In the synthesis

A -dialkylchloroalkylamines, R2N(CH2)nCI. Formed by treating the alkanolamine with thionyl chloride. Of importance in the synthesis of pharmaceuticals, particularly tranquillizers, e.g. amidons. 

Crystalline solid m.p. 35-36 "C, b.p. 154--156 C, prepared by oxidizing A,A -dicycIo-hexylthiourea with HgO in carbon disulphide solution, also obtained from cyclohexylamine and phosgene at elevated temperatures. Used as a mild dehydrating agent, especially in the synthesis of p>eptides from amino-acids. Potent skin irritant. 

HCOOCHjCHj. Colourless liquid with the odour of peach-kernels b.p. 54 C, Prepared by boiling ethanol and methanoic acid in the presence of a little sulphuric acid the product is diluted with water and the insoluble ester separated and distilled. Used as a fumigant and larvicide for dried fruits, tobacco and foodstuffs. It is also used in the synthesis of aldehydes. 

C, b.p. 205°C, forms monohydrate m.p. 58°C. Prepared from diacetoneamine and propanone or by passing NH3 gas into pro-panone containing fused CaCl2. Decomposes to phorone and ammonia, reduced to lelra-melhyl-3-hydroxypiperidine. Used in the synthesis of benzamine hydrochloride. 

Jaoob F and Monod J 1961 Genetio regulatory meohanisms in the synthesis of proteins J. Mol. Biol. 3 318-56... 

Turkevioh J, Stevenson P C and Hillier 1951 A study of the nuoleation and growth prooesses in the synthesis of oolloidal gold Trans. Faraday Soc. 11 55... 

Hendrickson (14,15] concentrated mainly on C-C bond-forming reactions because the construction of the carbon atom skeleton is the major task in the synthesis of complex organic compounds. Each carbon atom is classified according to which kind of atoms are bonded to it and what kind of bonds ([Pg.184]

The disconnection of the strategic bond rated 100 corresponds to an cstcrifiea-tion in the synthesis direction (Figure 10.3-51). Compound 1 is converted to 2 as a suitable synthesis precursor and, indeed, in the synthesis direction 2 can easily be converted to 1. 

One of the hits found in the Chem Inform reaction database is shown in the window for reaction substructure searches in Figure 10.3-55. It fits the synthesis problem perfectly, since in the synthesis direction it forms the coumarin ring system directly, in one step. 

The design of the synthesis foi 1 is now finished. The target eompound (1) can be simplified to eommeicially available starting materials which can easily be converted to the target compound in the synthesis direction, Figure 10.3-56 shows the entire synthesis tree interactively developed with the WODCA program. 

Review Problem 2 This allyl bromide is an important intermediate in the synthesis of terpenes (including many flavouring and perfumery compounds), as the five carbon fi agment occurs widely in nature. How would you make it ... 

Review Problem 3 Tliis odd-looking molecule (TM 34) was used by Corey as an intermediate in the synthesis of maytansine, an antitumour compound. 

Review problem 32 Design a synthesis for TM 303, an intermediate used in the synthesis of substances foimd in ants. 

The strategy of using intramolecular reactions to set up the correct relationslup between two groups is of more general importance. We obviously want to disconnect bonds a and b in TM 328 so that we add a four carbon fragment to PhOMe in the synthesis. 

The most important point in analysing the synthesis of a hydrocarbon is where to put the carbonyl group, and this can depend on features other than common atoms. What strategies might you use in the synthesis of TM 377 ... 

Though you can in principle add a carbonyl group anywhere in a target molecule, remember it means extra steps in the synthesis so use it only as a last resort. 

Revision Problem 10 This compound is an intermediate in the synthesis of an alkaloid. Don t worry about the half ethei aspect - there is a solution to this which will emerge as you go along. 

Strategy Problem 1 The wrong substitution pattern . Making aromatic compounds m-substituted with two o -directing groups is always a problem. What strategies can you suggest An example (TM 412) is the alkyl hahde used in the synthesis of some steroids. 

In the synthesis of complex organic molecules d -synthons have not become as important as their d and d counterparts. 

The following aspects are important for alkylation reactions in the synthesis of complex molecules and will be exemplified ... 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Surprisingly carbonyl-substituted carbanions of phosphonates, in which the negative charge is delocalized over two oxygen atoms, are much more nucleophilic than the corresponding phosphoranes. This effea has first been observed by Homer, and has often been utilized in the synthesis of acylated olefins (R.D. Clark, 1975). 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

In polycyclic systems the Birch reduction of C—C double bonds is also highly stereoselective, e.g. in the synthesis of the thermodynamically favored trans-fused steroidal skeletons (see p. 104 and p. 278). 

A few typical examples indicate the large variety of five-membered heterocycles, which can be synthesized efficiently by [2 + 3]-cycloadditions. [2 + 2]-Cycloadditions are useful in the synthesis of certain four-membered heterocycles (H. Ulrich, 1967), e.g. of 8-lactams (J.R. 

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). 

The following short descriptions of the steps involved in the synthesis of a tripeptide will demonstrate the complexity of the problem amino acid units. In the later parts of this section we shall describe actual syntheses of well defined oligopeptides by linear elongation reactions and of less well defined polypeptides by fragment condensation. 

The purity of the peptide finally obtained depends critically on the yield of each cycle. It must be extraordinarily good to produce even moderately pure products (K. Ltibke, 1975). If the average yield of amide formadon in the synthesis of an undecapeptide (n = 10) is. for example, 98< to, the product will contain already about 20% of different impurities which may be difficult to remove. 

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