Retrosynthetic analysis synthetic equivalents

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... 

Retrosynthetic analysis may identify a need to use synthetic equivalent groups. These groups are synthons that correspond structurally to a subunit of the target structure, but in which the reactivity of the functionality is masked or modified. As an example, suppose the transformation shown below was to be accomplished. 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

Retrosynthetic Analysis — One-Step Disconnections. For each of the following compounds, suggest a one-step disconnection. Use FGIs as needed. Show charge patterns, the synthons, and the corresponding synthetic equivalents. 

Synthesis. Outline a retrosynthetic scheme for each of the following target molecules using the indicated starting material. Show (1) the analysis (including FGI, synthons, and synthetic equivalents) and (2) the synthesis of each TM. 

Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs. 

Retrosynthetic analysis shows that 1-methylcyclohexanol can be formed from the reaction of cyclohexanone, the synthetic equivalent for the a-hydroxycarbocation, and methylmagnesium bromide, the synthetic equivalent for the methyl anion (Section 18.4). 

A useful step in a retrosynthetic analysis is a disconnection—breaking a bond to produce two fragments. Synthons are fragments of a discomiection. A synthetic equivalent is the reagent used as the source of the synthon. 

For disconnect fragments 22 and 23 in Section 1.2, convert each to a real molecule using synthetic equivalents in Table 1.2. Briefly discuss the retrosynthetic and synthetic sequences and show the complete retrosynthetic analysis based on this disconnection. 

In 1995 we accomplished the total synthesis of (+)-eremantholide A (8). Our synthetic scheme was completely different from that of the Boeckman group. We selected our building block 2 as the starting material, and the retrosynthetic analysis is outlined in Scheme 6. At first, disconnection of two carbon-carbon bonds in 8 as depicted leads to two fragments, an A/B ring equivalent 55 and known disubstituted 3(2if)-furanone derivative 56. We planned the direct connection of intact 3(2if)-furanone 56 to 55 at a... 

Maytansine can be interconvertible with maytansinol which has free C3-OH with no amino acid-derived ester. Maytansinol has also been found in nature [lb] and it can be a common synthetic precursor for maytansine as well as for other ansamitocins [2]. Retrosynthetic analysis to the maytansinol molecule is of extreme interest in the positions of bond disconnection. One of the possible strategies is to close the 19-membered ansa-ring by lactamization from the most convenient precursor, the so called s co-acid 5 or its equivalent. 

Retrosynthetic analysis of nitrile 164 disconnects the C-CN bond because it is clear that the six carbons of the methylcyclopentene starting material are more or less intact in the remainder of the molecule. This disconnection requires a C-C bond-forming reaction involving cyanide. Because cyanide is associated with a carbon nucleophile, assign Cj to the cyanide and to the cyclopentene carbon. The synthetic equivalent for Cg is an alkyl halide, and 2-bromo-l-methylcyclopentane (168) is the disconnect product. Bromide 168 is obtained directly from the alkene starting material, but it requires the use of a radical process to generate the anti-Markovnikov product (see Chapter 10, Section 10.8.2). 

Before consideration of the electronic stmcture of synthons and properties of their acceptable synthetic equivalents, let us see the general scheme that illustrates retrosynthetic analysis (Scheme 1.1). 

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