Stereochemistry chiral compounds without

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Cyclic molecules permit deductions about stereochemistry without the necessity of using resolved chiral compounds. The stereochemistry of a number of reactions of... 

A special attention is given to stereochemistry as some compounds are published without proper chirality representation even though the information is available, for example, for natural compounds and their derivatives. Furthermore, as illustrated in Figure 9.6, compounds published in medicinal chemistry literature are often depicted... 

The third example of chirality without a chiral centre is provided by spiro compounds, which we shall meet later when we consider the stereochemistry of polycyclic systems (see Section 3.5.1), but at this stage it is worth noting that they provide a third example of chirality... 

Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 °C without selfcondensation and other Lewis acids such as TiCl4 or SnCI4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3-OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a, -chiral aldehydes as substrates... 

Based on existing and available homo-chiral components (building blocks) the desired compound is built up without affecting the stereochemistry. A pertinent example is the synthesis of peptides from their amino acid precursors. 

Reduction of 5,6,7,8-tetrahydroquinazolin-2(l//)-one with sodium boro-hydride gave 3,4,5,6,7,8-hexahydroquinazolin-2(l//)-one (87) in high yield. When this hexahydro compound was fused with nitroacetic acid a stereospecific cis addition of the elements of nitromethane occurred and the 8a-nitromethyl adduct 88 was formed in quantitative yield. The stereospecificity was deduced by converting 88 into 89 which was synthesized from ds-l-methyl-l,2,3,6-tetrahydrophthalic anhydride in several steps without affecting the known stereochemistry of the chiral centers. The related 8a-aminomethyl-3,4,4a,5,6,7,8,8a-octahydroquinazolin-2(lH)-one... 

Some metallodendrimers with one or more stereogenic centers have been prepared without control of the chirality. Vogtle and Balzani [74] have tried several strategies to prepare dendrimers in which a ruthenium cation is the core of the final compound. In these compounds, the only centre of chirality is that of the metal, but as it was not controlled racemic mixtures were obtained. Controlling the stereochemistry of the starting complex would have allowed the authors to prepare a optically pure metallodendrimer. Denti, Campagna, Balzani, and their co-workers have studied polymetallic dendrimers based on bipyridine and 2,3- 7s -(2-pyridyl)pyrazine (2,3-... 

A special attention is given to stereochemistry, as some compounds are published without proper chirality representation even though the information is available, for example, for natural compounds and their derivatives. Furthermore, as illustrated in Fig. 13.2-8, compounds published in medicinal chemistry literature are often depicted in a human-readable format that is, structures are drawn in a format that chemists can interpret to reconstruct proper chirality. However, this format is not machine-readable , that is, cheminformatics software for 3D structural conversion, or for automatically generating IUPAC (International Union of Pure and Applied Chemistry) nomenclature, cannot perceive the stereo centers correctly... 

The reaction starts with racemic material (no stereochemistry is shown at the chiral centre) and makes a racemic product. Of course we have only drawn one enantiomer— the only way to draw one diastereoisomer is to choose one enantiomer and draw that— but the indication underneath tells you to expect an equal amount of the other enantiomer as well. Even without this indication, you should be able to work out, in any given case, whether a compound is racemic or not, providing you know where it comes from. Here the starting material is racemic and the reagent is achiral so the product must be racemic. 

Two Pd-catalyzed cyclizations were used for the enantioselective synthesis of (—)-cephalotoxine [109]. One-pot Pd-catalyzed domino reactions, namely intramolecular allylation of amine and HR of 256, seem to be the best path for the desired synthesis. However, attempted direct conversion of 256 to 258 with the Herrmaim complex was unsuccessful. Then selective intramolecular aminoallylation with the chiral cyclopentyl acetate occurred smoothly to give the Spiro amine 257 in 88 % yield when Pd(PPh3)4 and TMG (tetramethylguanidine) as a base were used. The cyclization proceeded with retention of stereochemistry without racemization. The next HR reaction of 257 gave the seven-membered compound 258 in 81% yield under Jeffery s conditions using the Herrmann complex as a catalyst. No transformation of 257 to 258 occurred when Pd(PPh3)4 was used. The results show that the best catalysts for the allylation and HR are different. 

Allylic carbonates are more reaetive than acetates. In addition, reaction of carbonates proceeds in the absence of bases [6]. Formation of jr-allylpalladium 9 from allyl methyl carbonates 8 proceeds by oxidative addition, followed by decarboxylation, and TT-allylpalladium methoxide 9 is generated at the same time, which abstracts a proton from a pronucleophile to form 10. In situ formation of methoxide is a key in the allylation under neutral conditions. Allylation under neutral conditions is useful for the reaction of base-sensitive compounds. For example, exclusive chemoselective reaction of the carbonate group in 4-acetoxy-2-butenyl methyl carbonate (11) occurred in the absence of a base to yield 12. Similar chemoselective reaction of the allyl carbonate group in the chiral cyclopentenyl methyl carbonate 13 with the jS-keto ester 14 without attacking the allylic acetate group to give 15 was observed even in the presence of NaH. As expected, retention of stereochemistry (see Chapter 4.2.1) was observed in this substitution [7]. 

The stereochemical results of these reactions have been carefully studied." If a chiral acetate is employed, then the product is found to have retention of stereochemistry. Hence, the cis acetoxy ester 9.98 gives the cis product 9.100, while the trans acetoxy ester 9.101 gives the trans product 9.103 (Scheme 9.32)." Retention is a result of two inversions - inversion during formation of the t -allyl complexes, 9.99 and 9.102, and a second inversion during attack by the nucleophile. In the case of the acetoxy esters 9.98 and 9.101, a curious observation can be made when the substrate is non-racemic. It is found that the product is racemic. This is not a general observation. It occurs here, because the intermediate V-allyl complexes, 9.99 and 9.102, each have a plane of symmetry - they are meso compounds and the nucleophile is equally likely to attack either terminus. Systems without the symmetrical intermediate do not show racemization (Scheme 9.33). 

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