Diastereo- and enantioselective synthesis of a conagenin skeletal amide moiety

A synthetic study was carried out to obtain epimers of a protected 2,4-dihydroxy-3-methylpentanoic ester 9, which is a central building block of the immunomodulator (+)-conagenin 1. The configuration of the three contiguous stereogenic centers was determined by NMR measurements and comparison with the stereogenic centers of lactone 10.     

Total synthesis of cruentaren B

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.     

Total synthesis and structural confirmation of (+)-longicin

A stereocontrolled total synthesis of (+)-longicin, a representative of the class of mono-THF-acetogenins, is described. The strategy involves the utilization of d- and l-glutamic acids as chirons that correspond to two five-carbon segments harboring stereogenic centers at C4 and at C17 of the C(32) polyketide-derived natural product. The use of Grubbs' RCM reaction as a novel "chain elongation" strategy for the synthesis of acetogenin-type structures and a new protocol for butenolide incorporation are also described. [structure: see text]     

Selective "one-pot" synthesis of functionalized cyclopentenones

Double addition (1,2-1,4) of vinyl magnesium bromide to squaric acid derivatives allows the preparation of polyoxygenated cyclopentenones (8) in a "one-pot" procedure. The reaction occurs through the intermediate formation of octatetraenes (6). Protonation of this latter intermediate at -78 °C with TFE occurs selectively at the vinyl CH(2) closer to the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity.     

First enantioselective synthesis of (−)-talaumidin, a neurotrophic diaryltetrahydrofuran-type lignan

The first enantioselective total synthesis of a neurotrophic (−)-talaumidin (1) is described in 16 steps from 4-benzyloxy-3-methoxybenzaldehyde in ca. 10.7% overall yield, and thus has established the absolute configurations of the four stereogenic centers C-2 ∼ C-5 of 1. The synthesis features the construction of the two successive chiral centers C-2 and C-3 by Evans asymmetric anti-aldol protocol as well as of the two chiral centers C-4 and C-5 in a highly stereocontrolled fashion by hydroboration/oxidation and epimerization, followed by Friedel-Crafts arylation.     

Total synthesis of amphidinolide X

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13-C14 bond was achieved by the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.     

Asymmetric synthesis of (E)-dehydroapratoxin A

An asymmetric approach to key intermediate 17 starting from lactone 7 is described, in which Evan’s alkylation and CBS-catalyzed reduction are used for construction of the chiral centers, respectively. Thus, the synthesis of (E)-dehydroapratoxin A 6 could be accomplished in a general fashion, therein FDPP has been proven as an efficient condensation reagent for the coupling of amine 25 and carboxylic acid 24.     

Total synthesis of natural products using a desymmetrization strategy

Total syntheses of SB-203207 (1) and sphingofungin E (2) were accomplished by utilizing an asymmetric desymmetrization strategy to introduce multiple stereogenic centers into meso starting compounds in a single step. Thus, rhodium carbenoid-mediated CH insertion into 3 provided the bicyclo[3.3.0]framework 4 for 1, while organocatalyst-mediated bromolactonization of 5 afforded 6 for the synthesis of 2. Similarly, we utilized desymmetric rhodium nitrenoid-mediated aziridination reaction of 5 to obtain a key intermediate required for a total synthesis of pactamycin (29), a complex aminocyclopentitol antibiotic featuring six contiguous stereogenic centers.     

Studies toward the synthesis of pinolidoxin, a phytotoxic nonenolide from the fungus Ascochyta pinodes. Determination of the configuration at the C-7, C-8, and C-9 chiral centers and stereoselective synthesis of the C(6)-C(18) fragment

The absolute stereochemistry at the C-7, C-8, and C-9 chiral centers of pinolidoxin (1) has been determined by chemical and spectral methods. First, the synthesis of four stereoisomeric fully benzoylated 2,3-erythro-1,2,3,4-heptanetetrols, corresponding to the C(6)-C(18) portion of the natural substance, has been accomplished starting from meso-tartaric acid. As next step, the selection of the synthetic tetrabenzoate possessing "natural" stereochemistry (10a'), suitable for absolute configuration determination, has been carried out by correlation with its "natural" homologue derived from degradation of pinolidoxin. Determination of the stereochemistry at the title chiral centers has been carried out by application of the Mosher's method both to 7a', a compound stereochemically related to 10a', and to pinolidoxin itself. The stereoselective synthesis of a protected form of the C(6)-C(18) portion of pinolidoxin, to be used in its total synthesis, has also been accomplished starting from commercially available D-erythronolactone.     

