Disconnections, retro-synthetic

A retro synthetic analysis corresponding to the synthesis in Scheme 13.23 is given in Scheme 13.22. The striking feature of this synthesis is the structural simplicity of the key intermediate IV A synthesis according to this scheme would generate the tricyclic skeleton in a single step from a monocyclic intermediate. The disconnection III => IV corresponds to a cationic cyclization of the highly symmetric cation IVa. 

SAMPLE SOLUTION (a) In a cyclopropane synthesis using the Simmons-Smith reagent, you should remember that a CH2 unit is transferred. Therefore, retro-synthetically disconnect the bonds to a CH2 group of a three-membered ring to identify the starting alkene. 

Retro-synthetic analyses ( = "antitheses") of relatively simple, but non-commercial target molecules are described. Stepwise disconnections and functional group interconversions are used to transform the desired molecule into inexpensive commercial compounds. 

The typical / -keto ester is ethyl acetoacetate (ethyl 3-oxo-butanoate). A retro-synthetic disconnection on this compound points to one of the most common methods for its synthesis, namely the Claisen ester condensation. 

Metathesis reactions may be intramolecular and ring-closing diene metathesis (RCM, implicated in Scheme 1.13, see Chapter 12) allows disconnections in retro-synthetic analysis otherwise of little use. The normal disconnection of the macrocyclic amide in Scheme 1.13 would be at the amide but, because of the ready reduction of alkenes to alkanes, the alternative disconnection now becomes a viable option. And since any of the C—C linkages could be formed by RCM, such a disconnection allows far greater synthetic flexibility than the conventional disconnection at the functional group. 

According to R. K. Boeckmann [6], the retro-synthetic analysis of ikarugamycin leads (by disconnection of the double bonds within the macro-cyclic ring) to the trieyclic building block 2 which,... 

Scheme 2.6 shows the synthetic strategy for the constmction of BTX A (35) (Scheme 2.6a), in bond disconnection (Scheme 2.6b), and retro-synthetic (Scheme 2.6c) formats. This strategy led to the expectation of using D-glucose 38 (Scheme 2.6c) and D-mannose 10 (Scheme 2.6c) as starting materials for the constmction of the requisite BCDE 36 (Scheme 2.6b) and GHIJ 37 (Scheme 2.6b) advanced intermediates, respectively. The union of 36 and 37 under Homer-Wittig conditions was... 

Organic synthesis has undergone the transformation from a purely heuristic discipline into a solid branch of science with its own logistics and technology based on the principles of retrosynthetic analysis. An essential part of retro-synthetic analysis involves the sequential disconnection of the target molecule... 

The construction of a synthetic tree by working backward from the target molecule (TM) is called retro synthetic analysis or antithesis. The symbol ==> signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, md functional group interconversions (FGI). 

Make C1-C5, C4-C6. Break C1-C4. The two new cr bonds have a 1,3-re-lationship in a new six-membered ring, suggesting that a Diels-Alder reaction has taken place. Disconnect the C1-C5 and C4-C6 bonds of the product to see the immediate precursor to the product, an o-xylylene. The double-bodied arrow (=>), a retro synthetic arrow, indicates that you are working backward from the product. 

The potential utility of an asymmetric addition to a prochiral carbonyl can be seen by considering how one might prepare 4-octanol (to take a structurally simple example) by asymmetric synthesis. Figure 4.16 illustrates four possible retro-synthetic disconnections. Note that of these four, two present significant challenges asymmetric hydride reduction requires discrimination between the enantiotopic faces of a nearly symmetrical ketone a), and asymmetric hydroboration-oxidation requires a perplexing array of olefin stereochemistry and regiochemical issues h). In contrast, the addition of a metal alkyl to an aldehyde offers a much more realistic prospect (c) or (d). 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

The final example illustrates yet another use of the biomimetic approach. Figure 10.9shows a retro-synthetic analysis for Masamune s synthesis of deoxyerythronolide B (213). The biosynthetic building blocks of this and other macrolide antibiotics are known to be acetate and/or propionate units combined head-to-tail, as seen in 213. 7 xhe stereocenters in 213 are clearly shown in the acyclic (seco acid) form of the macrolide 215. The specific biopathway is not utilized but rather modified to include the basic building blocks, seven propionate units (bold lines in 213).Seco acid 215 was constructed by sequential aldol condensation reactions (sec. 9.4.A) of propionaldehyde units, as shown by the disconnections in Figure 10.9. Asymmetric... 

A target may resist hydrolysis or chemical degradation, or the degradation products may not yield useful information. It is also common that insufficient material exists for proper analysis. In these cases, an alternative degradation technique is available that uses the ionizing electron beam of a mass spectrometer. The ionization pathways available from electron impact in the mass spectmm are bond fission processes that occur by known and predictable pathways. Indeed, each pathway usually follows analogous chemical reaction pathways in a retro-synthetic manner. It therefore follows that an examination of mass spectral ionization patterns can give clues for suitable disconnections and a synthetic tree. 

A synthon may be defined as— a structural unit that becomes an idealized fragment as a result of disconnection of a carbon-carbon or carbon-heteroatom bond in a retro synthetic step (transform) . 

In fact, the overall perspective and conception of a synthesis commences with a careful logical dissection of the tai et-drug-molecular skeleton into S3mthons. However, the disconnection of a bond within a monocyclic system shall be a retro-synthetic ring-opening phenomenon, otherwise termed as the retro-synthetic approach. Likewise, the disconnection of a bond caused in a bridged-structure would ultimately produce either a mono- or a di- substituted monocyclic structure. Sometimes, it may also be possible to accomplish two-bond disconnections taking place almost simultaneously. 

Retro synthetic disconnection of the ketal ester 1 appropriately begins at the cyclopentane ring E, which is expected to close by an intramolecular nucleophilic substitution of OR (tosylate) by the carbanion a to the methoxycarbonyl function in 2. The primary alcohol as the precursor of the methylether 2 turns out to be the product of esterification and reduction of the aldehyde carboxylic acid which is formed by ozonolysis of the enol 3 as a tautomer of the ketone 4. 

Section 8.12 Retro synthetic analysis can suggest a synthetic transformation by disconnecting a bond to a functional group and considering how that group can be introduced into the carbon chain by nucleophilic substitution. 

Retro synthetic analysis of alcohols via Gignard and organolithium reagents begins with a disconnection of one of the groups attached to the carbon that bears the oxygen. The detached group is viewed as synthetically equivalent to a carbanion, and the structural unit from which it is disconnected becomes the aldehyde or ketone component. 

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