SYNTHESIS highly substituted

Heterocycle synthesis. Highly substituted furans are obtained from 2-alkylidene-3-alkynones via conjugate addition to generate enols that show nucleophilicity at C-3." ... 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

Erythromycins. Erythromycin A (14, R = OH, R = CH3, R" = H), the most widely used macroHde antibiotic, was the principal product found in culture broths of Streptomjces eTythreus (39), now reclassified as Saccharopoljspora eythraea (40). It contains a highly substituted aglycone, erythronoHde A, (16, R = R = OH) to which desosamine (1, R = OH, R = H) and cladinose (8, R = CH ) are attached (41). The complete stereochemistry of erythromycin A was estabUshed by x-ray analysis of its hydroiodide dihydrate (42) total synthesis of erythromycin A was a landmark achievement (43), a task previously considered hopeless (44). 

A synthetically powerful method, an approach based on cycloaddition chemistry, allows one to assemble the pyridine ring in one step. Not only is this method efficient, atom economy, but also its convergency allows for the preparation for highly substituted systems in which one can, in principle, control all five positions on the pyridine ring. A versatile example of this methodology is the Boger reaction. It has been applied to the synthesis of a very diverse set of targets. 

Raney nickel desulfurization has been applied especially to the synthesis of different kinds of amino acids. a-Amino acids have been prepared by the Strecker synthesis of substituted thiophenealdehydes, followed by desulfurization of the thiophene a-amino acids. a-Amino-n-enantic acid, a-amino-n-caprylic acid, and norleucin have been obtained in about 50% yield from the appropriate thiophene aldehydes. From the desulfurization of thiophene -amino acids, obtained from the reaction of thiophenealdehydes with malonic acid in ammonia, aliphatic j8-amino acids, isolated as acetates, have been obtained in high yields. The desulfurization of 3-nitrothiophenes, such as (232), in ammonia leads to y-substituted amino acids (233). ... 

The McMurry procedure is a valuable method for the synthesis of highly substituted, strained alkenes such compounds are difficult to prepare by other methods. Diisopropyl ketone 6 can be coupled to give tetraisopropylethene 7 in 87% yield attempts to prepare tetra-t-butylethene however were not successful. ... 

Palladium-mediated catalysis has only been exploited relatively recently in the synthesis of substituted PPV derivatives. The use of aryl dibromides as monomers is particularly useful as it allows the synthesis of PPVs substituted with alkyl rather than alkoxy sidechains. The Suzuki [53, 54], Heck [55], and Stille [56] reactions have been used in the synthesis of new PPV derivatives, but attaining high molecular weight PPV derivatives by these methodologies has proved problematic. A phenyl-subslilutcd PPV material PPPV 31 was synthesized by a Suzuki coupling (Scheme 1-10) of dibromoethene and fo/.v-boronic acid 30. Its absorption (2ni ix=385 nm) and emission (2max=475 nm) maxima were strongly... 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

Recently, a study of this rearrangement has been repeated and extended in order to determine the influence of a- and y-substitution on the position of the 68-69 equilibrium in the presence of silica, and the utility of this reaction for a novel and convenient synthesis of highly substituted a, / -unsaturated ketones, by subsequent treatment with CuCl2 in methanol-water136. An ion-pair mechanism can also be suggested for the facile rearrangement of sulfone 70 to 71, a key intermediate in the Hoffmann-La Roche Sulfone Route to Vitamin A137. 

Scheme 2 RCM-based formation of a highly substituted cyclopentenone in Trost s synthesis of the cyclopentenyl core of viridenomycin (12) [22]...

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

Participation of aromatic groups in oxy-Cope reaction sequences enables the synthesis of highly substituted polyquinane ring systems (Scheme 10, <96JOC7976>). 

Bis-pyranoside alkenes are reported as novel templates for the stereoselective synthesis of highly substituted, adjacently linked tetrahydrofurans <96TL3619>. 

A highly diasteieoselective synthesis of substituted 1,2,3,4,4a,9,9a, 10-octahydroacridines 95 with five stereogenic centers has been achieved by domino imine condensation/intramolecular polar [4ti + 2k] cycloaddition of anilines and oo-unsaturated aldehydes 94 <96JPR(338)468>. 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

For the synthesis of the target structures, it is absolutely necessary to introduce solubilizing substituents in the positions peripheral to the benzoyl substituents. The primary coupling product, 117, a poly(2,5-dibenzoyl-l,4-phenyl-ene) derivative - a poly(para-phenylene) with two benzoyl substituents in each structural unit - is, as expected, very poorly soluble. Highly substituted monomers (2,5-dibromo-l,4-bis(3,4-dihexyloxy-benzoyl)benzene), containing four solubilizing alkoxy groups per monomer unit, allow the synthesis of polymeric materials with M of about 12,000 and M, of about 22,000 [139]. 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

The ring system can be generated by D-A addition of a substituted cyclopentadienone and an alkyne. A reaction sequence involving addition followed by CO elimination can be used for the synthesis of highly substituted benzene rings.308... 

More recently, this chemistry has been extended to the synthesis of isoquinolines by employing the i-butylimines of o-halobenzaldehydes (Scheme 4).5 By employing vinylic halides, one obtains highly substituted pyridines. 

Tridachiahydropyrone belongs to the family of marine polypropionates [69]. Efforts towards its total synthesis have recently led to a revision of the structure with the new proposal 2-147 [70]. The construction of the highly substituted cyclohex-enone moiety 2-146 which could be incorporated into this natural product [71] has been described by Perkins and coworkers (Scheme 2.33) [70, 72]. The conjugate addition/ Dieckmann-type cydization utilizing organocopper species as Michael donors afforded the enantiopure 2-145 in 68% yield. A further methylation of the (3-ketoester moiety in 2-145 followed by an elimination led to the desired cydohex-enone 2-146. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

A general method for the synthesis of highly substituted styrenes as 6/4-91, vinyl-cyclohexadienes and related compounds was developed by Xi, Takahashi and coworkers [301] by reacting an intermediately formed five-membered zirconacycle 6/4-89 with propargyl derivatives 6/4-90 or allyl bishalides in the presence of CuCl (Scheme 6/4.21). 

By adhering to these conditions, Kaupp and coworkers performed a remarkable one-pot synthesis of highly substituted pyrroles [21]. When primary or secondary enamine esters 10-58 were ground with trans- 1,2-dibenzoylethene 10-59 in a ball-mill, the pyrroles 10-60 were obtained in quantitative yield (Scheme 10.15). In contrast, when in solution the yields were much lower and the reaction also required higher reaction temperatures. 

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