Strategies synthetic

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24 

The restrictions applied to acceptable pathways will depend on the reasons for the synthesis. Control of stereochemistry is necessary if, for example, an optically active natural product with several chiral centers is the goal of the synthesis. A synthesis of a material to be prepared in substantial quantities may impose availability and cost of the starting material as the critical limiting factors. An industrial synthetic process would bear heavy restrictions as to acceptable by-products, a problem that is not as important in laboratory-scale syntheses. 

The development of a satisfactory plan for the synthetic task at hand is the initial intellectual challenge to a synthetic chemist. This task puts a premium on creativity and imagination. There is no single correct answer, nor is there an established routine by which a synthetic plan can be formulated. 

A detailed formal analysis of the concept of convergency has been presented by J. B. Hendrickson, /. Am. Chem. Soc. 99, 5439 (1977). 

The retrosynthetic analysis of a complex molecule to key intermediates will involve antithetic transforms or bond disconnections. That is, the retrosynthetic analysis consists of the reverse of the synthetic process. These steps must be made in light of the availability of synthetic methods to carry out the desired transformation in the forward synthetic direction. Thus antithetic transforms must consider the functional groups which must be present to permit individual bond formations to take place. 

Once candidates for key intermediates are recognized, the issues of stereochemistry must be faced. These take several forms cis-trans isomerism at carbon-carbon double bonds, stereochemistry at ring junctions, and the relative and absolute configuration at chiral centers. Only those pathways that promise stereoselective formation of the desired compound are likely to be acceptable. For example, a structure with one possibility for cis-trans isomerism and two chiral centers allows for 1/2(2 ) = 4 diastereomers. In a nonselective process the maximum yield for any one diastereomer is 25%. Furthermore, because diastereomers usually have rather similar physical properties, obtaining a single stereoisomer in pure form can be difficult. 

The restrictions applied to this pathway will depend on the reasons for the synthesis. Rigid control of stereochemistry is necessary if, for example, a biologically active natural product with several chiral centers is the goal of the synthesis. A 

These ideas can be illustrated by considering some examples of successful multistep syntheses. In these examples, we will have the benefit of hindsight, but let us attempt to recognize in particular the stages at which molecular skeleton, stereochemistry, and functionality were faced. The examples chosen are natural products, but the same ideas apply to any synthetic target. 

Juvabione. Let us look first at a molecule that has been synthesized in a number of alternative ways. Juvabione is a terpene-derived ketoester that has been isolated from certain plant species. It exhibits juvenile hormone activity that is, it can modify the process of metamorphosis in certain insects. At least seven syntheses of this 

There are two ionic modes of bond formation where one carbon fragment is nucleophilic (e rich) and the other is electrophilic (e poor). There is one free-radical mode in which each fragment has a single unpaired electron which becomes 

The spherical Jt-electron conjugated system of [60]fullerene contains the [lOjcyclo-phenacene system, which may be unraveled by removal of the top and bottom two [5]radialene structures (20jt electrons) at both poles of [60]fullerene. The approach shown in Fig. 2.4 constitutes double application of the method that removes one radialene moiety out of conjugation to leave a 50jt-electron bowl-shaped conju- 

The first step in the synthesis of a nanocrystal is a nudeation of the partides, as a successful nudeation will indicate whether the reaction in question is appropriate for the formation of nanocrystals. For a monodisperse sample, the nudeation event must be well separated in time from the growth step this generally means that nudeation must occur on a short time scale, on the order of a fraction of a second. In contrast, if nudeation is spread out in time, such that the nudeation and growth overlap, then different nudeation sites will undergo growth of varying durations, resulting in a broad size distribution. 

The chemistry of group III-V materials has proven to be more difficult with regards to designing a system with the attributes of both rapid and complete, yet controlled. 

---

The protecting groups are also used to solubilize synthetic intermediates in organic solvents, e.g. methylene chloride. Chromatography is then possible on a larger scale, since silica gel can be used as adsorbent. Six synthetic strategies have been developed (H. Kdster, 1979) ... 

