Chiral centre synthesis

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

On page 94 appeared a problem on the synthesis of acid (1), needed for conversion to ketone (2), The problem under investigation was sterlc hindrance in nucleophilic additions to ketones and a crowded ketone with a chiral centre was needed. 

Example Optically active acid (16) was needed (p T 107 ) for the synthesis of an ant alarm pheromone. The branch point ( in 16) is also the chiral centre so it is better to avoid disconnections there. The 1,2 C-C disconnection (16a) is ideal as it gives synthon (17), for which we use a malonate ester, and halide (18), available from optically active alcohol (19), a major by-product from fermentation. 

Aove Advanced Example Lactone (25) was needed in the synthesis of pcderamldc, an inhibitor of protein synthesis found in a beetle. Disconnection of the lactone reveals two stereochemical problems a c-ir, double bond is required and two adjacent chiral centres ( in 26) must be set up correctly. 

The synthesis of (23) illustrates how a six-membered ring may bo used to control even more remote chiral centres. Reverse Michael disconnection leaves enone (24), an oxidation product from allylic alcohol (25). The double bond can come from elimination on bromohydrln (26) and hence from (27). 

The one chiral centre in (30) is used to set up four other chiral centres stereoselectIvely. Draw out the synthesis, giving the correct stereochemistry for all compounds. 

The Dlels-Alder reaction is a favourite way of introducing many chiral centres at once, and we saw examples of this in Chapter 36. Compound (31) was used in a synthesis of quassin." It has seven adjacent chiral centres. How many can bo introduced in one step by a Diels-Alder reaction and what should the starting materials be ... 

Reaction of optically active a-sulphinyl acetate 298a with prochiral carbonyl compounds proceeds with a high asymmetric induction - , the degree of which depends on the nature of substituents at the carbonyl group (equation 252 Table 22) . The jS-hydroxy sulphoxides 422 formed may be transformed to optically active p-hydroxycarboxylic esters 423 (equation 253) and optically active long-chain lactones 424 99 (equation 254). Corey and coworkers have used this method to introduce a chiral centre at C-3 in their synthesis of maytansin °°, and Papageorgiou and Benezra for the synthesis of chiral a-hydroxyalkyl acrylates 425 ° (equation 255). 

Table 3.12 surveys current industrial applications of enantioselective homogeneous catalysis in fine chemicals production. Most chiral catalyst in Table 3.12 have chiral phosphine ligands (see Fig. 3.54). The DIP AMP ligand, which is used in the production of L-Dopa, one of the first chiral syntheses, possesses phosphorus chirality, (see also Section 4.5.8.1) A number of commercial processes use the BINAP ligand, which has axial chirality. The PNNP ligand, on the other hand, has its chirality centred on the a-phenethyl groups two atoms removed from the phosphorus atoms, which bind to the rhodium ion. Nevertheless, good enantio.selectivity is obtained with this catalyst in the synthesis of L-phenylalanine. 

In 2003, Bonini et al. reported a new synthesis of ferrocenyloxazolines based on an iodide-mediated ring expansion of A-ferrocenoyl-aziridine-2-carboxylic esters. The thus-formed ligands were successfully employed as palladium chelates for the test reaction, since they allowed the product to be formed in quantitative yields and good to high enantioselectivities (Scheme 1.69). According to the results, it seemed that the additional chiral centre present in the oxazoline backbone of these ligands did not play a major role for the asymmetric induction and the activity of the corresponding catalysts. 

Although the tin hydride reductions of alkyl halides seem simple, one must be careful because these reactions occur by a free radical mechanism. This is important, because the carbon radical produced in the reaction can isomerize68,78 and one often obtains two different stereoisomers from the synthesis. Another problem is that chiral centres can be lost in tin hydride reductions when an optically active halide is reduced. One example of this is the reduction of benzyl-6-isocyanopenicillanate with tributyltin deuteride78 (Scheme 14). The amount of isomerization depends on the temperature, the concentration of the tin hydride and the presence of and /-substituents78-82. However, some authors have reported tin hydride reductions where no racemization was observed78. 

Lewis acid catalysis is not limited to cases in which increased yields or enhanced selectivities are desired. Lewis acids offer also the possibility to induce chiral information leading to enantioselective product formation. The enantioselective induction by chiral Lewis acids found widespread application in organic synthesis, especially in the synthesis of natural products with many chiral centres. An enantioselective Diels-Alder reaction is the key step in the synthesis of an iodolactone prostaglandine precursor (Scheme 6).88... 

