Pentacyclic skeleton

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

Roseophilin (273), a deeply red-colored pentacyclic compound isolated from the culture broth of Streptomyces griseoviridis, is a novel antitumor antibiotic. Compound 273 possesses a topologically unique pentacyclic skeleton, consisting of a 13-membered macrocycle incorporated in an ansa-bridged azafulvene, which in turn is linked to a conjugated heterocyclic ring system. The absolute stereochemistry of roseophilin, as depicted in Fig. 9, was unknown until the first total synthesis published by Tius and Harrington in 2001 [125]. All syn-... 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

A new strategy has been developed for the construction of pentacyclic skeletons of alkaloids such as (-)-alloyohimbane [(-)-365] starting from optically active carbohydrate levoglucosenone (397). 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

In a synthesis of aspidospermidine [232] an alkylative rearrangement was employed to gain entry into the pentacyclic skeleton. 

Rh-mediated C-H insertion is also useful for carhocyclic construction, as illustrated by the new asymmetric route to (+)-morphine (11) recently reported by White [6]. Cyclopentane formation is used to fashion a pentacyclic skeleton (10) from which the piperidine ring of 11 is evolved at a later stage. 

Two novel alkaloids with an unprecedented fused-pentacyclic skeleton, daphmanidins C (68) and D (69), consisting of l-azabicyclo[5.2.2]undecane, hexahy-dronaphthalen-l-one, and cyclopentane rings, have been isolated from the leaves of D. tdjsmanii [79]. Daphmanidin C elevated the activity of NGF biosynthesis. New daphniphyllum alkaloids, daphmanidins E (70) and F (71), have also been isolated from the leaves of D. teijsmannii, and Daphmanidins E and F showed a moderate vasorelaxant effect on rat aorta [80]. 

The synthesis of alnusenone (119) utilized a different method of assembling the pentacyclic skeleton. Condensation of the ketones (120) and (121) led via the tetracyclic ketone (122) to two pentacyclic ethers (123) and (124). The trans,anti,cis-stereochemistvy of (123) was confirmed by X-ray analysis. The desired trans,anti,trans-ether (124) was transformed into alnusenone (119). 

Intramolecular Heck substitution reactions have been key steps in several recent synthetic endeavors directed toward Strychnos alkaloids (Scheme 6-11). In 1993, Rawal and coworkers reported a short stereocontrolled total synthesis of ( )-dehydrotubifoline (62) in which vinyl iodide 61 was converted to pentacycle 62 in good yield using Jeffery s cyclizatioti conditions [22]. Of note in this construction of the core pentacyclic skeleton of... 

Kopsia pauciflora also provided several new alkaloids (268 - 271) [174] possessing a pentacyclic skeleton similar to that of kopsijasminilam (272), deoxykopsijasminilam (273) and 14,15-dehydrokopsijasminilam (274) from the Thai species Kopsia Jasminiflora. The structure of272 was established by X-ray analysis [ISO]. These rare alkaloids can be considered as being derived from an aspidofractinine-type precursor by cleavage of the C(21)-C(20) bond. In pauciflorine A (268) and B (269), the double bond is located between C(19) and C(20) while in... 

Examples of migratory insertion to aromatic rings also include the total syntheses of anhydrolycorine-7-one (217) [102] and the f-azaebutnane series [103]. As illustrated in Scheme 38, an intramolecular Heck reaction of Af-acylindoline 216 installed the six-membered lactam in anhydrolycorine-7-one (217). In a similar process, the tetracyclic pyrido-[2 ,3 -prepared from bromopyridine 218 under phase-transfer catalysis conditions. Pyridyl indole 219 is a precursor of the pentacyclic skeleton of the E-azaeburnane series. 

The enaminone 124 on acylation with acryloyl chloride furnished mainly 127 by the intramolecular addition of enamine to the acrylamide moiety in initial intermediate 125 (Z = COCH = CH2). The cyclization of 127 is affected by TiCl4 to form aspidosperma alkaloid pentacyclic skeleton 128 (91T4165). 

In addition to their use in Mannich (and variant) reactions, iminium ions are useful for other cationic type cyclizations. Corey employed a novel tandem iminium ion cyclization as part of an elegant cascade used for the synthesis of aspidophytine. The reaction of tryptamine 292 and dialdehyde 293 in CH3CN at ambient temperature afforded the pentacyclic skeleton of the alkaloid (296 Scheme 54) (99JA6771). Condensation of the free amino functionality of 292 with the dialdehyde produced a dihydropyridinium intermediate 294 that then cyclized onto the indole n-bond to give 295. The iminium ion so produced underwent a second cyclization with the tethered allylsilane moiety to give 296. Protonation of the enamine in 296 provided still another iminium ion (297) that was then reduced with NaCNBH3 to furnish 298 in 66% yield. All of the above reactions could be made to occur in a single pot. 

A further intramolecular example of this approach Involving photo-spirocyclizatlon of N-silylallyl iminium salts has been employed in the construction of the pentacyclic skeleton of the Harring-tonine alkaloids irradiation of the iminium salt (139) in... 

Enamino ketoester 159 (in equilibrium with the corresponding imidizolidine) efficiently underwent aza-annulation with acryloyl chloride in the presence of pyridine and DMAP to give 160 (eq. 34).60 This dihydropyridone was then converted to 161, the pentacyclic skeleton of the 21-epimer of the aspidospermine alkaloids. 

Diels-Alder reactions. In an intramolecular cycloaddition approach to construct the pentacyclic skeleton of eburnamonine the catalytic system of LiCI04-Et20 is insufficient. The addition of 10 mol % of CSA is required. 

A more significant result is the twofold cyclization that completes the pentacyclic skeleton of certain Strychnos alkaloids. The product is converted to akuammicine in two more steps. 

Retrosynthetic analysis leads a new strategy in the synthesis of the ABC core using a Bradsher cycloaddition [83]. Cleavage of the resulting oxazolidinone ( Scheme 22) and a subsequent series of reactions gave a suitably substituted tricyclic core, which can be used in the synthesis of the pentacyclic skeleton ABCDE. 

C24H41O7N, would require the presence of a saturated pentacyclic skeleton this is unlikely to be correct, since the ultraviolet absorption spectrum of lycoctonine (75) is similar to that of aconine between 2200 and 2600 a. and exhibits a maximum near 2200 a. This maximum, not hitherto established in aconine (the absorption of which has not been examined below 2200a.), may be ascribed to an ethylenic linkage in the o , 3-position to the nitrogen atom (C=C— N chromophore), analogous to that assumed to be present in aconine and delphonine. 

The Padwa group then applied this methodology to expeditiously assemble the pentacyclic skeleton of the Aspidosperma family of alkaloids [58, 59]. When diazoimide 98 was treated with a catalytic quantity of rhodium (II) acetate in benzene at 50°C, the cycloadduct 100 was isolated in 95% yield as a single diastereomer (Scheme 25). Compound 100 was further elaborated in subsequent steps to desacetoxy-4-oxo-6,7-dihydrovindorosin (101), a close analog of vindo-line (102). 

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