Tetracyclic Enone Research Articles

Construction of Substituted [4]Acene Frameworks Based on Double Cationic Cyclizations of Fluoroalkenes

AbstractIn this study, 5-substituted and 5,6-disubstituted [4]acenes were synthesized by the double cationic cyclization of fluoroalkenes. (a) After being treated with Me2AlCl (1.2 equiv), 2-trifluoromethyl-1-alkenes bearing two aryl groups underwent domino Friedel–Crafts-type cyclization (two-ring construction) followed by dehydrogenation to generate 5-fluorinated [4]acenes. The same (trifluoromethyl)alkenes were treated with both Me2AlCl (1.2 equiv) and Me3Al (1.0 equiv), resulting in selective one-ring construction and the creation of bicyclic 1,1-difluoro-1-alkenes. (b) When treated with triflic acid, the bicyclic difluoroalkenes underwent regioselective protonation to generate CF2 cations; Friedel–Crafts-type cyclization of these cations provided tetracyclic ketones. The obtained ketones act as an appropriate platform for the introduction of substituents at the 5-position of [4]acenes. (c) When treated with DDQ/H+, the bicyclic difluoroalkenes underwent oxidative generation of allylic CF2 cations; Friedel–Crafts-type cyclization of these cations produced tetracyclic enones. The enones were subjected to double addition of carbanions to facilitate the introduction of two substituents at the 5- and 6-positions of dihydro[4]acenes.

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels

A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca2+ channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective reductive Robinson annulation was discovered for the formation of optically pure tricyclic terpenes. Stereoselective addition of cyanide to the hindered α-face of tetracyclic enone (−)-18 was found and subsequent transformation into the aldehyde function was affected by the formation of bicyclic hemiiminal (−)-4. Six selected synthetic tetracyclic terpenes show inhibitory activities in ET-1 induced vasoconstriction in the gerbil spiral modiolar artery with putative affinity constants ranging between 93 and 319nM. Moreover, one compound, (−)-3, was evaluated further and found to inhibit voltage-activated Ca2+ currents but not to affect Na+ or K+ currents in dorsal root ganglion cells under similar concentrations. These observations imply a dual mechanism of action. In conclusion, tetracyclic terpenes represent a new class of hit molecules for the discovery of new drugs for the treatment of pulmonary hypertension and vascular related diseases.

First Total Synthesis of Rhodexin A

An efficient total synthesis of rhodexin A (1) is reported. An initial inverse-electron-demand Diels-Alder reaction of the acyldiene 6 with the silyl enol ether 7 gave the cycloadduct 8 with the required 4 contiguous stereocenters in a single step. This compound was then transformed into the tetracyclic enone 16, which was converted to rhodexin A (1).

Gold‐Catalyzed Tandem Intramolecular Heterocyclization/Petasis–Ferrier Rearrangement of 2‐(Prop‐2‐ynyloxy)benzaldehydes as an Expedient Route to Benzo[b]oxepin‐3(2 H)‐ones

