synthetic approach to aconitine alkaloids, a formal total synthesis of (+)-atisirene and syntheses of indolizidine and quinolizidine alkaloids were performed as follows. (I) Synthetic Approach to Aconitine Alkaloids: Stereoselective Construction of CDE Ring System: 4-Formyl-4-methyl-1-pentene was transformed into the α,β-unsaturated enone ester, which was treated with lithium hexamethyldisilazide to give the bicyclo[184.108.40.206^<1,5>]undecane. After conversion of the ethoxycarbonyl group into the methoxymechyloxymethyl group and introduction of the epoxide, acidic treatment formed the alcohol having furan ring, whose solvolysis afforded the CDE part of lycoctonine skeleton. (II) Formal Total Synthesis of (+)-Atisirene: The trans-decaline derived from (+)-Wieland-Miescher ketone was converted into the α,β-unsaturated enone ester, whose intramolecular double Michael reaction using lithium hexamethyldisilazide furnished quantitatively 11-methoxycarbonyl-15-noratisiran-15-one. The tetracyclic product was transformed into 15-norisoatisirene, which had been correlated to (+)-atisirene. (III) Total Syntheses of Quinolizidine and Indolizidine Alkaloids: Novel syntheses of quinolizidines and indolizidines from α,β-unsaturated enamide esters by heating with TMSCl, Et_3N and ZnCl_2 at 180℃ or by treatment with TBSOTf and Et_3N at ambient temperature were exploited. Application of these methodologies led to facile total syntheses of (±)-epilupinine and (±)-tylophorine.
This stereo-controlled synthesis of the title alkaloids provides the first total synthesis of the naturally occurring homoerythrinan alkaloids. The key step of our synthesis of the homoerythrinan ring system lies in [2+2]. photocycloaddition of a benzaepino-pyrrolinedione to an activated butadiene followed by the anionic 1,3-rearrangement of the resulting vinyl-oxy-cyclobutane. Starting from safrole, the 2,8-dioxo-Δ^<1(6)>-homoerythrinan derivative 45 was synthesized in 22 steps through the cyclohomo-erythrinan derivative 35 utilizing the above 1,3-anionic rearrangement, 1,2-carbonyl transposition via phenylselenenylation and decarbomethoxylation reaction by group IIa metal halide-DMSO. The compound 45 was stereoselectively reduced to 3β-alcohol 48 by Bu_4NBH_4 and to 3α-alcohol 49 by NaBH_4-CeCl_3. Methylation and AlH_3 reduction of 50 gave (±)-schelhammericine 1. Similarly methylation and reduction of 51 gave (±)-epischelhammericine 2.
In the course of studies directed to synthetic approach to stenine (1), which was isolated from Stemona sessilifolia (Stemonaceae), at first the synthesis of few model compounds containing decalin-system in their molecules was carried out. The presence of six asymmetric centers in the A-ring and the novel structure of this alkaloid make them important synthetic targets. The ether monoacetal (7) was stereospecifically synthesized from the readily available Diels-Alder adduct (3) by five steps. The ether monoacetal (7) was converted to the unsaturated compound (21) and (23), respectively, with organo-copper reagents and aldehydes under regio- and stereoselective conditions, and further acid treatments. The compound (21) was reduced to give the diketo-ol (22) stereospecifically, which was subjected to Baeyer-Villiger rearrangement and followed by acid epimerization to afford the ketoester (28). The ketoester (28) was transformed to stenine derivative (38) by three steps.
