Stereospecific transformations additions

In the case of TGT structures which are acyclic or which contain isolated rings, the disconnection of non-ring bonds must be examined to identify those disconnections which may be most effective on topological grounds. However, for such acyclic disconnections the topological factors may be overshadowed by other structural considerations. For instance, if a powerful stereosimplifying disconnective transform, such as stereospecific organometallic addition to carbonyl... 

In the course of mechanistic studies it was established that aniline does not react with the cyclopropenones (153 and 154) even under reflux conditions. It was therefore assumed that the formation of (158) involves initial nucleophilic attack by the aminopyridine ring nitrogen on the electrophilic cyclopropenone ring. In this way 155 is formed, which is then transformed via the reactive intermediates (156, 157, and/or 161) to the prodticts. Kascheres et al. noted that the formation of 157 is formally a stereospecific trans addition of the 2-aminopyridines to the double bond of the cyclopropenone (153). Such sterospecificity has been observed in kinetically controlled Michael additions. 

A wide variety of enzyme controlled stereospecific transformations are known. These transformations include oxidations, reductions, reductive animations, addition of ammonia, transaminations and hydrations. In each case the configuration of the new asymmetric centre will depend on the structure of the substrate. However, substrates whose reactive centres have similar structures will often produce asymmetric centres with the same configuration. Enzyme based methods are economical in their use of chiral material but suffer from the disadvantage that they can require large quantities of the enzyme to produce significant quantities of the drug. 

Alkynes can also be hydroformylated, but hydrogenations of the starting materials or of the resulting olefinic products can not usually be suppressed. If one succeeds, however, to trap the primarily formed a,/ -unsaturated aldehydes intra-molecularly, preparatively useful transformations can be achieved for example, from -alky-nyl amines 44 one can obtain pyrroles 46 in good yields [19]. It is questionable whether the intermediate 45 is formed, since usually hydroformy-lation is a stereospecific cis addition (cf. Scheme 1), so that in this case an isomerization has to have taken place (Scheme 6). Recently, the hydrofor-mylation of non-terminal alkynes 47 was achieved for the first time in good yields leading... 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

Smooth and essentially stereospecific transformation was realized for the following Payne rearrangements of the (E)-92 substrates. The limited (29%) conversion of (E)-syn-92e (Table 10.2. entry 4) reflects the presence of a tertiary carbon direcdy attached to the epoxide three-membered ring in the corresponding product (Z)-anti-93e, affording significant steric repulsion with the trifluoromethyl-containing epoxide substituent. In the case of the substrates (E)-anti-92d and (E)-syn-92d, contamination of the desired product with about 15% of unidentified materials was detected, but formation of these byproducts was nicely suppressed by the addition of 3 equiv. of EtOH to the reaction mixture. 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators110-113 have employed the allylic sulfenate-to-sulfoxide equilibrium in combination with the syn elimination of the latter as a method for the synthesis of conjugated dienes. For example, Reich and coworkers110,111 have reported a detailed study on the conversion of allylic alcohols to 1,3-dienes by sequential sulfenate sulfoxide rearrangement and syn elimination of the sulfoxide. This method of mild and efficient 1,4-dehydration of allylic alcohols has also been shown to proceed with overall cis stereochemistry in cyclic systems, as illustrated by equation 25. The reaction of trans-46 proceeds almost instantaneously at room temperature, while that of the cis-alcohol is much slower. This method has been subsequently applied for the synthesis of several natural products, such as the stereoselective transformation of the allylic alcohol 48 into the sex pheromone of the Red Bollworm Moth (49)112 and the conversion of isocodeine (50) into 6-demethoxythebaine (51)113. 

Addition of such a-lithiosulfinyl carbanions to aldehydes could proceed with asymmetric induction at the newly formed carbinol functionality. One study of this process, including variation of solvent, reaction temperature, base used for deprotonation, structure of aldehyde, and various metal salts additives (e.g., MgBrj, AlMej, ZnClj, Cul), has shown only about 20-25% asymmetric induction (equation 22) . Another study, however, has been much more successful Solladie and Moine obtain the highly diastereocontrolled aldol-type condensation as shown in equation 23, in which dias-tereomer 24 is the only observed product, isolated in 75% yield This intermediate is then transformed stereospecifically via a sulfoxide-assisted intramolecular 8, 2 process into formylchromene 25, which is a valuable chiron precursor to enantiomerically pure a-Tocopherol (Vitamin E, 26). 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

Although these allylic stannanes are rather resistant to uncatalysed or Lewis acid-catalysed carbonyl addition , they are valuable, shelf-stable homoenolate reagents (see Section IV.C.5), which are activated by Lewis acids or lithiodestannylation. Titanium tetrachloride converts the allylstannanes stereospecifically with inversion into very reactive intermediates (equation 83) . Both isomers, (R,Z)- and (5, )-315, are transformed... 

Epoxides are useful synthetic intermediates, and the conversion of an alkene to an epoxide is often part of a more extensive molecular transformation.85 In many instances, advantage is taken of the high reactivity of the epoxide ring to introduce additional functionality. Because epoxide ring opening is usually stereospecific, such reactions can be used to establish stereochemical relationships between adjacent substituents. Such two- or three-step operations can accomplish specific oxidative transformations of an alkene that may not easily be accomplished in a single step. Scheme 12.13 provides a preview of the type of reactivity to be discussed. 

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