Double cyclization structure

An impressive achievement of this strategy has been the construction of three-dimensional structures. Utilizing branched phenylacetylene sequences, double cyclization yielded macrobicyclic arrays 54 and 55 [43]. The zenith of Moore s approach is macrotricycle 56, a freely hinged system with a sizable 36xl2xl2A molecular cavity [44]. 

An unusual photochemical reaction of 2-pyridones, 2-aminopyridinium salts and pyran-2-ones is photodimerization to give the so-called butterfly dimers. These transformations are outlined in equations (13) and (14). Photodimerization by [2+2] cyclization is also a common and important reaction with these compounds. It has been the subject of particular study in pyrimidines, especially thymine, as irradiation of nucleic acids at ca. 260 nm effects photodimerization (e.g. equation 15) this in turn changes the regular hydrogen bonding pattern between bases on two chains and hence part of the double helix structure is disrupted. The dimerization is reversed if the DNA binds to an enzyme and this enzyme-DNA complex is irradiated at 300-500 nm. Many other examples of [2+2] photodimerization are known and it has recently been shown that 1,4-dithiin behaves similarly (equation 16) (82TL2651). 

The pure thiacyclols incorporating the cis cyclodipeptide structure have been subsequently prepared by mild double cyclization of the corresponding linear precursors [84JCS(P1)1153] (Scheme 19). 

Azacyclols arising from amide-amide interaction have been extensively investigated. The p-nitrophenyl ester (60) of the linear tripeptide N-benzyloxycarbonyl-L-alanyl-L-phenylalanyl-L-proline undergoes a double cyclization when left in an aqueous buffer-dioxane (1 1) solution for 1 h, to produce cyclol (61) (7 ICC 1605). The hydroxyl group of the cyclol could be converted to the methyl ether by treatment with methyl iodide-silver oxide. The structure of the cyclol (61) could be confirmed by X-ray crystallography of the corresponding p-bromobenzyloxycarbonyl derivative (7 ICC 1607). 

As indicated in the section describing the structures of natural dilactones, wentilactone B was wrongly assigned when the structure of 30-hydroxy-13,14,15,16-tetranorlabda-7,9(ll)-dien-(19,6(J),(12,17)-diolide was isolated. Our synthesis of this compound allows the reassignment of the structure of wentilactone B. Thus, the hydroxyl group of this natural podolactone should be relocated at C-2 with an a- configuration [87]. Two double cyclization steps were employed in this synthesis. The first involves the construction of the bicyclic skeleton via a Mn(III)-mediated... 

At this juncture, we felt confident that the chemistry was robust enough to explore a series of double cyclizations in this way access to polyvalent structures would be possible. The application of our methodology to the synthesis of P-C-trisaccharides (25) was therefore considered (Scheme 18). In order to attempt the double cyclizations, it became clear that an efficient synthesis of the required diacid was required and that the possibility of macrocycle formation and other competing side reactions had to be considered. 

In 2006 Fukuyama published a total synthesis of racemic morphine starting from isovanillin and a cyclohexene-epoxide [16, 17]. The key features in their synthesis are (1) a construction of the ether linkage between A and C rings by Tsuji-Trost coupling, (2) an intramolecular Heck reaction to construct A-C-E tricyclic system, and (3) an intramolecular Mannich-type reaction of a ketone with an aminal to provide the pentacyclic structure of morphine in a one-step reaction by double cyclization. 

Figure 34 PksA deconstruction, (a) Enzymatic domain architecture of PksA. (b) PksA utilizes a starter hexanoyl-CoA and seven malonyl-CoAs to produce the covalently linked intermediate (brackets). The PT domain acts as an aromatase/cyclase facilitating the closure of the first two rings on the intermediate. In the absence of the TE/CLC domain the intermediate undergoes C-O cyclization to spontaneously form the naphthopyrone. In the presence of the TE/CLC domain, the intermediate undergoes C-C cyclization to from the norsolorinic acid anthrone, which autooxidizes to form norsolorinic acid, (c) Observed PPant ejection ions confirming the structures of the proposed intermediates bound to the active site of the PksA T domain. The first intermediate (left) was detected on the T domain active site after incubation of SAT-KS-MAT with T domain alone. Incubation of SAT-KS-MAT with PT-T results in the formation of the intermediates containing first a single-cyclization product (middle) followed by a double-cyclization product (right).

MacDowell and Patrick127 effected cyclization of 359 to a diketone (24%, m.p. 335°C) and reduction to 360 (22%, m.p. 216°C) (Scheme 29). However, their sample of 360 appears to be different from the product of m.p. 292°C described by Friedmann, and ascribed structure 360, from the reaction of sulfur with indene at 180°C.1,128 MacDowell and Patrick obtained only intractable tar from the Friedmann procedure. A double cyclization was also employed by Cagniant and co-workers (Scheme 30). 29... 

