Carbon skeletons, assembly

The widespread use of cinnamic derivatives has led to the pursuit of reUable methods for thek dkect synthesis. Commercial processes have focused on condensation reactions between ben2aldehyde and a number of active methylene compounds for assembly of the requisite carbon skeleton. The presence of a disubstituted carbon—carbon double bond in the sidechain of these chemicals also gives rise to the existence of two distinct stereoisomers, the cis or (Z)- and trans or (E)- isomers ... 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

A related IMDA key step, however with exo geometry, was apphed in Mulzer s synthesis of ehsabethin A (22) [32]. According to the retrosynthetic plan (Scheme 14) the elisabethane carbon skeleton would be assembled via an IMDA cychzation of quinone 86 which would be generated by oxidation of the corresponding hydroquinoid precursor. Selective hydrogenation, base-catalyzed... 

The same natural product was synthesized by Paterson et al. [45] who assembled the carbon skeleton of the macrolide from three larger subunits as well. Instead of the Evans-Metternich variant they used their boron-mediated antz-selective aldol strategy which relies as the Evans-Metternich aldol on stereo-induction from the a-chiral center and translates the E-enolate geometry, established due to the use of Cy2BCl, to the anti aldol product (Scheme 33). 

One synthesis of the potent estrogen antagonist nafoxidine (14-9) [15] involves assembly of the full carbon skeleton prior to formation of the bicyclic nucleus. 

Because of the importance of carbonyl groups to the mechanism of condensation reactions, much of the assembly of either straight-chain or branched-carbon skeletons takes place between compounds in which the average oxidation state of the carbon atoms is similar to that in carbohydrates (or in formaldehyde, H2CO). The diversity of chemical reactions possible with compounds at this state of oxidation is a maximum, a fact that may explain why carbohydrates and closely related substances are major biosynthetic precursors and why the average state of oxidation of the carbon in... 

In addition to connecting skeletal fragments by formation of carbon-carbon single bonds, it is also possible to utilize reactions which give carbon-carbon double bonds to assemble carbon skeletons. It should be recognized that while die final products of such reactions contain a carbon-carbon double bond, they are generally sequential processes in which a single carbon-carbon bond is formed first and die n bond is formed in a subsequent elimination step. 

The Heck reaction was discovered in the early 1970s and is extremely useful for rapidly assembling carbon skeletons. This reaction is unique to palladium A great deal of information is known about the reaction. For example, the success of the reaction depends on each of the three steps involved. Electron-donating groups decrease the reactivity of alkenyl halides and triflates toward Pd(0), whereas electron-withdrawing group increase the rate of oxidative addition. In cases where Pd(II) salts are used, it is assumed that they are converted to Pd(0) by some redox process. 

Next consider compound R. When the relevant facts are considered, we see diat R is merely an olefin with a saturated ring present. Because of the five-membered ring and because the target has 12 carbon atoms, it is unlikely that compounds with the carbon skeleton of R will be available commercially hence carbon-carbon bond-forming reactions will be needed to assemble the carbon skeleton. 

The carbon skeleton can be assembled in one step by the reaction of ethylmagnesium bromide and ethyl acetate. 

The carbon skeleton of butanoic acid may be assembled by an aldol condensation of acetaldehyde. 

The assembly of the carbon skeletons of these unusual hydrocarbons was first studied in Carpophilus freemani Dobson, through careful GC-MS and Nuclear Magnetic Resonance (NMR) studies of the incorporation of 2H or 13C-labeled precursors (Petroski et al., 1994). Assembly of the carbon skeleton of the aggregation pheromone of C. freemani, (2 , 4 , 6ii)-5-ethyl-3-methyl-2,4,6-nonatriene, involves initiation with acetate elongation with first propionate (to provide the methyl branch), then butyrate (to provide the ethyl branch) and chain termination with a second butyrate (Figure 6.7). At some point, loss of C02 from one of the butyrate units occurs to yield the appropriate hydrocarbon, but Petroski et al. (1994) were unable to determine which of the butyrate units loses its carboxyl group. Bartelt and Weisleder (1996) studied the biosynthesis of 15 additional methyl- and/or ethyl-branched, tri- and tetraenes in the related... 

Much of the published work dealing with the synthesis of the phomoidrides has centered on devising methods for assembling their unique bicyclic carbon skeleton. The construction of this bicyclic core with additional potential for subsequent functionalization is a central... 

For domino Heck reactions the initial carbometallation step must lead to intermediates that do not readily undergo /1-hydride elimination and can thus serve as starting points for additional Pd-mediated transformations [7]. Such processes, as exemplified in Scheme 6, have been used extensively by de Meijere, Grigg, Overman and others for assembly of complex carbon skeletons. 

Sesquiterpenoids (Sq) are Cj5 compounds formed by the assembly of three isoprenoid units. They are found in many living systems but particularly in higher plants. There are a large number of sesquiterpenoid carbon skeletons, which arise from the common precursor, farnesyl diphosphate, by various modes cyclization followed, in many cases, by skeletal rearrangement. 

Anionic-anionic cascades are also effective for the rapid assembly of carbon skeletons. For example, double Barbier cyclisations were used by Cook for the synthesis of tetracyclic polyquinenes.21 Molander has shown that such sequences can be used to access a range of fused polycyclic systems (Scheme 6.17).13... 

Organic synthesis is the preparation of desired compounds from readily available materials. Synthesis is one of the major areas of organic chemistry, and nearly every chapter of this book involves organic synthesis in some way. A synthesis may be a simple one-step reaction, or it may involve many steps and incorporate a subtle strategy for assembling the correct carbon skeleton with all the functional groups in the right positions. 

The starting materials are acetylene and compounds containing no more than four carbon atoms. In this problem, it is necessary to consider not only how to assemble the carbon skeleton and how to introduce the functional groups, but also when it is best to put in the functional groups. We begin with an examination of the target compound, and then we examine possible intermediates and synthetic routes. 

Compare methods for assembling the carbon skeleton of the target compound. Which ones provide a key intermediate with the correct carbon skeleton and functional groups correctly positioned for conversion to the functionality in the target molecule ... 

Working backward through as many steps as necessary, compare methods for synthesizing the reactants needed for assembly of the key intermediate with the correct carbon skeleton and functionality. 

Grignard and organolithium reagents provide some of the best methods for assembling a carbon skeleton. These strong nucleophiles add to ketones and aldehydes to give alkoxide ions, which are protonated to give alcohols. 

We can now extend our systematic analysis to problems involving alcohols and Grignard reactions. As examples, we consider the syntheses of an acyclic diol and a disubstituted cyclohexane, concentrating on the crucial steps that assemble the carbon skeletons and generate the final functional groups. 

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