Synthesis of dicyclopenta[a,e]pentalenes via a molybdenum carbonyl mediated tandem allenic Pauson-Khand reaction and the X-ray crystal structure of a planar dicyclopenta[a,e]pentalene

Two 14 pi cross-linked annulenes which belong to the family of dicyclopenta[a,e]pentalenes have been synthesized, 14 pi bis enol triflate ester 27 and the 3,7-diisopropylsilyl substituted 14 pi dicyclopenta[a,e]pentalene 30. The new allenic tandem Pauson-Khand reaction mediated by Mo(CO)(6) was employed as the key process to construct the core of the tetracycles. The two linear dicyclopenta[a,e]pentalenes 27 and 30 underwent significant electronic delocalization, perhaps even aromaticity, as revealed by the X-ray structure of 27. The tetracyclic rings in 27 assumed a flat geometry (Figure 4); the bond lengths of the tetracycle in 27 also fit well into the criteria for aromatic compounds. A comparison of the NMR and UV spectra of both 27 and 30 demonstrated that they both exhibited similar electronic properties, therefore, the purple colored 14 pi cross linked annulene 30 is planar as well as delocalized.     

The synthesis of a dicyclopenta[a,e]pentalene via a molybdenum hexacarbonyl-mediated tandem allenic Pauson-Khand reaction

An approach to the 14pi annulene has been developed, by employing the molybdenum hexacarbonyl-mediated tandem allenic Pauson-Khand reaction as a key step. A di-triisopropylsilyl substituted dicyclopenta[a,e]pentalene was synthesized. This 14pi annulene showed some electronic delocalization, which was not observed in previous cases.     

Light-induced coumarin cyclopentannelation

[reaction: see text] Whereas cyclopentenylcarbenes resulting from photocycloaddition of 4-alk-1-ynylcoumarins to 2,3-dimethylbut-2-ene undergo tandem cyclization to hitherto unknown tetracyclic (4-hetera)cyclopent[b,c]acenaphthylenes, the corresponding cyclopentenylnitrenes stemming from 4-cyanocoumarins and the same alkene are converted into tricyclic imines via H-abstraction.     

Generation of N-acyliminium ions via intramolecular conjugate addition reactions: a strategy for the total synthesis of nakadomarin A

[reaction: see text] The rapid construction of the tetracyclic core ring system of nakadomarin A via a tandem enecarbamate Michael addition/N-acyliminium ion cyclization is described.     

General approach for the synthesis of 12-methoxy-substituted sarpagine indole alkaloids including (-)-12-methoxy-N(b)-methylvoachalotine, (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline

[structures: see text] The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Sch?llkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-N(b)-methylvoachalotine in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross-coupling processes served as key steps. The quaternary center at C16 of 12-methoxy-N(b)-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-N(a)-methylvellosimine and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion at [C6] to form a cyclic ether [C6-O17]. After oxidative formation of the alpha-ester at C16, the ether bond was reductively cleaved with TFA/Et3SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids.     

Construction of the Tricyclo

Histrionicotoxin derivatives have long been attractive targets for synthetic chemists as a result of their useful neurophysical properties, low natural abundance, and the unique structural features of the azaspiro[5.5]undecane ring system. Utilizing our tandem pinacol rearrangement-ene strategy and regiospecific Baeyer-Villiger oxidation as key steps, we have successfully synthesized an advanced synthetic intermediate, spiro[5.4]decane 4, which has previously been converted to (+/-)-perhydrohistrionicotoxin (5b). Pinacol rearrangement of simple Diels-Alder derived bicyclo[2.2.2]octene system 2a, followed by an ene reaction, led to the efficient formation of the highly fuctionalized tricyclo[5.3.1.0(1,5)]undecane system 1a. This tricyclic system 1a was selectively transformed into spiro[5. 4]decane system 4 via a regiospecific Baeyer-Villiger oxidation reaction. We also report the results of systematic studies of Baeyer-Villiger oxidation reactions of tricyclo[5.3.1.0(1, 5)]undecanone systems to elucidate the origin of the regioselectivity of this process.     

Reactivity of functionalized N,S-ketene acetal: regioselective construction of tetrahydrobenzo[b]pyran and chromeno[2,3-b]quinoline derivatives

Regioselective synthesis of functionalized tetrahydrobenzo[b]pyrans has been developed by multicomponent reactions (MCRs) and tandem [3 + 3] annulations of β-benzoylthioacetanilides or β-(2-haloaroyl)thioacetanilides as valuable sources with aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione catalyzed by triethylamine. This MCR followed by a postcondensation cyclization via an intramolecular S(N)Ar in the presence of K(2)CO(3) led to an unprecedented novel chromeno[2,3-b]quinoline framework containing an important chromene moiety in good yields. The reactions were very mild, convenient, and o-selective to form new fused tetracyclic target molecules.     

Synthesis of a tricyclic mescaline analogue by catalytic C-H bond activation

[reaction: see text] A tetrahydrobis(benzofuran) mescaline analogue has been prepared in six steps and 38% overall yield from (4'-O-methyl)methyl gallate. The key step in this synthesis is a tandem cyclization reaction via directed C[bond]H activation followed by olefin insertion.     