Partially or fully hydrogenated benzo[b]oxepines are common ring motifs found in many pharmaceutically interesting and potentially bioactive natural compounds. Representative examples range from the structurally simple and bioactive heliannuol A, pterulone, and radulanin A to the architecturally challenging compounds edulisone A and ovafolinin B. For this reason, the establishment of new synthetic methods to construct this biologically important class of compounds has received an immense amount of attention. The synthetic strategies toward functionalized benzo[b]oxepines can be divided into two groups: manipulation of a pre-existing oxygen-containing cyclic core or assembly from acyclic precursors. Despite the advances made through both these approaches, the development of new synthetic methods to prepare this class of oxygen heterocycles from readily available substrates and catalysts with selective control of substitution patterns under mild and operationally simplistic conditions remains desirable. The emergence of gold complexes as powerful and versatile Lewis acid catalysts that can mediate a plethora of C X (X=C, N, O, S) bond formations has been well documented in recent years. Among this myriad of works, one notable innovation has been the formation of carbocycles and heterocycles from cyclization of a carbonyl compound tethered to an alkyne in the presence of a gold catalyst. For example, Yamamoto and Jin recently reported an efficient synthetic route to fused triand tetracyclic enones based on the AuCl3/AgSbF6-catalyzed tandem heteroenyne metathesis/Nazarov cyclization of 1,3-enynyl ketones. On the basis of this and other previous studies on carbonyl metathesis, we reasoned that a strategy that made use of Opropargylated salicylaldehydes in the presence of a Lewis acid gold catalyst would hold promise as a new method for benzo[b]oxepin-3 ACHTUNGTRENNUNG(2H)-one synthesis. As part of an ongoing program exploring the scope of gold catalysis in heterocyclic synthesis, our discovery that Au complex 3 can effect tandem intramolecular heterocyclization/Petasis–Ferrier rearrangement of 2-(prop-2-ynyloxy)benzaldehydes is reported herein (Scheme 1). This process provides a convenient synthetic route to benzo[b]oxepin-3ACHTUNGTRENNUNG(2H)-ones in 21– 99% yield for a wide variety of substrates under mild and operationally simplistic conditions that did not require the exclusion of air or moisture. A study that delineates the influence on reactivity of a substituent at the ortho position to the ethereal moiety on the salicylaldehyde is also presented. To the best of our knowledge, synthetic methods involving metal-mediated cyclizations of propargylic aldehydes of type 1 have thus far been reported to typically give the benzopyran product. We began by examining the cyclization of 1a by a variety of Lewis and Bronsted acids to establish the optimal reaction conditions (Table 1 and Table S1 in the Supporting In[a] E. M. L. Sze, Dr. W. Rao, M. J. Koh, Prof. Dr. P. W. H. Chan Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 (Singapore) Fax: (+65)6791-1961 E-mail : waihong@ntu.edu.sg Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201003096. Scheme 1. Gold(I)-catalyzed synthesis of benzo[b]oxepin-3 ACHTUNGTRENNUNG(2H)-ones from 2-(prop-2-ynyloxy)benzaldehydes. R=H, alkyl, aryl, halide, or NO2; R , R=H or alkyl.

Gold-Catalyzed Synthesis of Polycyclic Enones from Carbon Tethered 1,3-Enynyl Carbonyls via Tandem Heteroenyne Metathesis and Nazarov Reaction

An efficient and general Au(III)-catalyzed tandem reaction, heteroenyne metathesis and Nazarov cyclization, of 1,3-enynyl ketones to produce fused tri- and tetracyclic enones has been developed. The products were formed with excellent regioselectivity of the double bond position and with very high diastereoselectivities. In this reaction, the Au(III) catalyst exhibits dual roles for activating both alkynes and carbonyls.

Biosynthetic Studies of Platensimycin

Platensimycin is a novel Gram-positive broad spectrum antibiotic that inhibits bacterial growth by specifically and potently inhibiting the condensing enzyme (FabF) of the fatty acid biosynthesis pathway. It is produced by several strains of Streptomyces platensis and comprises a 3-amino-2,4-dihydroxybenzoic acid and C-17 tetracyclic enone moieties linked by an amide bond. Feeding experiments using 13C precursors suggest that the aminobenzoic acid unit is derived from the TCA cycle, and the tetracyclic enone moiety of platensimycin in S. platensis is derived from the non-mevalonate MEP terpenoid pathway by oxidative excision of three carbons from ent-kaurene.

Sequential Diels-Alder and Cobalt Octacarbonyl Catalyzed Pauson-Khand Reactions in the Formation of Polycyclic Enones

Sequential reactions of Diels-Alder and Pauson-Khand reactions between dienynes and dienophiles in a one-pot reaction have been demonstrated using 10 mol% dicobalt octacarbonyl. Synthesis of tetracyclic enones is reported.

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.