Synthetic approaches to fumitremorgins, tremorgenic micotoxins, from tryptophan in two biomimetic ways are described. I. Oxidative cyclization to β-carboline. Dye-sensitized photo-oxygenation of the 1,2-diisopentyltryptamine (5) gave the 3a-hydroxypyrroloindole (6) which was converted to the β-carboline (8) on warming in trifluoroacetic acid. On the other hand, the 1,2-diprenyltryptamine (3) gave the β-carboline (10) by NBS-CCl_4-AIBN. However, these oxidative cyclizations were not effective to prepare the basic ring system (16) of fumitremorgins from the diketo-piperazines (14,15). II. Preparation of the basic ring system of fumitremorgins. The Pictet-Spengler reaction of the L-tryptophan (18) and isovaler-aldehyde in the presence of trifluoroacetic acid gave the cis β-carboline (19) in 62% and the trans isomer (20) in 33% yields. Condensation of 19 with Z-L-proline chloride followed by the deprotection readily gave the desired cis-cis pentacyclic compound (21). Furthermore, the the 6-methoxy-L-tryptophan (25) has been prepared by the oxidation of the cyclic tautomer (23). The methoxylated pentacyclic compound (29) was prepared from 26 in the similar manner as above. III. Oxidation of the C-ring of the pentacyclic compound (33). The DDQ oxidation of 33 or 35 did not give neither the ketone nor the dehydro derivative of the C-ring. However, the 12-epi compound (39) gave the dehydro derivative (40) on the DDQ oxidation in aqueous acetonitrile. Further investigation to prepare tetrahydro-fumitremorgin B or its epimer from 40 is now in progress.
We have now established a common and practical short step synthetic method, as shown in chart 5, which is widely applicable for various ergot alkaloids and their analogs only by changing a reagent in each step and without changing the reaction type. Thus, when 2-methyl-3-buten-2-ol is used as an olefin in the second step, X, L, R^1, and R^2 of the formulas in chart 5 are I, OH, H, and H, respectively, and (±)-6,7-secoagroclavine (9) was synthesized in 36% overall yield. In the case of using 2-methoxy-2-methyl-3-buten-1-ol as an olefin, X, L, R^1, and R^2 are I, OMe, OH, and H, respectively, and (±)-6-norchanoclavine-I (20 or G) and (±)-6-norisochanoclavine-I (23 or G, R^1=H, R^2=OH) were obtained in good overall yields. These synthetic alkaloids were readily converted to (±)-chanoclavine-I (22 or I) or (±)-isochanoclavine-I (25 or I, R^1=H, R^2=OH), respectively. Treatment of 25 with thionyl chloride produced (±)-agroclavine (26). Since the alkaloid (26) has already been led to festuclavine, costaclavine, setoclavine, and isosetoclavine, formal syntheses of these alkaloids were also achieved. For the syntheses of above mentioned ergot alkaloids in large quantity, experimental procedures were extensively examined and now we can carry out successfully each of all steps involved in chart 1 in 50g scale.
According to the strategy of synthesizing all members of one group of alkaloids by one methodology, we have successfully applied reductive photocyclization of N-furoylenamines to the synthesis of ergoline group of alkaloids. Reductive photocyclization of the N-furoylenamines (2a, b) afforded the C/D-trans-lactams (3a, b) and cis-lactams (4a, b) respectively. Cleavage of the dihydrofuran ring of these lactams was performed by two routes to afford useful key compounds, 1,3-diols (8) and (10-12). Constructions of the ring D-structures characteristic to respective alkaloids were accomplished as follows. Regioselective dehydration of 9α-hydroxy group in the synthetic intermediates (15, 16, 19, and 22) with thionyl chloride afforded the 8-ergolenes (24, 27, and 29) and the 9-ergolenes (21, 25, and 28) respectively. Inversion of 9α-hydroxy group of the monomesylate (30) with potassium superoxide and double elimination of the dimesylates (32 and 33) with potassium t-butoxide gave the indolines (31 and 34) respectively. A convenient procedure for dehydrogenation of indolines into indoles by the reaction with phenylseleninic anhydride in the presence of indole was developed and successfully applied to the final steps in total synthesis of eight ergot alkaloids, lysergol, isolysergol, elymoclavine, isolysergine, agroclavine, agroclavine-I, fumigaclavine B, and lysergene, as racemates, with 80-97% yields.