The first total synthesis of tryptoquivaline G (FTG) was achieved by Biichi et al. (158) (Scheme 15), which confirmed the proposed structure and established the relative and absolute configurations. Subsequently, Ban s group (159) effectively prepared Biichi s intermediate (90) through thallium(III) trinitrate (TTN) oxidation at a crucial step of spirolactonization. More recently, Hino s group achieved a short-step total synthesis of tryptoquivaline (160,161) and tryptoquivaline G (162) through oxidative double cyclization of the N-acyltryptophan precursor with A-iodosuccinimide (NIS) in CF3COOH (Scheme 16). 

In the dihydro-1,2,4-trithiin series, the solid-state structures of the dimer 58 <1997AXC748> (obtained as a side product during the intramolecular double cyclization of m-disodium ethene-l,2-dithiolate with I2/KI at —10°C in a... 

The polymers from the three compounds will have ladder-type structures. However, the polymers from compounds B and C will have at least one and two skeletal bond(s) per repeating unit while a double-cyclization polymer will result from compound A. The presence of one or two consecutive single bonds between aromatic units will enhance polymer susceptibility to thermal degradation. In principle, therefore, under identical conditions the thermal stability of the resulting polymers will be A more than B more than C. 

The cyclization of arynes can be applied to the synthesis of various polycyclic aromatics. Hexabenzo[a,c,g,/,w,o]triphenylene (260) was obtained as a single product in 39 % yield from 9,10-didehydrophenanthrene generated from 259 [80]. Cyclization of 3,4-didehydrophenanthrene 261 gave rise to the polycyclic compound 262, which has a double helicene structure, in 26 % yield [81]. 

Structurally interesting polycyclic aromatic hydrocarbons can be readily constructed by using a cyclization method, for which the reactions in Equations 10.32-34 are representative examples [53-55]. In the double cyclization of Equation 10.33, the arylation of the C(sp )-H bond as well as that of the C(sp )-H bond is involved. 

FIGURE 10.3 Common methods of interlocked structure formation. Cyclization (a) and double cyclization (b) of catenanes. Clipping (c), stoppering (d), and snapping (e) approaches for rotaxane synthesis. 

In the screening of solvents for the domino cyclization of allenes with 2-formylindoles 47 (Scheme 27), PEG 400 was found to provide the highest yield [51]. The reactions proceeded better in case of 3-chloro substituted 2-formylin-doles 47 (X=C1) without this substitution, only arylallenyl phosphonates were involved in the reaction though providing the products with lower yields (50-60%). Interestingly, the reaction of methylallenyl phosphonates proceeded with the addition to another double bond. Structures of the compounds were confirmed by X-ray crystallography. 

Also in 2010, the Jacobsen group reported the combined use of hydrochloric acid and thiourea catalysts for the highly enantioselective cationic double cyclization reaction initiating from an A-acyliminium ion (Fig. 23) [78]. The catalyst optimization research led to the identification of a pyrenyl-substituted thiourea structure, which seems to indicate the importance of cationic-Ti interaction during this reaction. 

Although the structures of the four isolated compounds could not be proved completely, they are characterized as tricyclic systems, formed by double cyclization of the substrate during the oxidative conversion (see also 13.1.6. and 13.1.11.). 

More recently the addition of a,j -unsaturated carboxylic acids to polydienes such as cis-1,4-polybutadiene (1,4-P), 1,2-polybutadiene (1,2-PB) and polypentenamer poly(l-pentenylene) (PP) was investigated in the presence of acid catalysts the products are cyclized rubbers with pendent a,j -unsaturated carboxylate groups. It was shown that acid adds only to the original double bonds of the polydienes and not to those of cyclized structure, with cyclization taking place in the following order 1,2-PB > 1,4-PB > PP. 

In the alkylative cyclization of the 1,6-enyne 372 with vinyl bromide, formation of both the five-membered ring 373 by exn mode carbopalladation and isomerization of the double bonds and the six-membered ring 374 by endo mode carbopalladation are observed[269]. Their ratio depends on the catalytic species. Also, the cyclization of the 1,6-enyne 375 with /i-bromostyrene (376) affords the endo product 377. The exo mode cyclization is commonly observed in many cases, and there are two possible mechanistic explanations for that observed in these examples. One is direct endo mode carbopalladation. The other is the exo mode carbopalladation to give 378 followed by cyclopropana-tion to form 379, and the subsequent cyclopropylcarbinyl-homoallyl rearrangement affords the six-membered ring 380. Careful determination of the E or Z structure of the double bond in the cyclized product 380 is crucial for the mechanistic discussion. 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

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