Disconnections, Synthons, and Synthetic Equivalents

When synthesizing an alkene using a Wittig reaction, the first thing you must do is decide which part of the alkene should come from the carbonyl compound and which part should come from the ylide. If both sets of carbonyl compound and yhde are available, the better choice is the set that requires the less sterically hindered alkyl haUde for the synthesis of the ylide via an Sn2 reaction. (Recall that the more stericaUy hindered the alkyl hahde, the less reactive it is in an Sn2 reaction see Section 9.1.) 

For the synthesis of 3-ethyl-3-hexene, for example, it is better to use a three-carbon alkyl hahde for the ylide and the five-carbon carbonyl compound than the five-carbon alkyl hahde for the ylide and the three-carbon carbonyl con touni because it is easier to form an yhde fi om a primary alkyl halide (1-bromopropane) than from a secondary alkyl hahde (3-bromopentane). 

Solution to 49a (1) The atoms on either side of the double bond can come from the carbonyl compound, so two pairs of compounds could be used. 

Solution to 49b (1) The alkyl halide required to make the phosphonium ylide would be 1-bromobutane for the first pair of reagents or 2-bromopropane for the second pair. 

Solution to 49c (1) The primary alkyl halide would be more reactive in the 8 2 reaction required to make the ylide, so the best method would be to use the first set of reagents (acetone and the ylide obtained from 1-bromobutane). 

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Designing a Synthesis V Disconnections, Synthons, and Synthetic Equivalents... 

The hydroxycarbocation and the hydride ion formed after disconnection of cyclohexanol are synthons. The synthetic equivalents of hydroxycarbocation and the hydride ion are cyclohexanone and sodium borohydride, respectively. Thus, the target molecule cyclohexanol can be prepared by treating cyclohexanone with sodium borohydride. 

The synthetic equivalents of the synthon H" are the hydride donors sodium borohydride NaBH4, and lithium aluminium hydride LiAIHi. How might you make TM 21 using this disconnection ... 

Figure 3.3 shows a simple example of a retrosynthetic synthesis of cyclohexanol. Cyclohexanol may be disconnected to a hydride ion and a hydroxycarbocation (the synthons). Sodium borohydride and cyclohexanone are the synthetic equivalents of these two synthons. Thus, reacting cyclohexanone with NaBH will produce cyclohexanol. 

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. 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

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. 

Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, and a donor synthon, a carbanion. In a formal sense, the reverse reaction — the formation of a C-C bond — then involves the union of an electrophilic acceptor synthon and a nucleophilic donor synthon. Tables 1.1 and 1.2 show some important acceptor and donor synthons and their synthetic equivalents. "... 

The "right half of the sesquiterpene (+)-p-selinene (as drawn below) includes (R)-(+)-limonene as a substructure. Retrosynthetic disconnection to (if)-(+)-limonene leads to the intermediate carbenium ions la and lb via 15-nor-ll-eudesmen-4-one (carbonyl alkenylation) and 15-nor-13-chloro-2-eudesmen-4-one (dehydrogenation, protective masking of the double bond in the side chain). These carbenium ions arise from (if)-9-chloro-p-menth-l-ene and the acylium ion Ic (synthone) originating from 3-butenoic acid as reagent (synthetic equivalent). (i )-/7-Menth-l-en-9-ol, on its part obtained by hydroboration and oxidation of (if)-(-l-)-limonene, turns out to be the precursor of the chloromenthene. 

Propose a reaction with a reasonable reaction mechanism. Look for familiar nucleophiles and electrophiles to undergo predictable reactions. A poor choice for a bond disconnection can lead to impossible synthons (and impossible reagents). However, we will learn that certain seemingly impossible synthons are, in fact, possible with the use of synthetic equivalents. 

Two synthons, cationic A and anionic B, which are the result of disconnection (a), have a couple of synthetic equivalents, for example, (1) and (2) in Table 10.3. 

First we accentuate that the most important retrosynthetic mle is related to the basic property of the C-C bond, electronic structure and electronic charges of the fragments that emerge on disconnection of this bond. The mle states that disconnection should follow the correct mechanism. Products of disconnection are synthons—anionic or cationic fragments or radicals. Behind synthons, however, real molecules should exist, denoted as reagents or synthetic equivalents. 

Scheme 2.2 presents disconnections of the methyl and cyclohexyl group. With participation of the carbinolic hydroxyl group, disconnection affords anionic synthons, methyl and cyclohexyl carbanion. Both have proper synthetic equivalents in the corresponding Grignard reagents. 

The above scheme presents disconnections of oxiranes (epoxides), aziridines and thiiranes (thioepoxides) leading to six-electron synthons and their synthetic equivalents. 

Retro-aldol disconnection of a,P-unsaturated ketone leads to 1,4-diketone TM 5.19a. By disconnection of the central C-C bond, we generate two synthons, a-carbanion of cyclohexanone and a-carbocation in acetone. Synthetic equivalents for two synthons are the enamine of cyclohexanone TM 5.19b and a-chloroacetone TM 5.19c (Scheme 5.45). 

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