Oxidation of o-tyrosine ethyl ester 5, or preferably 2-carboethoxy-5-hydroxyindole 6 with Fremy's salt gave the p-quinoneimine 7. Michael addition of the nitroester 10 to 7 yielded the p-quinonemethine 11 which could be converted to a mixture of diastereomeric chlorides 12 and the imine 13 with the aid of N-chlorosuccinimide and either MnO_2 or DDQ. Trifluoroacetic acid treatment of 13 caused ring formation, and thermolysis of the resulting oxazolone 14 gave methoxatin triester 15 which was hydrolyzed to methoxatin 1 following a known procedure.
Four chiral bicyclic lactone carbamates (11)-(14), potential synthons for the synthesis of the heteroyohimbine type indole alkaloids, are prepared in highly selective manners from a single chiral precursor diethyl L-tartrate by employing the intramolecular hetero-Diels-Alder reaction with inverse electron demand as a key step. Thus, we develop a selective way for the modification of diethyl L-tartrate to give the isomeric threitol derivatives (16) with E olefin and (17) with Z olefin which then are oxidatively converted into the glyceladehydes derivatives (20) and (24), respectively. Condensation of the former with Meldrum's acid yields the tricyclic lactone (22) with cis ring juncture selectively by spontaneous intramolecular hetero-Diels-Alder reaction, on the other hand, the latter affords the tricyclic lactone (5b) with trans ring juncture selectively under the same conditions. We can conclude that the stereochemistry of the adducts is directed by the configuration of the dienophile moiety. Conventional chemical transformation allows the formation of the key intermediates (13) and (14) from (22), while (11) and (12) from (5b) without difficulties.
Benzo[c]phenanthridine alkaloids have been shown to be biosynthesized from the corresponding protoberberine alkaloids through oxidative C_6-N bond cleavage, followed by recyclization between C_6 and C_<13> position of the latter alkaloids via the hypothetical enamino-aldehyde (A). This enamino-aldehyde (A) has also supposed to be the key intermediate for biosynthesis of 3-arylisoquinoline alkaloids from protoberberine alkaloids. According to the above biogenetic process, we have accomplished a novel and efficient synthesis of dihydrosanguilutine (7) and sanguilutine (8), 2,3,7,8,10-pentaoxygenated benzo[c]phenanthridine alkaloids, and (±)-corydalic acid methyl ester (20), a representative 3-arylisoquinoline alkaloid. 2,3,9,10,12-Pentamethoxyprotoberberine (2) was converted to the enamide (4) through the Hofmann degradation. Oxidation of 4 with thallium trinitrate followed by acidic treatment afforded oxysanguilutine (6), reduction of which with LiAlH_4 and then with NaBH_4 provided dihydrosanguilutine (7). The Hofmann degradation of the N-methyl derivative (14), derived from corysamine (12C), gave the enamine (15), which was reduced with NaBH_3CN to yield the trans amine (16) as a major product. On sequential treatment with Tl(NO_3)_3, 5% HCl, Jones reagent, and diazomethane, the trans amine (16) afforded (±)-corydalic acid methyl ester (20). Furethermore we have developed a convenient method for a synthesis of 13-methylprotoberberine alkaloids (12) from protoberberines (9) through photo-induced electrocyclic reaction of the 13-methylene-8,14-cycloberbines (11), derived from 10 by the Wittig reaction.
Clitocybe acromelalga Ichimura, a poisonous mushroom distributed in Japan only, exhibits unique toxicity. If one takes it accidentaly, one will have intolerable pain in fingers and toes after some days and the pain continues for about a month. We were interested in these remarkable physiological activities and fractionated various constituents of the mushroom testing the lethal effect on mice. As a result of the studies we recently isolated new amino acids acromelic acid A and B as the toxic principles, and inferred their structures to be 1 and 2 respectively by spectral analyses. For establishing the structures and investigation of biological activities, our efforts have been directed toward syntheses of these compounds. The synthesis of 1 was accomplished starting from kainic acid 3, which established the structure of acromelic acid A. In addition, the analogs 16 and 17 were synthesized from the synthetic intermediates of 1. In the neurobiological tests using crayfish neuromuscular preparation, all of these compounds 1, 16 and 17 showed the most potent depolarizing effect among the compounds related to L-glutamic acid known so far.
