Double cyclization synthesis

Scheme 9.17 Domino reductive ring-opening/double cyclization synthesis of phosphodiesterase (PDE) IV inhibitor.

Scheme 9.21 Domino Smij-mediated reductive dialdehyde double cyclization synthesis of (—)-maoecrystal Z.

Scheme 92. Synthesis of cu-alpinigenine (445) and alpinigenine (441) by photochemical double cyclization. Reagents a, Mel b, IRA-400 c, A d, NBS, 1 N HO e, HI04, H2S04 f, Av, /-BuOH.

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

The first synthesis of an optically active isopavine, (—)-reframoline (29), has been achieved by the acid-catalyzed double cyclization process described previously. The properly substituted diarylamine 109 was resolved using (-t-)-di-benzoyltartaric acid to afford the (-I-) enantiomer. Conversion to the acetal 110 was accomplished without racemization. Subsequent acid-catalyzed cyclization yielded the levorotatory alkaloid 29 (Scheme 21) 112). 

A facile acid-catalyzed double cyclization of A,A-dibenzylaminoacetaldehyde dialkyl acetals of type 125 has been known to generate l-azadibenzo[c,/]bicy-clo[3.3.1]nona[3,6]dienes 126 in high yields 120,121,147). A novel and convenient synthesis of ( )-amurensinine (25) and ( )-reframine (28) (Scheme 25) proceeds from the quaternary salt 127, where proper choice of base and reaction... 

A stereoselective one-pot synthesis of furo[3,2- ]pyran, 80, has been reported. The key step in the synthesis includes a double cyclization reaction along with a rearrangement (Scheme 16) <1998TL3605>. 

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... 

Zhang and Tempest optimized the Ugi/de-Boc/cyclization synthesis for quinoxahnones 27 and benzimidazoles 28 developed by Humles (Scheme 19) [47]. The original thermal reactions required 36-48 h for the Ugi reaction and the condensed products were purified by double scavenging with an immo-... 

The primary synthesis of 1,5-naphthyridines may be accomplished by double cyclization of appropriate aliphatic substrates by cyclization of appropriately substituted pyridines by cyclocondensation of pyridine substrates with one or more aliphatic synthons or from other heterocyclic substrates by degradation, rearrangement, or the like. Partially or fully reduced 1,5-naphthyridines are often made by somewhat similar procedures such cases are usually illustrated toward the end of each subsection. Some reviews of naphthyridine chemistry contain material on the primary synthesis of 1,5-naphthyridines49 52 61 231 265 670 1260 1273 1430 1432... 

A biogenetic-type synthesis of the bicyclic penicillin-cephalosporin antibiotics from an acyclic tripeptide equivalent involves a double cyclization of compound (383) to form both the thiazoline and the /3-lactam rings in one step (384 Scheme 235) (75JA5008). 

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. 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

This method has been applied to the synthesis of various polycyclic aromatic compounds [91]. Among the interesting applications are lactone formation in the preparation of natural products having biaryl skeletons (Eq. 42) [87] and double cyclization leading to spirocyclic compounds (Eq. 43) [92] and a fullerene fragment (Eq.44) [93]. 

Double cyclizations to butenolides and furanes. Radicals can undergo intramolecular addition to triple bonds when separated by three carbons. This strategy can be used for synthesis of butenolides (equation 1) and -substituted furanes (equation II). Cyclization of vinyl bromides." Fused and bridged ring systems can be prepared... 

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. 

An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer s enantioselective synthesis of a heteroyohimbine alkaloid, (-t-j-B-isorauniticine (267) [117]. Substrate 263 was prepared from a commercially available glycinate equivalent by Malkylation, installation of the sultam chiral auxiliary followed by a sultam-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba), Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67 22 11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the n-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a n-allylpalladium complex with concurrent release of CO, and... 

The second synthesis of fascaplysin (44), from labs at the CNRS, is also very high in overall yield (157). Palladium-catalyzed cross-coupling of the boronic ester 189 with the halogenated pyridine 190 lead to intermediate 191 (Scheme 20). Metalation of 191 with n-BuLi was regioselective, due in part to the inductive effects of nearby electronegative groups. The double cyclization of 192 to fascaplysin provides the natural product in 76% overall yield. 

Several routes involving thiophene ring synthesis towards more complex heterocycle fused thiophene systems should also be mentioned. Thus for example, the alkaloid thienodolin 56 has been prepared by reaction of l-(/ert-butoxycarbonyl)-2,6-dichloroindole-3-carboxaldehyde with 2-mercaptoacetamide <04EJO2589>, while a double cyclization of 2,6-dichloropyridine-3,5-dicarbonitrile or the corresponding pyrazine derivative with ethyl 2-... 

The xanthate group may be reduced away using any of the methods described above for the Barton-McCombie reaction. The lauroyl peroxide/isopropanol system appears to be especially useful in this respect [32a]. This is demonstrated by the transformation in Scheme 16, a key step in the synthesis of (+)-matrine [32b]. Thus, upon heating in refluxing isopropanol with portion-wise addition of a stoichiometric amount of lauroyl peroxide, the double cyclization is followed by the reductive removal of the xanthate group. The reaction gives a 3 1 mixture of isomers, the minor having the relative stereochemistry of a//o-matrine. 

The isolation of the active immunomodulator kifunensine has provoked interest in the synthesis of the 2,3-dioxoperhydroimidazo[l,2-a]pyridine ring system. One approach involved the double cyclization of (91). Many conditions were attempted but only 6M NH3-MeOH at room temperature, which produced (92) in 71% yield, was successful. It was proposed that the six-membered ring was formed first <91CPB1392>. 

A very common method for the synthesis of berbine alkaloids is based on the one-pot double cyclization of iV-(phenylethyl)benzeneacetamide derivatives (e.g. 305) in the presence of phosphorus pentachloride or phosphorus oxychloride (Scheme 67) <81H(16)449,81S818,85AP(318)168,85IJC(B)360>. 

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