Di- and trinucleotides may be used as units instead of the monomers. This convergent synthetic strategy simplifies the purification of products, since they are differentiated by a much higher jump in molecular mass and functionality from the educls than in monomer additions, and it raises the yield. We can illustrate the latter effect with an imaginary sequence of seven synthetic steps, c.g. nucleotide condensations, where the yield is 80% in each step. In a converging seven-step synthesis an octanucleotide would be obtained in 0.8 x 100 = 51% yield, compared with a 0.8 x 100 = 21% yield in a linear synthesis. 

Another synthetic strategy is based on self-assembly driven by molecular recognition between complementary TT-donors and 7T-acceptors. Examples include the synthesis of catenanes and rotaxanes that can act as controUable molecular shuttles (6,236). The TT-donors in the shuttles are located in the dumb-beU shaped component of the rotaxane and the 7T-acceptors in the macrocycHc component, or vice versa. The shuttles may be switched by chemical, electrochemical, or photochemical means. 

In several important cases, new synthetic strategies have been developed into new production schemes. An outstanding example of this is the production of an entire family of terpene derivatives from a-pinene (29), the major component of most turpentines, via linalool (3) (12). Many of these materials had been produced from P-pinene, a lesser component of turpentine, via pyrolysis to myrcene and further chemical processing. The newer method offers greater manufacturing dexibiUty and better economics, and is environmentally friendly in that catalytic air oxidation is used to introduce functionality. 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

In most cases the prolonged treatment of a closo carborane or borane with strong base results in the removal of a single-boron vertex to yield a nido cluster, inert to further degradation. This principle is exploited in the polyhedral contraction and subrogation synthetic strategies. In the prototypical case. 

Many stmctures are possible for the smaller metaHacarboranes and various synthetic strategies are available. Especially noteworthy is the occurrence of triple- and tetradecker sandwich compounds (214). The polyhedral expansion synthetic strategy can also be used with small carboranes (212). Eor instance, the small metaHacarborane /(9j (9-l,l,l-(CO)3-l,2,3-EeC2B4H3 [32761-40-3] (212) is obtained from C2B4Hg upon treatment with Ee(CO)3. 

Utilization of carbenes in the synthesis of five-membered heterocycles with two or more heteroatoms has not been featured prominently in the synthetic strategies developed for these ring systems. The following illustrations show their considerable promise. 

Early attempts to apply the Sheehan penicillin synthetic strategy to the total synthesis of cephalosporins were not particularly successful. Although the key step, formation of the /3-lactam CO—N bond, could be carried out efficiently (46->47), subsequent conversion of the lactone to a free C-4 carboxyl could only be accomplished in poor yield (B-72MI51007). 

Scheme 63 illustrates another synthetic route leading to the penam ring system (78JA4597). lis sequence contains some interesting points of synthetic strategy which are discussed in... 

Synthesis of cryptands which contain nitrogen atoms in the bridges has also attracted Lehn s attention. In general, a similar synthetic strategy was utilized, but ni-... 

A synthetic strategy which ensures retention of the monomeric form of SnR2 even in the crystalline state is to use functionalized R groups which contain a chelating substituent, e.g. by replacing the H atom in -CH(SiMe3)2 with a 2-pyridyl group. 

An alternative synthetic strategy for sulfur-nitrogen oxides is exemplified by the more recent reaction ... 

Novel synthetic strategies for DNA binding pyrrolobenzodiazepine antibiotics 98KGS1588. 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

Tliis chapter focuses on betetoatomcuprates and a-beteroatomalkylcuprates and the potential they offer in the development of synthetic strategies.. Alkylcuprate chemistry involving betetoatom functionality at a location other than the a-position is the topic of Cbapt. 2. 

The synthetic strategy towards the copolymers is shown in Figure 16-3. The use of bifunctional monomers in a Heck reaction allows the synthesis of polymers, and the great potential of this approach has been demonstrated previously [53-55]. The syntheses have been described in detail by Hilberer el al. [16],... 

---