Tricyclic aldehyde intermediate, synthesis

Aldol condensations of more complex aldehydes are often sufficiently slow to allow successful alkylation reactions. There are numerous examples of aldehyde enolate methylations in the field of natural product synthesis. As shown in Scheme 29, the methylation of a tricyclic aldehyde, which was employed in the synthesis of ( )-rimuene, provides an illustrative case. As expected for an exocyclic enolate intermediate such as (61), the methyl group was introduced equatorial to the six-membered ring with a high degree of stereoselectivity. a-Alkylated aldehydes may be prepared efficiently by alkylations of enamines, Schiff base anions, hydrazone anions and other methods. A discussion of this methodology is provided in Section 1.1.5. 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

A most expeditious synthesis of triquinacene was described by Deslongchamps and his co-workers in 1973 (Scheme 58).3S°) This approach comprised degradation of Thiele s acid (363) to diketone 364 and photolysis of this intermediate to give keto aldehyde 365. Aldolization of365 led to construction of the tricyclic nucleus sequential hydride reduction, mesylation, and elimination of this intermediate over alumina efficiently provided 356. 

Key step of Nicolaou s synthesis is the stereoselective hydrogenation of the unsaturated cyclo-dodecanone 17 which was obtained via intramolecular acetylide-aldehyde condensation of 6. The intermediate (Z)-olefm immediately rearranges to the tricyclic dihydrofuran 18 (Scheme 2). Solely the hydroxyl group at the quaternary carbon atom... 

The structures of the vast majority of PD-5 inhibitor compounds aimed at erectile dysfunction consist of modified purines. The structure of the recently approved drug for this indication tadalafll (113) differs markedly from the prototypes. Tryptophan methyl ester (108) provides the starting material for large scale enantioselective synthesis. Condensation of that compound with piperonal (109) in the presence of acid leads to formation of the tricyclic intermediate (110). This transform involves initial addition of the amine to the aldehyde. The carhocation from the newly formed carhinolamine then attacks the indole 2-position to form the the fused piperidine. The stereochemistry of the new chiral center is guided by that from the tryptophan carhon across the ring. The secondary amine is next acylated with chloroacetyl chloride in the presence of triethylamine to afford 111. Reaction of this intermediate with methylamine goes on to form the desired product in a single step. This reaction can he rationalized... 

In a study focusing on the synthesis and reactions of 2-(2-aminoethyl)pyrroles, a preparation of the tricyclic ring-system 64 was accomplished by reduction of the succinimides 65, followed by cyclization of the intermediates 66. Moreover, 2-(2-aminoethyl)pyrroles were demonstrated to undergo cyclization with aldehydes to provide 4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines <03T5265>. 

The cytotoxic sesquiterpenoid (-)-quadrone, isolated from the fungus Aspergillus terreus, possesses the constitution and absolute stereochemistry shown in (218). The tricyclic carbon skeleton of this interesting natural product is the same as that found in compound (198), which, as described above (Scheme 28), is readily prepared by thermolysis of the tricyclic diene (197). Thus, it appeared that the Cope rearrangement of a suitably substituted and functionalized derivative of (197) might serve effectively as a key intermediate in a total synthesis of ( )-quadione (218) that is, successful Cope rearrangement of a substrate, such as (219), would provide, stereoselectively, the tricyclic substance (220). Presumably, the intermediate (220) could then be converted into the keto aldehyde (221), which had already been transformed into ( )-quadrone (218). ... 

A successful formal total synthesis of ( )-quadrone (218) via a route in which a divinylcyclopropane rearrangement played a key role was achieved by employing the substrate (228 Scheme 32). This material is readily prepared from the ketone (227) and, in contrast to compounds (219) and (224), undergoes smooth Cope rearrangement to the tricyclic diene acetal (229), which is easily transformed into the keto acetal (230). A rather lengthy sequence of reactions effects conversion of (230) into the keto aldehyde (221), which, as mentioned previously, has served as an intermediate in a total synthesis of ( )-quadione (218)."... 

The products of the asymmetric alkylation have been used as key building blocks in syntheses of morphanes, phyllanthocin, and periplanone B natural products. In the case of the synthesis of the morphane skeleton, a phenolic nucleophile was reacted with cyclohexenyl methyl carbonate and the resulting ether was subjected to a europium-induced Claisen rearrangement followed by an intramolecular aldehyde-ene reaction to generate the key tricyclic intermediate. Scheme 27 [56]. 

The Wadsworth-Emmons reaction of the aldehyde (190) with the complex phosphonate (191) has been used to construct the Cio-Cn double bond in a convergent synthesis of lacrimin A (192) (Scheme 27). Phosphonate-based olefination has been extensively used in the synthesis of cytohalasans (e.g. 193), a group of biologically active fungal metabolites. 12 The phosphonate (194) has been used to construct a triene function which ultimately forms the tricyclic structure through an intramolecular Diel s Alder reaction. 14,15-Dehydroforskolin (196) has been prepared by the base-induced reaction of the aldehyde (195) with dimethyl diazomethylphosphonate.l 13 Under certain conditions the phosphonate (197) can be isolated and this provides evidence for the involvement of the Wadsworth-Emmons intermediate (198) in the reaction. The phosphonate... 

The preceding schemes for preparing estrone have the disadvantage that they yield the steroid as a mixture of the two enantiomers. Preparing material identical with that which occurs in Nature requires resolution of those diastereomers. This also implies loss of half of the mass of final product. A synthesis that produces estrone and its derivatives directly without the need for that extra step depends on the use of chiral auxiliaries in the formation of ring C. The crucial step in this synthesis involves Diels-Alder condensation of the diene 16-1 with the fumaric ester aldehyde 16-2 in the presence of the oxazaborolidinium salt shown in Figure 3.1 this reaction affords the tricyclic intermediate 16-3 as a single enantiomer (Scheme 3.16). 

Meyers, with the tricyclic (117) as a starting point, used the reactivity of the quinoline a-methylene to make a dihydropyridone intermediate (118) (Scheme 28). The main difficulties in the synthesis were concerned with the selective release of one protected aldehyde from intermediates such as (119), and unwanted cyclizations such as that [—> (120)] which resulted from treatment of (119) with non-selective hydrolytic conditions. 

Resolution by transesterification. A procedure for the large-scale preparation of (15,25)-tran -2-methoxycyclohexanol, which is a key intermediate for the synthesis of tricyclic 3-lactam antibiotics, has been worked out." Monoprotected 1,2-diols and acetals of a-hydroxy aldehydes afford chiral acetates hy the lipase-catalyzed transesterification. a-Ketols are also resolved. Dimethyl /nejo-2,5-dibromoadipate is readily desymmetrized by the transesterification protocol, permitting the synthesis of chiral cA-2,5-disubstituted pyrrolidines. ... 

The Claisen-Johnson rearrangement is also a reaction of choice for the construction of quaternary centers in the synthesis of triquinanes and related ter-penes. Accordingly, transposition of aUyUc alcohol 125 is a cornerstone reaction in the synthesis of tricyclic compound 124, a key intermediate for the access to several triquinanes described by Iwata [28] (Scheme 6.17). Acid 126 was obtained in 57% yield after transposition and saponification. Claisen allyl vinyl ether rearrangement was also applied to allylic alcohol 125. Oxidation of the aldehyde inter-... 

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