Retrosynthetic analysis aldol reaction

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

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. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

In comparison to other aldolases, DERA has a rather broad substrate range. DERA-catalyzed aldol reactions were used to get an access to key intermediates for epothilones (Fig. 36) [194]. According to retrosynthetic analysis, both fragments of the molecule could be obtained from aldol building blocks, and two out of seven stereocenters were established enzymatically. For the southern part of epothilone A,... 

Thus the two mandelic acid-based boron enolates described in this section may be regarded as sources of propionic acid which add to aldehydes to give erythro aldol products of high stereochemical purity. An elegant synthesis of the macrolide, 6-deoxyerythronolide B, uses three mandelic acid-based boron enolate/aldehyde reactions. The retrosynthetic analysis of the synthesis is shown in Figure B5.ll. 

Inspired by the biosynthesis of carbohydrates we envisaged a direct de novo synthesis of carbohydrate derivatives by using the DHA-equivalent 4 in a C3+Cn-sirategy. As can be seen from the retrosynthetic analysis, the desired building blocks 5 should be prepared from the dioxanone (4) and an aldehyde component 6 in an organocatalytic aldol reaction... 

Our retrosynthetic analysis of the desired sphingoids relies on the previously developed diastereo- and enantioselective (S)-proline-cata-lyzed aldol reaction of the readily available dioxanone (4). In a second step, the amino group should be installed by reductive amination (Scheme 6) (Enders et al. 2006a). 

The (3-hydroxy carbonyl products of aldol reactions are often very easily dehydrated to give a, 3-unsaturated carbonyl compounds and, if you spot an a,p-unsaturated carbonyl group in the molecule, you should aim to make it by an aldol reaction. You will 6rst need to do an FGI to the P-hydroxy carbonyl compound, then disconnect as before, oxanamide intermediate retrosynthetic analysis... 

This scheme comprises many important organic reactions additions and eliminations, substitution reactions or certain pericyclic reactions. In fact, it is estimated that about 50 percent of all organic reactions can be represented by this reaction scheme. Application of such a reaction scheme onto bonds of a target molecule directly leads to precursors in the synthesis. Figure 5 illustrates how an aldol condensation can be found in a retrosynthetic analysis. 

The functional groups created by the aldol reaction are a j8-hydroxy carbonyl or an a,)8-unsaturated carbonyl. Whenever you encounter these patterns in a target molecule, you should consider using an aldol reaction for its construction. Using retrosynthetic analysis (Section 7.9), the aldol product can be dissected into the... 

To become skilled at retrosynthetic analysis, it is important to recognize that the a, 8-unsaturated carbonyl and S-hydroxy carbonyl functional groups are the characteristic products of an aldol reaction. 

Now apply a retrosynthetic analysis. The bond between the a and (3 positions is the bond formed during an aldol reaction. To draw the necessary starting materials, break apart the bond between the a and P positions, drawing a carbonyl group in place of the OH group. 

All P"hydroxy carbonyl compounds are potential products of an aldol reaction. Whenever you see one, your thoughts about synthesis must turn first to the aldol reaction. The same is true for the dehydration products, the a,P-unsaturat-ed carbonyl compounds. It is important to be able to go quickly to the new bond, to find the one formed during the aldol condensation, and to be able to dissect the molecule into its two halves. In doing this operation, you are merely carrying out a retrosynthetic analysis and following the mechanism backward (Fig. 19.76). 

ANSWER (b) In any aldol, or aldol-like condensation, the carbon-carbon n bond is formed through an elimination reaction (Rg. 19.73). So, the first part of our retrosynthetic analysis recognizes that the precursor to the final product is... 

Based on the concept of tandem reaction, a series of synthetic routes have been developed, including an intramolecular Aldol/Oxa-Michael/Aldol/Lactonization synthetic strategy (see Fig. 1.17). The retrosynthetic analysis indicated that the synthesis starts from compound 1.7.21, which first undergoes an intramolecular Aldol reaction then immediately intramolecular Oxa-Michael reaction to form the tricyclic system. Finally through the intermolecular Aldol reaction and intramolecular esterification reaction, the tetracyclic skeleton of Maoecrystal V can be constructed. And 1.7.21 can be provided by the relatively simple materials 1.7.22 and 1.7.23 through Suzuki cross-coupling reaction. 

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