Prosurugatoxin, a neurotoxin having a selective affinity for ganglionic nicotinic receptors, was newly isolated from the toxic ivory shell (Babylonia japonica) together with Surugatoxin 3 and Neosurugatoxin 2 by Kosuge et al. and the structure has been proposed to be 1 on the basis of chemical transformation (1→3) and spectroscopic data. Concerning the recent progress on the chemistry of these metabolites, we will discuss the following subjects: 1) Synthesis of Prosurugatoxin 1. 2) Development of an alternative synthetic method toward prosurugatoxin analogs (4, 5, and related stereoisomers) and their mydriasis activities in mice. 3) Mechanistic studies on the ring transformation of 1 into 3 using model compounds.
The structures of patellamides A, B, and C, cytotoxic lipophilic cyclic peptides from a marine tunicate, were proposed by C.M. Ireland et al to be 1, 2, and 3, respectively, containing unusual fused thiazole-oxazoline units. We synthesized patellamides B and C with proposed structures by the use of diphenyl phosphorazidate (DPPA) and diethyl phosphorocyanidate (DEPC). However, the synthetic peptides with proposed structures 2 and 3 were not identical with natural patellamides B and C, respectively. An inspection of evidences used for the originally assigned structures and a synthetic study on the partial hydrolysate of patellamide B led us to deduce that the structures of patellamides B and C could be reassigned as 8 and 9, respectively, having the reverse order of amino acid residues. This deduction was fully confirmed by the syntheses of patellamides B and C with the revised structures 8 and 9, which were completely identical with natural ones. The structure of patellamide A was analogously revised as 12 by its synthesis. Thus, we could synthetically establish the real structures of patellamides A, B, and C as 12, 8, and 9, respectively.
Approaches to the total synthesis of echinocandin C(2), a 21-membered cyclic hexapeptide antibiotic isolated from Aspergillus ruglosus, have been described. The syntheses of four unusual amino acid moieties 3, 4, 5, and 6 in echinocandin C were carried out mainly from the allylglycine derivative and/or the vinylglycine equivalent in an efficient manner via a stereoselective introduction of β- or γ-hydroxyl group. The acyclic hexapeptide of echinocandin C, cleaved at the amide acetal part, was constructed as described in the followings. Synthesis of the left half was achieved by the use of a newly developed trimethylsilylimidazol method; The threonine moiety 33 , an amino acid free form, was condensed with the pyridine thiol ester 32 in an one-pot. 4-Hydroxy-L-proline(5) was connected with 39 by trimethylsilylimidazol/triethylamine. These peptide moieties were condensed with DEPC to the pentapeptide 41. Finally, 43 was condensed with 42 using DEPC to the hexapeptide 44. The cyclization step to echinocandin C is in progress.
In 1979, we proposed the revised structure 1 for carthamin, the red pigment of the flowers of Safflower (Carthamus tinctorius L.). In connection with the synthetic studies of 1, the synthesis of dehydro-3,3'-diacetyl-5,5'-methylenedifilicinic acid (2), dehydro-3,3'-bis(p-hydroxycinnamoyl)-5,5'-methylenedifilicinic acid (3), and dehydro-2,2'-bis(p-hydroxycinnamoyl)-4,4'-dihydroxy-4,4'-dimethyl-1,1',3,3',5,5'-hexaoxo-6,6'-methylenedicyclohexane (5), the analogs of 1, have been carried out. Interestingly, cotton or silk could be dyed with 4 and 5 in a similar manner as carthamin. Further, 2,6-diacetyl-4-C-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-hydroxycyclohexane-1,3,5-trione (25), a building block for the synthesis of 1, was obtained by the C-glucosylation of 2,6-diacetyl-1,3,4,5-benzenetetrol (24) with α-acetobromoglucose.