A chiron approach to the total synthesis of (+)-aculeatin D

A synthesis of natural aculeatin D has been achieved, with the key stereogenic centers taken from inexpensive and readily available D-xylose. In elaboration of D-xylose into a desired form readily applicable in synthesis a previously misinterpreted and overlooked abnormal selectivity in hydroxyl protection was noticed and exploited. Protocols were developed for monotosylation of a triol insoluble in CH2Cl2 and "freezing" the less stable isomer (aculeatin D) at the PIFA-mediated oxidative spirocyclization, respectively. An unexplained deprotonation at a benzyl protecting group by a thermodynamically more stable dithiane carbanion in the literature was also addressed.     

Optically active 2-cymantrenyloxazolines: synthesis and regioselective metallation

Three optically active oxazolines with a cymantrenyl substituent at position 2 of the heterocycle have been prepared. Metallation of these compounds withn-BuLi proceeds only at the two diastereotopic - and '-positions of the Cp-ring to an equal extent. The dependence of the sign of Cotton effect in the region of 300–350 nm upon the absolute configuration of chiral centers remote from the Cp-ring has been demonstrated.Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 1, pp. 182–183, January, 1993.     

New advances in the field of synthesis of natural polyhydroxysteroids

This review of the literature and of the authors' own work, devoted to a discussion of new methods for the synthesis of sections of steroid molecules responsible for their biological action, consists of two parts. The first is devoted to methods of constructing polyoxygenated side chains C₃-C₈ of steroids. In it are discussed the Grignard, Wittig, and Claisen reactions using Me-organic complexes including the C-20, C-21, C-22, C-23, and C-24 compositions, the C-22(23) double bond, the C-22, C-23, and C-24 centers, and the C-24 and C-25 centers, and other methods. In the second part methods of constructing the A/B rings of natural polyhydroxysteroid are discussed: the construction of the 2,3-vicinal diol grouping in the 5H-⁷-6-keto fragment of the ecdysones, the construction of the 2,3-cis-diol grouping in the 7-oxa-6-keto-B-homo rings of the brass inolides, and methods of creating the ⁵-7-oxygen-containing ring B of steroids of the antheridiol group.N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 3–28, January–February, 1988.     

Macroheterocycles. 49. Simple synthesis of cryptands based on intracomplex macrocyclization

An effective method for synthesizing cryptands by reaction of bis(methyleneepoxy) diazacrown ethers with benzylamine and N,N-dibenzylethylenediamine is reported. The good yields of cryptands are explained by formation of an intermediate in which the placement of reaction centers is favorable for intramolecular closure due to binding of the macrocycle to substrate.For Communication 48, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1673–1675, December, 1989.     

Total synthesis of the proposed structure of iriomoteolide-1a

Full details of the total synthesis of the proposed structure of iriomoteolide-1a (1) are described. The key steps include (i) a Sakurai reaction between allylsilane 11 and aldehyde 10 that bears both a tertiary chiral center and vinyl iodide moiety (ii) an anti-aldol reaction to construct the C18/C19 chiral centers (iii) a B-alkyl Suzuki-Miyaura coupling reaction to assemble the C7-C23 fragment, and (iv) a macrocyclic ring-closing metathesis to complete the construction of the target molecule. Two different approaches to access penultimate precursor 2 are delineated. The NMR spectra of the synthetic iriomoteolide-1a (1) were found not to match those reported for the natural product bringing into question its true structural identity.     

