Alkenes retrosynthesis

Initially, after the retrosynthesis of the target substrate, the starting reagents are chosen (for I, nitroolefin and two alkenes with opposite demands). Then intermediate six-membered cyclic nitronate (259) is synthesized (Scheme 3.172). 

For the retrosynthesis of the isoxazole system (see Fig. 5.12), it is essential that the heterocycle possesses the functionality of an oxime and of an enol ether, and that C-3/C-5 are at the oxidation level of a carbonyl function. Therefore, a logical retrosynthetic route (a - c) leads by way of the monoxime 2 to the 1,3-diketone and hydroxylamine. If the retrosynthetic operation a to d is generalized, one arrives at the 4,5-dihydroisoxazole 1. Its analysis, according to a retroanalytically permitted cycloreversion, leads to an alkene unsubstituted by a leaving group and to a nitrile oxide 3. These fragments represent the two components of a 1,3-dipolar cycloaddition. 

The ether is prepared via the corresponding halide. If the C-0 bond in 163 is disconnected, the logical bond polarization makes O 6- and a donor site Cj, and that of C2 is 6+, or (an acceptor site). In Chapter 25, Table 25.1 indicates that a synthetic equivalent for Cg is an alkyl halide. Therefore, a reasonable disconnection of 163 leads to 2-bromopentane (167) and the nucleophilic methoxide ion. This suggests a Williamson ether synthesis (Section 11.3.2). Can 167 be prepared directly from 1-pentene The answer is yes, by reaction of the alkene with HBr (Chapter 10, Section 10.2). Therefore, the retrosynthesis shown leads to the synthesis shown in which 1-pentene reacts with HBr to give 167, and a subsequent Sn2 reaction with... 

The readily available 1-propyne reacts with HBr to obtain 29. Disconnection of the bond adjacent to the carbonyl in 27 (the functional group) leads to 30 and 31. Because 30 is the one-carbon fragment, it becomes the acceptor and the synthetic equivalent is iodomethane. This makes 31 the donor, and a reasonable synthetic equivalent is the enolate anion of acetaldehyde, 32 (see Chapter 22, Section 22.9, for alkylation of enolate anions). This leads to the overall synthesis shown, based on the retrosynthesis (see Figure 25.11). The ability to see the relationship between an alkene and an alkyne allowed identification of a logical disconnection and a reasonable synthesis. 

The retrosynthesis of an alkyl halide TM involves an FGI to a suitable alkane, alcohol, or alkene starting material. 

If an elimination reaction is planned, the retrosynthesis of an alkene involves an FGI that adds either HX or water to the alkene to give an alkyl halide or an alcohol starting material, respectively. The stability of the alkene TM will help determine whether an E2 or El elimination would be more suitable. For example, an unstable, terminal alkene cannot be prepared via dehydration because a rearrangement of the carbocation intermediate would be expected. Care must be taken such that the alkyl halide or alcohol starting material would give only the desired TM as the major product. 

At first, this transformation might seem challenging, since no reaction exists that adds an alkynyl group to an alkene. However, a systematic approach to these problems always begins with the ending a retrosynthesis of the desired product. Once the alkyne TM is disconnected to give an acetylide nucleophile and a five-carbon electrophile (1-bromopentane), the solution becomes clear. 

The retrosynthesis of an alkane TM generally begins with an FGI that adds a functional group of your choice (an alkyl halide, alkene, alkyne, aldehyde, or ketone), and continues with a disconnection consistent with that functional group. Addition of the functional group at a branch point will likely lead to a good disconnection, but its precise location is not critical since it will ultimately be removed. 

The retrosynthesis of a 1,2-diol leads to an alkene, and the resulting alkene can be further analyzed retrosynthetically (e.g., the alkene can be prepared by a Wittig reaction or by dehydration of an alcohol, if it is not commercially... 

The target molecule must first be rotated to fit the Sharpless asymmetric epoxidation model (need to have allylic alcohol group in bottom right position). The retrosynthesis of the epoxide leads to an alkene with the stereochemistry shown. Since the oxidation has occurred at the top face, the (+) enantiomer of diethyl tartrate (DET) is required. Note that only the alkene with the aUyUc hydroxyl group is oxidized in the Sharpless epoxidation. 

However, we know of no reactions that convert alcohols directly to epoxides. Because we do know that epoxides are prepared from alkenes, we expand our retrosynthesis to reflect that. 

The problem specifies that a hydrocarbon be the starting material, so hydroboration-oxidation of an alkene is a reasonable possibility for completing the retrosynthesis. 

Abstract A problem-solving approach to retrosynthesis is introduced. Basic principles for good disconnections are postulated. Examples of interconversion and disconnection of carbinols, alkenes, ketones and nitro compounds are discussed. Concepts of retro-Diels-Alder and re/ro-Wittig disconnections are presented and the mechanisms of reactions explained. Application of the Wittig reaction on the industrial scale is exemphfied by the synthesis of the analog of bombykol, the principal of pear odor and anti-appelizer chlorphentermine. 

Note The reader is prompted to consider a retrosynthesis that includes the retro-Diels-Alder disconnection of the precursor of TM 9.1 to isoprene and nitro-alkene as a dienophile. The retrosynthesis presented in Sect. 2.5, Example 2.20, provides a hint. 

---