Ascofuranone (1) is an antitumor hypolipidemic antibiotic isolated from the mycelium of Ascochyta viciae Libert and recently found to have an antitumor protective effect also. The structure of ascofuranone is characterized by a fully substituted benzene ring and a sesquiterpenoid side chain having 4, 5-dihydro-3(2H)-furanone moiety. Our synthetic approach consists of (1) construction of the hexa-substituted benzene 6 (or 7), (2) synthesis of the terpenoid side chain precursor 15, (3) coupling of the two segments, and (4) regeneration of the phenolic hydroxyls. Feasibility of the strategy was first tested by the synthesis of model compounds, colletochlorin B (2a) and colletochlorin D (2b). Bromobenzene 6 (or 7) was prepared from dimethyl malonate and 3-penten-2-one through 3 and 4 and metallated to give a mixed cuprate which was allowed to react with geranyl bromide to give 8 (or 9). This was transformed into 10 (or 11). Deprotection of the phenolic hydroxyls of 10 with EtSNa gave colletochlorin B (2a) which was also afforded by treatment of 11 with Bu_4NF. Colletochlorin D (2b) was prepared similarly, starting with 10 and 1-bromo-3-methyl-2-butene. The bromide 15, synthesized by transformation of the aldehyde 12 to 13 followed by silver(I)-mediated dihydrofuranone formation, deprotection of the primary alcohol, and bromination with CBr_4 and (octyl)_3P, was connected with 6 (or 7) and the resulting 16(or 17 or 18) was successfully transformed to 19(or 20) in a like manner as above. Though neither EtSNa nor Bu_4NF was proved to be ineffective to yield ascofuranone from 19(or 20), P_2I_4, when applied to 20, gave rise to the target compound, ascofuranone (1).
Diels-Alder reaction of chloroprene with qunizaline quinone (6) followed by aromatization and hydrolysis, readily produced the tetracyclic trione (8). This was elaborated to (±)-7-deoxy-4-demethoxy-daunomycinone ((±)-9) by addition of the ethynylcerium reagent followed by hydrolysis. Conventional cyanohydrin formation of 8 and hydrolysis produced (±)-α-hydroxy acid ((±)-10), which could be also converted to (±)-9 by sequential acylimidazole formation and addition of methylmagnesium bromide in the presence of trimethylsilyl triflate (TMSOTf). Optical resolution of (±)-10 by the use of (-)-N-methyl-ephedrine gave (R)-10. Preparation of optically pure (-)-9 was accomplished by optical resolution of (±)-9 with (2R,3R)-(+)-1,4-bis(4-chlorobenzyloxy)butane-2,3-diol or treating (R)-19 in a similar manner to that described for (±)-10. Optically pure (-)-9 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-11) by C_7-bromination and stereoselective hydroxylation. Further C_<14>-bromination of (+)-11 and substitution gave (+)-4-demethoxyadria-mycinone ((+)-12), (+)-14-formyloxy-4-demethoxydaunomycinone ((+)-13), and (+)-14-acethoxy-4-demethoxydaunomycinone ((+)-14). (+)-4-Demethoxydaunorubicin ((+)-4-HCl) was prepared by the novel glycosidation of (+)-11 with (-)-1,4-di-O-p-nitrobenzoly-L-daunosamine ((-)-22) in the presence of TMSOTf followed by sequential O- and N-deprotections. (+)-4-Demethoxyadriamycin ((+)-3-HCl) could be also synthesized starting from (+)-4-HCl or by way of 3'-N-trifluoroacetyl-4-demethoxyadriamycin ((+)-28) prepared from (+)-13 and (+)-14, and was fully characterized by its spectral properties.
