Enantioselective total synthesis of (1R,3S,4R,5R)-1-amino-4,5-dihydroxycyclopentane-1,3-dicarboxylic acid. A full-aldol access to carbaketose derivatives

The enantioselective synthesis of cyclopentanedicarboxylic amino acid 1, a novel rigid and functionalized L-glutamic acid analogue, has been achieved in 15 linear steps from silyloxypyrrole 3, utilizing L-glyceraldehyde 4 as the source of chirality. The key steps in the synthesis are three sequential aldol-based carbon-carbon bond-forming reactions: two crossed vinylogous aldol additions (2 + 3 --> 8 and 4 + 5 --> 10 + 11) and one intramolecular silylative aldolization (6 --> 7). En passant, the short syntheses of (2S)-2-hydroxymethylglutamic acid (16) and its (2R)-enantiomer ent-16, a potent metabotropic glutamate receptor agonist, have been achieved.     

Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogues

The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed epothilones including an epothilone B10 (3), epothilone F (5), 16-desmethylepothilone B (14), pyridine epothilones 57a-57g, dimeric epothilones 59 and 61, and benzenoid epothilones 63a-63g.     

Practical asymmetric synthesis of aprepitant,a potent human NK-1 receptor antagonist,via a stereoselective Lewis acid-catalyzed trans acetalization reaction

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.     

A short, formal, biomimetic synthesis of (+/-)-polygalolides A and B

[reaction: see text] Reaction of bisacetoxy pyranone 9 with Et3N gave 3-oxidopyrylium ylide 10, which underwent a stereo- and regiospecific [5 + 2] cycloaddition with alpha-methylenebutyrolactone to afford 16 (34%). Treatment of 16 with Cs2CO3 resulted in hydrolysis of the lactone and acetate and conjugate addition of the hydroxyethyl group to the enone. Lactonization on acidification afforded 4 (57%), completing a two-step, formal synthesis of polygalolides A and B.     

Total synthesis of dl-asparenomycins A,B and C,novel carbapenem antibiotics

Total synthesis of dl-asparenomycins was accomplished with direct conversion of carbonates 13a, 13b and 14a, 14b to asparenomycin esters 15 and 16 and carboxy deprotection by the AlCl₃-anisole method.     

The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.     

Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.     

The first enantiospecific total synthesis of the 3-oxygenated sarpagine indole alkaloids affinine and 16-epiaffinine, as well as vobasinediol and 16-epivobasinediol

The first enantiospecific total synthesis of the 3-oxygenated sarpagine indole alkaloids affinine (1) and 16-epiaffinine (2) as well as the synthesis of vobasinediol (3) and 16-epivobasinediol (4) was accomplished from d-(+)-tryptophan methyl ester.     

First enantiospecific total synthesis of the important biogenetic intermediates, (+)-polyneuridine and (+)-polyneuridine aldehyde, as well as 16-epi-vellosimine and macusine A

The first enantiospecific total synthesis of the alkaloids 16-epi-vellosimine (1), (+)-polyneuridine (2), (+)-polyneuridine aldehyde (3), and macusine A (4) is reported. The key oxidation was accomplished with the Corey-Kim reagent to provide the important biogenetic intermediates, 16-epi-vellosimine (1) and polyneuridine aldehyde (3), the latter of which is required for the conversion of the sarpagan skeleton into the ajmalan system in the biosynthesis of quebrachidine. [reaction: see text].     

Synthesis, Structure, and Reactivity of Enediyne Macrocycles

The reaction of bis-propargyl bromide enediyne 4 with weakly basic nucleophiles allows the facile synthesis of acyclic and macrocyclic enediynes. Depending on the bis-nucleophile employed, 12- to 16-membered enediyne macrocycles were obtained. The thermal stability of the new cyclic enediynes was investigated by differential scanning calorimetry. Upon coordination of the macrocycle 5c with Hg(O(2)CCF(3))(2), a drop of the enediyne cyclization temperature of nearly 100 K was observed.     

Design,synthesis, and toward a side-ring optimization of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and their effect on melanin synthesis in murine B16 cells

Abstract

Herein, we report the synthesis of 48 novel 3-sulfonylamides containing a tricyclic thieno[2,3-d]pyrimidin-4(3H)-one moiety, and their influence on melanin synthesis in murine B16 cells. All target sulfonylamides were synthesized through key intermediate 3-nitro-thieno[2,3-d]pyrimidin-4(3H)-ones using three types of ipso-nitration reactions. In this case, we converted the pyrido[1,2-a]- fragment of the thieno[2,3-d]pyrimidine moiety to pyrrolo[1,2-a]- and azepino[1,2-a]- side-rings in order to evaluate the bioactivities of the synthesized derivatives for a structure activity-relationships point of view. The obtained results suggest that some of the selected compounds revealed a promising influence on melanin synthesis in murine B16 cells and may serve as lead compounds for further drug discovery and development.     

Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation

In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.     

基于长链离子液体模板合成Fe(Co、Ni)-MCM-48

以两亲长链离子液体(氯化-1-十六烷基-3-甲基咪唑)为模板剂,采用水热合成方法,分别合成了含铁、钴和镍的立方介孔分子筛MCM-48。通过XRD、TEM、ICP-AES、FTIR、UV-Vis和N₂吸附/脱附实验对其结构和形态进行了表征,并考察了钴掺杂量和模板剂用量对合成立方相结构的影响。结果表明,用该方法合成的试样具有较高的比表面积和规则的立方介孔孔道结构等特征;相对于铁和镍的掺杂试样,钴物种能以四面体的结构稳定地存在于立方介孔分子筛骨架中。     

A Total Synthesis of Aphidicolin: Stereospecific Synthesis of (±)-3α, 18-Dihydoxy-17-Noraphidicolan-16-one

A simple, efficient, and stereospecific total synthesis of (±)-3α, 18-dihydroxy-17-noraphidicolan-16-one (2) , by solvolytic rearrangement of the endo-bicyclo-[2.2.2]oct-5-en-2-yl methanesulfonate 16 , is described. Since aphidicolin (1) has already been obtained from 2 , the preparation of the latter formally constitutes a new total synthesis of 1 .     

Regiospecific,enantiospecific total synthesis of the alkoxy-substituted indole bases, 16-epi-N(a)-methylgardneral, 11-methoxyaffinisine,and 11-methoxymacroline as well as the indole alkaloids alstophylline and macralstonine

A regiospecific, enantiospecific approach to the synthesis of ring-A-substituted indole alkaloids was developed via a doubly convergent strategy. The asymmetric Pictet-Spengler reaction and enolate-driven palladium cross-coupling processes were both executed in stereospecific fashion and served as the stereochemical basis of this approach. The synthesis of 16-epi-N(a)-methylgardneral (15), 11-methoxyaffinisine (16), and 11-methoxymacroline (22) has been accomplished in high yield and in enantiospecific fashion. Moreover, the key C-19 ketosarpagine system (borane adducts) 19a,b employed for the construction of 11-methoxymacroline (22) was also transformed into alstophylline 25, which resulted in completion of the total synthesis of the bisindole macralstonine (1). [reaction: see text]     

Stereospecific,enantiospecific total synthesis of the sarpagine indole alkaloids (E)16-epiaffinisine, (E)16-epinormacusine B,and dehydro-16-epiaffinisine

[reaction: see text] The first stereospecific total synthesis of the sarpagine indole alkaloids (E)16-epiaffinisine (1), (E)16-epinormacusine B (2), and dehydro-16-epiaffinisine (4) has been completed; this method has also resulted in the synthesis of dehydro-16-epinormacusine B (5). The formation of the required ether in both 4 and 5 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF in 98% and 95% yields, respectively.     

Stereoselective synthesis of marine sesterterpenes, 16-deacetoxy-scalarafuran, (+)-scalarolide and their analogs

The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpenes 16-deacetoxy-scalarafuran, (+)-scalarolide and their unnatural analogs were described. Three key transformations were involved in their synthesis, which are the ring-opening rearrangement of epoxide, stereoselective Diels-Alder addition, and one-pot γ-butenolide formation process, and the absolute configurations of natural (+)-scalarolide and 16-deacetoxy-scalarafuran were confirmed.     

A practical and facile synthesis of azetidine derivatives for oral carbapenem, L-084

An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1beta-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.     

A new synthetic route to 7-halo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,an intermediate for the synthesis of quinolone antibacterial agents

Starting from m-fluorotoluene, 7-chloro-6-fluoro- and 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquino-line-3-carboxylic acids, 3 and 16 were synthesized. Compounds 3 and 16 are useful intermediates for the synthesis of a class of quinolone antibacterial agents. The synthetic route involves two processes; i) construction of the quinoline ring by an intramolecular cyclization accompanied by the elimination of a nitro group and ii) introduction of fluorine atom by replacement of a nitro group with potassium fluoride. 7-(3-Amino-1-pyrroli-dinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (18) was prepared from 3 or 16. The antibacterial activity of 18 compares favorably with that of ciprofloxacin (2) .     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).