Development of an approach to the synthesis of the ABC ring system of Hemibrevetoxin B

An efficient approach for the synthesis of a model of the ABC ring system of Hemibrevetoxin B is described. Key features include a ring expansion to yield the ring C oxepane, the reduction of a 2-furyl ketone with high levels of 1,3-stereocontrol, and an Achmatowicz oxidative ring expansion to yield the ring A tetrahydropyran. All seven stereogenic centers present in the model compound were controlled with high levels (>98:<2) of diastereoselectivity.     

Simple Synthesis of Versatile Coumarin Scaffolds

We describe an approach using ring‐closing metathesis (RCM) to synthesize versatile coumarin derivatives that present appropriate substitutions both at the aromatic and at the α,β‐unsaturated lactone ring. The obtained compounds can be used as molecular scaffolds suitable for further diversifications through a combinatorial approach.     

New regiocontrolled synthesis of functionalized pyrroles from 2-azetidinone-tethered allenols

A new one-pot approach to synthesize densely substituted racemic and enantiopure pyrroles from beta-lactams has been developed. The approach relies on the regiocontrolled cyclization of beta-allenamine intermediates derived from the ring opening of 2-azetidinone-tethered allenols. In this approach four points of diversity are introduced, one of which is the position of the allene moiety on the beta-lactam ring.     

Model studies on the ring construction of the auriside macrolactone

The preparation of a 12-membered ring macrolactone model of auriside that contains a pendant diene chain bearing a bromide was investigated employing two approaches. The first approach utilized an oxidative rearrangement of a tertiary allylic alcohol on a 12-membered ring. The second approach was based on a 1,4-methylation of an ynone followed by macrolactonization.     

Synthetic study of gymnocin-A: synthesis of the ABC ring fragment

The synthesis of the ABC ring fragment of gymnocin-A is described. The key feature of this approach was the convergent BC ring formation using an oxiranyl anion coupling, which was followed by intramolecular Williamson ether synthesis and the reductive etherification of an α-acetoxy acetal. The five-membered A ring was then constructed on the seven-membered B ring by radical cyclization of a β-alkoxy acrylate derivative.     

A new synthetic approach to the C ring of known as well as novel bryostatin analogues

[reaction: see text] A new approach to the synthesis of the C ring subunit of known and potential bryostatin analogues is described. The convergent approach, illustrated above, requires fewer steps and offers greater flexibility in rapidly accessing diverse C ring analogues.     

The furan approach to azacyclic compounds

We describe an efficient new approach to the synthesis of azacyclic compounds that extends our recently developed methodology based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular hetero Michael addition. The new approach gives access to the readily opened bicyclic lactones and novel tricyclic heterocycles containing the piperidine ring.     

Diastereoselective synthesis of a highly substituted cis-decahydroquinoline via a Knoevenagel condensation

A diastereoselective approach to 3,7,8-trisubstituted cis-decahydroquinolines is described. This ring system forms the core of rings B and E of the norditerpenoid alkaloid methyllycaconitine. This approach starts with a known disubstituted cyclohexene. The remaining carbons are attached via a Knoevenagel condensation followed by an intramolecular lactam formation. The stereochemistry of the substituents is controlled by the cis-substitution of the starting cyclohexene ring.     

Total Synthesis of Codeine

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C?H olefination of unactivated aliphatic alkene to install the morphinan ring system.     

First and second generation total synthesis of the teicoplanin aglycon.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.     

A Pauson-Khand and ring-expansion approach to the aquariane ring system

[Structure: see text] The carbocyclic ring system of the aquariolide diterpenes has been synthesized by two routes involving a diastereoselective Pauson-Khand reaction and subsequent ring expansion. In one route, a tetracyclic enone was elaborated to generate the nine-membered ring by Grob fragmentation. In the second approach, a spirocyclic tricycle underwent a facile anionic oxy-Cope rearrangement to complete the synthesis of the desired ring system.     

A new approach to A/B ring analogue of eleutherobin and sarcodictyns through a sequence of highly diastereofaceselective Diels-Alder reaction and ring opening-ring closing metathesis (RO-RCM)

An approach to the construction of A/B ring analogue of antitumour compounds eleutherobin and sarcodictyns is described. The key steps involve a highly diastereofaceselective Diels-Alder reaction of a dienophile containing a furanosugar moiety with cyclopentadiene and ring opening-ring closing metathesis of the resulting adduct.     

