Retrosynthetic Alcohol Synthesis

FIGURE 16.75 A retrosynthetic analysis of ways of making a tertiary alcohol. 

WORKED PROBLEM 16.26 Here is a specific example of using retrosynthetic analysis. Provide a retrosynthetic synthesis of 2-phenyl-2-butanol. Assume that you have benzene, ethanol, pyridine, and access to any inorganic reagents you might need. 

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The retrosynthetic analysis of fumagillol, the alcohol from which the antibiotic fumagillin is derived, has been outlined in Section 2.3. The experimentally demonstrated synthesis of fumagillol was derived by T-goal directed search to apply the Diels-Alder transform. 

A salient structural feature of intermediate 18 (Scheme 2b), the retrosynthetic precursor of aldehyde 13, is its y,r5-unsaturated ester moiety. As it turns out, the Johnson ortho ester variant of the Clai-sen rearrangement is an excellent method for the synthesis of y,<5-unsaturated esters.11 In fact, the Claisen rearrangement, its many variants included, is particularly valuable in organic synthesis as a method for the stereocontrolled construction of trans di- and tri-substituted carbon-carbon double bonds.12,13 Thus, it is conceivable that intermediate 18 could be fashioned in one step from allylic alcohol 20 through a Johnson ortho ester Claisen rearrangement. In... 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

ANSWER We are using a Williamson Ether synthesis, so we will need to start with an alcohol and an alkyl halide to form the ether linkage. Working backwards (retrosynthetic analysis), we get the following ... 

In continuation of our investigations on asymmetric nucleophilic acylations with lithiated a-aminonitriles [40], we envisaged the asymmetric synthesis of 3-substituted 5-amino-4-oxo esters A, bearing both a-amino ketone and 5-amino ester functionalities (Scheme 1.1.14) [41]. Since a-amino ketones are precursors of chiral p-amino alcohols [42, 43] and chiral amines [43], their asymmetric synthesis has the potential to provide valuable intermediates for the synthesis of biologically active compounds, including peptidomimetics [44]. The retrosynthetic analysis of A leads to the a-aminoacyl carbanion B and p-ester carbocation... 

As an example of this strategy, let s consider the synthesis of 2-methyl-6-methylene-7-octen-4-ol, an insect pheromone. (As described in the Focus On box on pages 1025-1026, pheromones are compounds used by animals, especially insects, for communication.) The synthesis of this alcohol, a component of the sex attractant of the male bark beetle, has been described in the literature. Retrosynthetic analysis, similar to that described earlier, suggested the use of a Grignard reaction to prepare this alcohol ... 

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