Mechanistic considerations synthesis

The telomer of nitroethane, 134, was used for the synthesis of 11-hydroxy-8-frans-dodecenoic acid (135) (125). Apparently, the internal double bond of 134 must have a trans configuration from a mechanistic consideration. The nitro group was converted to alcohol via ketone, and the two-carbon homologation was carried out from the terminal double bond. This acid is converted to recifeiolide (136), a naturally occurring macrolide. 

The [2+2]-photocycloaddition of carbonyl groups with olefins (Paterno-Buchi reaction) is one of the oldest known photochemical reactions and has become increasingly important for the synthesis of complex molecules. Existing reviews have summarized the mechanistic considerations and defined the scope and limitations of this photocycloaddition73. Although this reaction likely proceeds via initial excitation of the carbonyl compound and not the excited state of the diene, the many examples of this reaction in natural product synthesis justify inclusion in this chapter. 

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

The structure of the products and mechanistic considerations are proved by independent synthesis from 5-benzalbarbituric acid... 

Malononitrile and cyanoacetamide only give aminopyrans. However, in reaction with cyanoacetic ester 27b aminopyran 233 has been isolated from the mother liquor and also side product 234 from the cooled mixture. Mechanistic considerations have been proved by the isolation of a deace-tylated intermediate (95M615). Similar transformations occur in the synthesis of spiropyrans 235 from benzothiazole 236 (97G605) (Scheme 90). 

These mechanistic considerations led to the design of a four-component pyranopyrazole synthesis (09RCB2362, 09JCO914). 

Synthetic applications as well as mechanistic considerations were reviewed recently24. Extension of the methodology to the seven-membered ring resulted in the first asymmetric synthesis of chiral benzazepines by alkylation with primary alkyl halides (92-96% ee) in 57-82% yield25. 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

Perreux, L. and Loupy, A., A tentative rationalization of microwave effects in organic synthesis according to the reaction medium, and mechanistic considerations, Tetrahedron, 2001, 57, 9199-9223. 

Thermodynamic considerations are obviously dominant in planning a synthesis, and these, of course, include solubilities, boiling points etc. Kinetic and mechanistic considerations will determine the rate of the reaction(s) involved in the preparation, the extent of competing reactions (which may affect the yield of the desired product and the ease of its isolation) and, where appropriate, which of the possible isomeric forms of the product is favoured. 

Reports on ruthenium catalytic activity focus more on mechanistic consideration of the prototypical phenylacetylene dimerization than in establishing its synthetic applicability. It is not unusual that changing the alkyne substituents results in reversed selectivity (i.e. R = Ph or SiMe3 gave ( )- or (Z)- isomers, respectively) [27]. Competitive alkyne cyclotrimerization (R = COOMe) [27] or butatriene formation (R= CH2Ph, Bu) [10, 21] have occasionally been reported as possible drawbacks in enyne synthesis. The operating mechanism restricts the reaction to terminal alkynes. 

The stereochemistry outcome of the aldol additions is an issue of paramount importance in the synthesis of iminosugars. Based on mechanistic considerations of the DHAP aldolases [29, 30] it can be assumed that the absolute configuration at C-3 (i.e. the stereocenter arising from DHAP) is independent of the acceptor used in the reaction. Analysis of the stereochemistry at C-4 (i.e. the one generated from the aldehyde) can be used to infer the kinetic stereoselectivity of the aldolases towards each of the N-protected amino aldehydes (Figure 19.4). For the selected... 

In the 80 years since the original report of a photochemical addition to form an oxetane, the Patemo-Btichi reaction has become increasingly familiar to chemists engaged in the synthesis of complex molecules. Existing reviews have summarized mechanistic considerations and defined the scope and limitations of the photocycloaddition reactions. In confluence with the widespread advances in synthetic methods and asymmetric synthesis, the Patemo-BQchi reaction has prospered and led to significant developments in the area of organic synthesis. 

This chapter is concerned specifically with olefin metathesis reactions catalyzed by ruthenium-carbene complexes, mainly because of their great success during recent years. We begin with an overview of these catalysts, and then focus on mechanistic considerations that are important for understanding the reactivity profiles of various catalyst derivatives. The second part of the chapter deals with applications of ruthenium-catalyzed olefin metathesis, especially RCM, CM, and combination processes in organic synthesis. 

Additional readings about peptide synthesis and its practical and mechanistic considerations can be found in many books, chapters in books and reviews. A good starting point for the interested person includes the items listed within the Further Reading section. 

Dahlen, A, Sundgren, A, Lahmann, M, Oscarson, S, Hilmersson, G, Sml2/water/amine mediates cleavage of allyl ether protected alcohols — application in carbohydrate synthesis and mechanistic considerations, Org. Lett, 5, 4058-4088, 2003. 

The eco-friendly advantages of these reactions may be found in instances where catalytic amounts of reagents or supported agents are used since they provide reduction or elimination of solvents or utilize water as reaction media, thus preventing pollution at source . Although not delineated completely, the reaction rate enhancements achieved in these methods may be ascribable to non-thermal effects. The rationalization of microwave effects and mechanistic considerations possibly involving the intermediacy of polar transition states have been discussed.The use of synthesis processes that employ MW/ultrasonic irradiation to shorten the reaction time and eliminate or minimize side product formation is already finding acceptance in pharmaceutical industry (combinatorial chemistry) and polymer syntheses... 

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