Cyclic ketene acetals, which have utility as co-polymers with functional groups capable of cross-linking, etc., have been prepared by the elimination of HX from 2-halomethyl-l,3-dioxolanes. Milder conditions are used under phase-transfer conditions, compared with traditional procedures, which require a strong base and high temperatures. Solid liquid elimination reactions frequently use potassium f-butoxide [27], but acceptable yields have been achieved with potassium hydroxide and without loss of any chiral centres. The added dimension of sonication reduces reaction times and improves the yields [28, 29]. Microwave irradiation has also been used in the synthesis of methyleneacetals and dithioacetals [30] and yields are superior to those obtained with sonofication. 

A more complicated example, in which the presence of symmetry reduces the problem of creating eight chiral centres to only four, is the case of (+)-a-onocerine (8), the synthesis of which [15] was performed by coupling of the two enantiomerically pure C 5 units (7, X = COOH), with the correct stereochemistry, in order to prevent the formation of the unnatural meso form d,l + l,d) (Scheme 4.2). 

When the target molecule bears several chiral centres, the most obvious simplification in the retrosynthetic analysis is to eliminate all the chiral or stereogenic centres and then to design the synthesis with as much stereoselectivy as possible (for the concept of "selectivity" see below 8.2). However, as pointed out by Corey... 

Therefore, a fundamental axiom in the synthesis of complex organic compounds bearing chiral centres is the necessity of resorting to rigid structures whether in the starting materials (monocyclic or polycyclic molecules) or in the transition states (as in pericyclic reactions, for instance) in order to ensure an... 

In the synthesis of reserpine by Woodward (see Scheme 8.5) the stereochemical control of the five chiral centres follows a more elaborated route, but equally efficient and elegant. 

Caryophyllenes, as an example of two naturally occurring isomeric sesquiterpenes containing a medium-sized ring, in which the success of the total syntheses lies in the stereoselective control of a chiral centre, in a common synthetic key intermediate, which governs the configuration (JE or Z) of the double bonds present in each one of the two isomers. In this context, a brief reference to Cecropia Juvenile Hormone synthesis by the Syntex group, as well as to Johnson s cationic cyclisation of unsaturated polyolefins to fused polycyclic compounds, is made. 

It is worth noting that in this synthesis of Cecropia juvenile hormone a strategy which is the reverse of the one developed by W.S. Johnson [8] for the synthesis of steroids and other fused polycyclic systems bearing cyclohexane rings is used. This method involves a non-enzymatic cyclisation of a polyunsaturated intermediate with the appropriate stereochemistry (all-trans) (Scheme 13.3.6). Such cyclisation occurs with a really amazing stereoselectivity and several new chiral centres with the correct stereochemistry are created in one single step ... 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

The synthesis of " C-labelled o-glucose starts with the pentose o-arabinose and " C-labelled potassium cyanide, which react together to form a cyanohydrin (see Section 7.6.1). Since cyanide can attack the planar carbonyl group from either side, the cyanohydrin product will be a mixture of two diastereoisomers that are epimeric at the new chiral centre. The two epimers are usually formed in unequal amounts because of a chiral influence from the rest of the arabinose structure during attack of the nucleophile. 

The apparently latest total synthesis of a dolastane diterpene was published by Williams and coworkers in 1993 as a short communication (Fig. 16) [91]. (-)-Clavulara-l(15),17-dien-3,4-diol (129) was synthesized using a strategy that relied on the availability of the enantiomerically pure building block 162 from (+)-9,10-dibromocamphor (163) (Fig. 16). Cornerstones of the synthesis are a macrocyclization that afforded the 11-membered (A+B)C-ring (160) and a transannular cyclization that converted a bicyclic into a tricyclic ring system. Two of the seven chirality centres in the synthetic clavu-... 

A large proportion of NCEs will have one or more chiral centres. Only single enantiomers can be used nowadays, whereas previously a racemic mixture would have been tested. Different enantiomers produce different pharmacological responses, with one enantiomer usually being more active by at least an order of magnitude. There has been considerable debate on the administration of racemates versus the single active enantiomer or eutomer however, the current trend is to develop only the active optical isomer. The synthetic route employed will, if required, have to utilise chiral-specific reagents and catalysts or the compound will have to be purified after synthesis. With this type of compound, an additional specification or limit is required for the presence of the inactive enantiomer. ... 

Chiral synthesis during the coupling reaction betw een an a-methoxy amide and a nucleophile can be achieved. One approach to this problem uses a nucleophile derived from a 2-niethyloxazoIine possessing a chiral centre, for example in the formation of the chiral amine 27 [123], A second approach uses esters of pyroglu-... 

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