The first, enantiospecific total syntheses of pyranonaphthoquinone antibiotics, (-)-nanaomycins (1 and 5) and their enantiomers, (+)-kalafungins (2 and 5') are described in overall yields of approximately 18% and 13%, respectively, by an "enantiodivergent" strategy from a common optically active intermediate 7, which has been derived from L-rhamnose (11) via condensation of the α,β-unsaturated ketone 10 and the phthalidylsulfone 9. The Wittig reaction of the key intermediate 7 with ethoxycarbonylmethylene-triphenylphosphorane gave the C-3 epimers 21 and 22, the former of which was converted into (-)-nanaomycins (1 and 5). The latter 22 was led to (+)-kalafungins (2 and 5') through the fascinating epimerization at C-1 and C-4 positions of 24 by sulfuric acid.
Enantioselective synthesis of some important antibiotics has been investigated by combination of enzymatic and non-enzymatic procedures. The synthetic strategy developed here is based on symmetrization-asymmetrization concept. Thus, retrosyntesis was carried out to generate, from target molecules, simplified symmetric diesters (symmetrization), and then the symmetric diesters were subjected to asymmetric hydrolysis with pig liver esterase to create the corresponding chiral half-esters. The chiral half-esters were converted to the target molecules by non-enzymatic procedures. Various types of carbapenem antibiotics, negamycin, showdomycin, 6-azapseudouridine, cordycepin, aristeromycin, neplanocin A, and aminocyclitol precursors of fortimicin were efficiently synthesized with the desired absolute configurations. The structure-stereospecificity relationships revealed by the present study give significant and useful information about the topography of the active site of PLE and allow us to propose the working active site model.
Stereocontrolled synthesis of macrolide and polyether antibiotics is one of the most attractive areas in current synthetic organic chemistry. Recently, we planned to synthesize representative macrolide antibiotics and their aglycones such as methynolide (12-membered), picronolide (14-membered), erythronolide A (14-membered), and tylonolide (16-membered) from D-glucose by a common methodology. In the macrolide synthesis, macro-lactonization of active esters has been used, though often in poor yield. We report here that the Wittig-Horner cyclization was proved to give excellent results in the case of the synthesis of methynolide (30), tylonolide (33), and a model compound (35) of pironolide (14-membered). When esters having both aldehyde and keto-phosphonate groups, 28, 31, 34, were exposed to powdered anhydrous K_2CO_3 (6 eqv.) and 18-crown-6 (12 eqv.) in dilute toluene solution (1 mM) at 80℃ (several hrs.), the expected macro-cyclic enones, 29, 32, 35, were readily obtained in high yields.
Naturally occurring antibiotic macrodiolides, pyrenophorin (1), vermiculine (2), and colletallol (3), were synthesized in their racemic forms from the corresponding hydroxycarboxylic acids (16), (23), and (44) respectively via stereoselective formation of the requisite trans double bonds after macrocyclization. Pyrenophorin (1): Hydroxycarboxylic acid (16) readily prepared from glycol (8) was subjected to lactonization to give rise to diolide (17) in 60% yield which was converted to the bis trans α,β- unsaturated lactone (11) in the desired sence. Colletallol (3): The method was further applied to the synthesis of the non-symmetric diolide colletallol (3). Lactonization of (23) by treatment with diethyl phosphoro-chloridate followed by exposure to a solution of acetonitrile in the presence of catalytic amounts of DMAP gave diolide (24) in 90% yield, which was transformed to dl-colletallol (3) under the same procedures. Vermiculine (2): Oxidation of selenide (30) furnished cis diolide (32) as the only observed product in 86% yield. These results were completely different from those of trans stereoselection observed in the case of pyrenophorin and colletallol syntheses. Consequently, dl-vermiculine (3) was synthesized via oxidative elimination of (45) followed by oxidation of (46) and deketalization of (47) with trifluoro-acetic acid.