A transient N-O-linked Pauson-Khand strategy for the synthesis of the deschloro carbocyclic core of the palau'amines and styloguanidines

A stereocontrolled route to the deschloro cyclopentyl core of the palau'amines and styloguanidines has been developed. This strategy makes use of the intramolecular Pauson-Khand cyclization of an enyne with a "transient N-O tether" to construct a five-membered carbocycle in a diastereoselective fashion. [reaction: see text]     

Regiospecific, enantiospecific total synthesis of the 12-alkoxy-substituted indole alkaloids, (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline

[reaction: see text] The enantiospecific synthesis of 7-methoxy-d-tryptophan was completed by combination of the Larock heteroannulation process with a Sch?llkopf-based chiral auxiliary in good yield. This ester was then employed in the first total synthesis of (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline in regiospecific, stereospecific fashion in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross coupling processes served as key steps.     

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]     

Synthesis of bridged medium-sized rings through the intramolecular Pauson-Khand reaction

[reaction: see text] A series of aromatic enynes containing steric buttressing elements were prepared and evaluated in the NMO-mediated Pauson-Khand cyclization. O-Allyl systems led to the expected angularly fused products, whereas the O-butenyl and O-pentenyl derivatives afforded the unprecedented bridge systems.     

Synthesis of a ketone analogue of biotin via the intramolecular Pauson-Khand reaction

We report an improved synthesis of 5-(5-oxohexahydrocyclopenta[c]thiophen-1-yl)pentanoic acid (ketone biotin, 1) based on the intramolecular Pauson-Khand cyclization. The synthesis proceeds in eight steps and in 2.7% overall yield from cyclohexene.     

Dragmacidin E synthesis studies. Preparation of a model cycloheptannelated indole fragment

[reaction: see text] The conversion of N-2,2-dichloropropionyl indole methyl ester into a tetracyclic cycloheptannelated indole model compound for the synthesis of dragmacidin E was accomplished in 10 steps. Key reactions include a Witkop cyclization to fashion a C-C bond at C(4) of the indole nucleus and a subsequent Dieckmann cyclization to deliver the desired cycloheptanoid ring.     

Total synthesis of diptoindonesin G via a highly efficient domino cyclodehydration/intramolecular Friedel-Crafts acylation/regioselective demethylation sequence

A highly efficient total synthesis of diptoindonesin G is described employing a domino dehydrative cyclization/intramolecular Friedel-Crafts acylation/regioselective demethylation reaction of aryloxyketone 7 by the action of BCl(3) wherein the tetracyclic 6H-anthra[1,9-bc]furan-6-one skeleton was constructed via the 3-arylbenzofuran in a one-pot manner. This is the first example of the strategic combination of these three reactions in a cascade fashion. The routes presented here allow for direct access to diptoindonesin G and its analogues.     

First approach to the frondosin C ring system via a tandem cyclization/Claisen rearrangement sequence

[reaction: see text] A one-pot tandem 5-exo cyclization/Claisen rearrangement strategy is utilized as the key step in the straightforward construction of the tetracyclic ring system of frondosin C. This reaction is done under microwave irradiation in the presence of catalytic MeLi.     

Synthesis of anti-HIV lithospermic acid by two diverse strategies

An efficient and convergent route for the synthesis of the natural product (+)-lithospermic acid, which possesses anti-HIV activity, was accomplished. The (±)-trans-dihydrobenzo[b]furan core therein was prepared by two different strategies. The first strategy involved the use of a palladium-catalyzed annulation to generate an appropriately substituted benzo[b]furan ester followed by a stereoselective reduction of a carbon-carbon double bond with Mg-HgCl(2)-MeOH. The second strategy relied on an aldol condensation between a suitably substituted methyl arylacetate and 3,4-dimethoxybenzaldehyde, followed by cyclization. Finally, a total synthesis of (+)-lithospermic acid was completed via coupling of a trans-dihydrobenzo[b]furan cinnamic acid with an enantiomerically pure methyl lactate.     

Reaction of 2-Oxoindolin-3-Ylidene Derivatives with Heterocyclic Enamines. A Convenient One-Pot Synthesis of Pyrimido [5,4:5',6']Pyrido[2,3-b]-Indole-2,4-Dione and Spiro Indolin-2-One-3,5'-Pyrido [2,3-d] Pyrimidines

The reaction of 6-aminouracils 2a, b with 2-oxoindolin-3-ylideneacetophenones 1a-h afforded Pyrimido[5,4:5', 6'] pyrido-[2, 3-b] indole- 2,4-diones 3 a-k via a regiospecific Michael addition, followed by cyclization. Alternatively, the reaction of 2a with 2-oxoindolin-3-ylidenemalononitriles 6a, b gave rise to regiospecific formation of spiro indolin-2-one-3, 5'-pyrido[2,3-d]pyrimidines 7a,b.     

A Pauson-Khand approach to the synthesis of ingenol

[reaction: see text] Pauson-Khand cyclization of dioxanone photoadduct 21 leads to the formation of a single product in good yield. However, retro-aldol fragmentation of the pentacyclic cyclopentenone 22 leads to the formation of 23, with cis C-8/C-10 intrabridgehead stereochemistry, unlike the target compound ingenol 1, which possesses C-8/C-10 trans intrabridgehead stereochemistry.     

A new efficient synthesis of pyranoquinolines from 1-acetyl N-aryl cyclopentanecarboxamides

A new efficient synthesis of pyrano[2,3-b]quinoline derivatives is developed via the H2SO4-mediated tandem cyclization/ring-opening/recyclization reaction of readily available 1-acetyl N-aryl cyclopentanecarboxamides, during which a novel ring-cleavage fashion of the cyclopentane unit is involved and possible mechanisms are discussed.