Retrosynthetic analysis construction

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

A retrosynthetic analysis of fragment 152 can be completed through cleavage of the C16-C17 bond in enone 155, the projected precursor of epoxide 152. This retrosynthetic maneuver furnishes intermediates 156 and 157 as potential building blocks. In the forward sense, acylation of a vinyl metal species derived from 156 with Weinreb amide 157 could accomplish the construction of enone 155. Iodide 153, on the other hand, can be traced retrosynthetically to the commercially available, optically active building block methyl (S)-(+)-3-hydroxy-2-methyIpropionate (154). 

Retrosynthetic analysis can identify component segments of a target molecule that can serve as key intermediates, and the subunits that are assembled to construct... 

The first diastereoselective syntheses of juvabione are described in Schemes 13.11 and 13.12. Scheme 13.10 is a retrosynthetic analysis corresponding to these syntheses, which have certain similarities. Both syntheses started with cyclohexenone, there is a general similarity in the fragments that were utilized, although the order of construction differs, and both led to ( )-juvabione. 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

Retrosynthetic analysis of the carbazomycins C (263) and D (264) based on the iron-mediated construction of the carbazole framework leads to tricarbonyl [3-methoxy-(l-5-ri)-cyclohexadienyl]iron hexafluorophosphate (779) and the aryl-amines 780a and 780b (see Scheme 5.84) as synthetic precursors (611). The arylamines 780a and 780b have been used previously as precursors for the total syntheses of carbazomycin A (260) and B (261) (see Schemes 5.86, 5.87 and 5.88). 

For the puiposes of retrosynthetic analysis, a six-membered ring in a target can be related to a Robinson annulation of an existing ketone with an a,/3-unsamrated ketone. Normally cc,/3-unsaturated methyl ketones are used to facilitate the ring closure, but this is not an absolute requirement. Thus the target steroid S could potentially be constructed by a series of Robinson annulations as shown. The last retrosynthetic step (the first synthetic step) could be problematic as a mixture of regioisomers would be formed. 

This time-honoured view of ring construction preceded the retrosynthetic approach it is still of value since it provides an indication of which bonds could be selected for disconnection. The more rigorous application of the principles of retrosynthetic analysis leads of course to the formulation of synthons and their reagent equivalents. 

A retrosynthetic analysis of (50) and (52) involving disconnection at both carbon-heteroatom bonds reveals hexane-2,5-dione as the four-carbon fragment needed for ring assembly ring construction is thus of type (45). The most convenient reagents for the appropriate heteroatom synthons are ammonium carbonate and phosphorus pentasulphide (Expts 8.11 and 8.13). 

An example of the Knorr pyrrole synthesis is provided by the formation of 3,5-diethoxycarbonyl-2,4-dimethylpyrrole (55). Overall ring construction in this case may be related to (46) above. A retrosynthetic analysis involving disconnection of the N—C2 bond, appropriate prototropic shifts, and finally a retro-aldol reaction to effect disconnection of the C3—C4 bond, reveals ethyl acetoacetate and ethyl a-aminoacetoacetate (ethyl 2-amino-3-oxo-butanoate) (56) as reagents. An FGI transform on this latter compound generates the corresponding nitroso (oximino) compound which may also be derived from ethyl acetoacetate. 

Corey (E.J Corey Pure Appl Chem 1969,14, 30) introduced the term synthon in 1969 when he published his innovative strategies for the construction of complex molecules by considering a retrosynthetic analysis. Later on, Hanessian s (Total Synthesis of Natural Products The Chiron Approach Pergamon Press, 1983) introduction in 1983 of the term Chiron referring to chiral synthons became the general strategy of carbohydrate like symmetry in new molecular targets of many natural products. 

The first phase of the total synthesis of thiostrepton 303, a highly complex thiopeptide antibiotic, has been described. Retrosynthetic analysis of thiostrepton revealed units 304-308 as potential key building blocks. Concise and stereoselective constructions of all these intermediates have been achieved. The synthesis of the dehydropiperidine core 308 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 305 and the thiazoline-thiazole segment 306 were synthesized by a series of reactions that included asymmetric and other stereoselective processes (Scheme 113) <2005JA11159>. 

Many natural compounds include heterocyclic systems constructed by hemiacetal formation between a hydroxyl group and a keto group of the chain in a 1,4- or 1,5-relative disposition. It is advantageous in a retrosynthetic analysis to take this point into account and to devise a disconnection next to the carbonyl group. Moreover, the synthetic connection does not involve chiral center formation. An obvious translation of this principle in carbohydrate chemistry is the formation of a carbon-carbon bond at the anomeric center by nucleophilic addition to lactones. However, other methods have also been devised to reach this goal. 

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