Synthesis of a pentacyclic lactone related to quinovaic acid and emmolactone using an anionic polycyclization strategy

In an effort to discover a versatile and convergent synthesis of pentacylic triterpenes, we have synthesized a tetracyclic enone via a highly stereocontrolled cycloaddition between a Nazarov precursor and a cyclohexenone followed by an aldol condensation. Introduction of a C14 nitrile was made by hydrocyanation on a protected derivative of this tetracyclic enone. Reduction and subsequent hydrolysis of the latter intermediate concluded this expedient synthesis of a pentacyclic lactone.

Total synthesis of (+/-)-scopadulin.

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.

A scalemic synthesis of the scopadulcic acid skeleton. II: Ring-D formation via regiospecific intramolecular aldol and alkylation reactions

The propensity of abietenones such as 2 to form exclusively the extended enol(ate) into ring-B can be curbed by introducing an alkoxy group at C-7 in the abietane framework. Thus, the 7- trimethylsilyloxy enone-aldehydes 11 and 13 cyclize to form only the C-12 aldol products 12 and 14. Furthermore, the 9-iodoethyl-12-methyl-enone 19 cyclizes via its putative enol to give only the tetracyclic enone 20. Compounds 12 and 20 contain the complete carbon skeleton of scopadulcic acid B.

Synthetic Studies on Aphidicolane and Stemodane Diterpenes. IV. A Stereoselective Formal Total Synthesis of (.+-.)-Aphidicolin.

A formal total synthesis of (±)-aphidicolin (1) was accomplished starting from the tricyclic ketone (2) corresponding to the B/C/D ring system. The quaternary carbon center adjacent to the spirocarbon was constructed stereoselectively by conjugate addition of a methyl group to the enone (7) obtained from 2 in a four-step sequence. The tetracyclic enone (3) was obtained via acid-catalyzed intramolecular aldol condensation of the tricarbonyl compound (10) followed by 1,3-carbonyl transposition, in which Pd(O)-catalyzed reductive deacetoxylation of γ-acetoxy-α,β-enone (15) was a crucial step. The A-ring manipulation was performed by a similar procedure to the Ireland method to give the keto-acetonide (4), a degradation product of 1, which has already been efficiently reconverted to 1

Synthetic Studies on Aphidicolane and Stemodane Diterpenes. V. A Facile Formal Total Synthesis of (.+-.)-Aphidicolin via a Lewis Acid-Mediated Stereoselective Spiroannelation.

Formal total synthesis of (±)-aphidicolin (1) was achieved via a Lewis acid-mediated stereoselective spiroannelation reaction as a key step. The bisbenzyl acetal (2) was synthesized from the readily available dimethyl acetal (4). Treatment of 2 with trimethylsilyl trifluoromethanesulfonate (TMSOTf) afforded a 69 : 31 mixture of the spirocyclic enones (9 and 10) in excellent yield. The tricyclic ketal-ketone (3) corresponding to the B/C/D rings of 1 was easily generated from the enone (9) by intramolecular alkylation and catalytic hydrogenation as principal steps. The A-ring construction was performed by a procedure similar to one used previously. Barbier reaction of 14, followed by oxidative rearrangement, stereoselective 1, 4-addition of a methyl group, and subsequent intramolecular aldol-condensation afforded the tetracyclic enone (18), which has already been transformed into (±)-aphidicolin (1).

The structure of a tetracyclic enone containing the 5–7–6 ring system of the tiglianes

Le 1,2,3,6a,7,8,9,10b-octahydro-9-oxa-3,6-epoxy-3aH,6H-benzo [e] azulene, C 14 H 16 O 2 , cristallise dans P2 1 /n avec a=5,7314, b=15,577, c=12,334 A, β=90,11 o , Z=4; affinement jusqu'a R=0,025. Le cyclopentane est dans une conformation demi-chaise, tandis que le cycle pyrane est dans une conformation bateau ideale. Le cycloheptene se presente sous forme d'un bateau deforme, le cyclohexanone sous forme d'un soja deforme. Il existe une jonction quasi-trans entre le cyclohexenone et le cycloheptene. Le cyclopentane et le cyclohexenone ont fusionne de facon trans a travers le cycloheptene