Construction of spiro-oxaquinolizidinone framework of Upenamide via organoiron complexes

An organoiron approach toward the synthesis of an elaborated tricyclic spiro-oxaquinolizidinone ring has been accomplished. The key intermediate was efficiently prepared through a nitrile addition to the appropriately functionalized cyclohexadienylium-Fe(CO)₃ perchlorate salt to install the requisite quaternary center in the spiro-oxaquinolizidinone ring.     

A tandem oxidative dearomatization/intramolecular Diels-Alder reaction: a short and efficient entry into tricyclic system of maoecrystal V

A short and efficient route to tricyclic ring system containing bridged bicyclo[2.2.2]octanone annulated with a lactone ring present in the maoecrystal is described. In-situ generation of spiroepoxycyclohexa-2,4-dienone and intramolecular cycloaddition are the key features of our approach.     

A Topological Approach to the Problem of Ring Structures

In the mechanized documentation of chemical literature, the definition of structural concept is very important. The usual for definitions for ring structures are inadequate. Essential ring structures are sometimes not recognized on the basis of these definitions and are therefore missed in a literature search. This is particularly true of bridged ring systems. The ring concept and ring condensation types are now redefined on a topological basis in the closest possible analogy to the intuitive approach of the chemist. In complicated molecular structures, these “fundamental rings” can be easily determined, either manually or by means of a programmed computer. The concept of the “ring complex” is defined and suggested as a preliminary screen in literature searches for ring structures. This will save machine time, and so reduce the cost of searches.     

Expedited approach to the vitamin D trans-hydrindane building block from the Hajos dione. Comparative study on various methods for the selective deoxygenation of one of the hydroxy groups in a diol

1 alpha,25-Dihydroxyvitamin D3 (calcitriol, 1) is a bioregulator important for the treatment of various human metabolic diseases and biomedical research. Herein, we report an efficient diastereoselective approach to the key trans-hydrindane building block for calcitriol synthesis (2a) starting from the readily accessible optically active tetrahydroindenedione derivative (Hajos dione, 3). It was found that epoxide ring opening in a related hydroxy epoxide (7) with sodium cyanoborohydride-BF3 x Et2O occurs by hydride anion addition at the ring juncture position to produce a vicinal diol with the trans-hydrindane ring system (6a). Four methods for selective deoxygenation of the sterically less shielded hydroxy group in diol 6a were examined with an approach based on a cyclic sulfate of the diol as the most efficient and operationally convenient method.     

Total synthesis of (+/-)-asteriscanolide.

The total synthesis of asteriscanolide (1) has been achieved by taking advantage on an intermolecular Pauson-Khand cycloaddition and a ring-closing metathesis as key bond-forming transformations. The approach incorporates the cyclooctane stereogenic center prior to ring formation. Interestingly, the ring-closing metathesis generates a new eight-membered ring with an "in-out" intrabridgehead relationship.     

Collective Synthesis of Chiral Tetrasubstituted Cyclobutanes Enabled by Enantioconvergent Negishi Cross-Coupling of Cyclobutenones

Cyclobutenones provide a straightforward four-carbon ring platform for further structural elaborations in that every carbon atom of the ring could be potentially functionalized. We report here a nickel catalyzed enantioconvergent Negishi coupling of 4-iodocyclobutenones with an array of aryl or alkenyl zinc reagents to access enantioenriched 4-substituted cyclobutenones, from which a modular approach to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was demonstrated.     

Synthesis of cryptophycins via an N-acyl-beta-lactam macrolactonization

An efficient and concise approach to the synthesis of the macrolide core of the cryptophycins has been developed. A novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate incorporates the beta-amino acid moiety within the 16-membered macrolide core. This modular approach, involving a cyanide-initiated acyl-beta-lactam ring opening followed by cyclization, was successfully applied to the total synthesis of cryptophycin-24. The strategy was also used in an efficient synthesis of the 6,6-dimethyl-substituted dechlorocryptophycin-52. In this case, the cyanide-initiated ring opening of the bis-substituted 2-azetidinone followed by macrolactonization was achieved through a catalytic process.     

Ring expansive routes to quinolizidine alkaloids: formal synthesis of (-)-lasubine II

The application of two nitrogen ring expansion reactions to lasubine alkaloid synthesis is reported. The approach involves a conjugate reduction/alkylation sequence carried out on triisopropylsilyl-protected (S)-4-(-)-hydroxycyclopentenone, the formation of the quinolizidone ring system through nitrogen ring expansion, and the addition of an arylmetallic species to the resulting lactam. This work resulted in the preparation of 2-epi-lasubine II and a formal synthesis of lasubine II. [reaction: see text]