New approach toward the total synthesis of (+)-aphidicolin by tandem transannular Diels-Alder/aldol strategy

The synthesis of a 15-membered macrocyclic triene containing all the required substituents of ring A of (+)-aphidicolin (1) is reported. This compound underwent a thermal transannular cycloaddition followed by an intramolecular aldol reaction to yield tetracycle 32 containing 8 chiral centers which is considered a key intermediate for the synthesis of (+)-aphidicolin and related analogs.     

The staged synthesis of 2-methylimidazole from ethylenediamine and acetic acid in the presence of a bifunctional aluminoplatinum catalyst

An investigation has been conducted into the staged synthesis of 2-methylimidazole from ethylenediamine and acetic acid in the presence of a bifunctional aluminoplatinum catalyst. It has been shown that the formation stage of 2-methylimidazoline occurs more quickly on -Al₂O₃ than its dehydrogenation on the Pt centers. From a comparison of the processes of dehydrogenation of 2-methylimidazoline in the molten phase and in aqueous solution it follows that the water eliminated in the imidazoline formation stage could cause the decrease in activity during the dehydrogenation on the Pt centers. The structures of the secondary and intermediate products have been established for each stage of the process and their formation routes are discussed.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 9, pp. 1997–2002, September, 1992.     

Stereoselective total synthesis of ophiocerin D from d-xylose

A stereoselective total synthesis of ophiocerin D is reported by a combination of a ‘chiron’ approach and an asymmetric synthesis, from d-xylose. Of the four stereogenic centers, the vic diols C3/C4 and C5/C6 were obtained by Sharpless asymmetric dihydroxylation and from d-xylose, respectively.     

P-heterocyclic building blocks: application to the stereoselective synthesis of P-sugars

A strategy relying on the utilization of stereoselective additions to allyldiphenylphosphonate esters and subsequent ring-closing metathesis (RCM) to access P-chiral P-heterocyclic building blocks for the synthesis of phosphono sugars is described. These building blocks possess several attractive components, including the following: (i) P(2) and C(6) stereogenic centers for directing stereoselective transformations; (ii) an activated C(3) methylene group that promotes base-mediated olefin transposition to generate vinyl phosphonates available for further stereoselective reactions; and (iii) a P(2)-stereogenic center containing an exchangeable phosphonate ester armed to attenuate the "stereochemical environment" at phosphorus. Taken collectively, these attributes contribute to a concise method for the stereoselective synthesis of an array of P-sugars.     

Design, synthesis, and chemistry of sterically nondemanding primary bisphosphines

Design and synthesis of chelating bisphosphines functionalized with the smallest chemical unit "H" on the P(III) centers ((PH(2)CH(2))(2)CHCH(2)NHPh (4) and (PH(2)CH(2))(2)CHCONHPh (5)) are described. Studies demonstrating that no bulky chemical substituents are necessary to offer thermal/oxidative stability to the -PH(2) groups in 4 and 5 are described. The H atoms around the P(III) centers in 5 (or 4) concur limited/no steric influence, but yet the phosphines manifest high nucleophilicity to coordinate strongly with W(0) and Re(I). The studies include synthesis and X-ray structural characterization of an air-stable primary bisphosphine (5) and its transition-metal chemistry with W(CO)(6) and Re(CO)(5)Br to produce the complexes (eta(2)-(PH(2)CH(2))(2)CHCONHPh)W(CO)(4) (6) and (eta(2)-(PH(2)CH(2))(2)CHCONHPh)Re(CO)(3)Br (7), respectively.     

Multicomponent synthesis of epoxy-tetrahydronaphthyridine and structural diversification by subsequent fragmentation

Three-component reaction of an α-isocyanoacetamide 7, an homoallylamine 8 and an aldehyde 9 in methanol at room temperature provides oxa-bridged tricycle 4 in good to excellent yield as a mixture of two separable diastereoisomers. In this one-pot multicomponent process, one C-N, one C-O and three C-C bonds are formed with concomitant creation of five asymmetric centers and three rings. Fragmentation of epoxy-tetrahydronaphthyridine 4 affords differentially substituted 5,6,7,8-tetrahydro-1,7-naphthyridine (5, 6) depending on the reaction conditions, providing thus additional structural diversity. A one-pot three-component synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine (6) from 7, 8 and 9 is also documented.