Aldol-dehydration, intramolecular

The final two stages are very straightforward. Oxidative scission of the C3-C5 double bond in 6 with ozone provides triketone 5 which, without purification, is subjected to a base-induced intramolecular aldol/dehydration reaction. The crystalline product obtained from this two-step sequence (45 % overall yield) was actually an 85 15 mixture of ( )-progesterone and a diastereomeric substance, epimeric at C-17. Two recrystallizations afforded racemic progesterone [( )-(1)] in diastereomerically pure form. 

The reaction is carried out in vapour phase (250°C) using a flow system (see methods section). This procedure turned out to be essential in order to mantain the hydrogen transfer as the main reaction pathway. A batch experiment carried out in an autoclave actually showed a wide range of condensation products besides some saturated ketone [6]. Reactions of ketones over oxide catalysts can lead to a variety of products due inter alia to aldol condensation, intramolecular dehydration and intermolecular disproportionation [16]. However, the presence of a good hydrogen donor such as a secondary alcohol and vapour phase conditions favour the transfer hydrogenation as the major reaction [16,17]. In our reaction conditions, products attributable to crotonic condensations and subsequent 1,4 Michael addition [18] were observed by g.l.c.-m.s. (Table 1). 

One of the most important reactions for the construction of six-member rings (the Diels-Alder reaction is another) is based on a tandem reaction sequence a Michael addition reaction followed by an intramolecular aldol-dehydration reaction. This sequence is called the Robinson annulation (Sir Robert Robinson, Nobel Prize, 1947). " ... 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to /3-hydroxy aldehydes/ketones and then to a,/8-unsaturated products after dehydration. Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five- and six-membered rings. 

Keeping in mind that 1 was projected as a key intermediate for the synthesis of a variety of steroids, the Woodward group next turned to contraction of the D-ring to the required acyl cyclopentene. The diol was liberated and cleaved to a dialdehyde using periodic acid. The dialdehyde was then subjected to piperidinium ion mediated intramolecular aldol-dehydration to provide 18. The aldol-dehydration also provided the regioisomeric enal as a minor product. The regioselectivity of this reaction was attributed to the apparent steric accessibility of the C17 methylene in the intermediate dialdehyde relative to the C15 methylene. The synthesis of 1 was completed in a straightforward manner. 

Let s revisit the Wieland approach to steroids (Steroids-7). The reaction of 87 with the enone derived from in situ dehydrohalogenation of 88 gave 89. This was followed by an intramolecular aldol-dehydration to give 90. This is variation of 68 -I- 69 67 66 (followed by hydration to a cyclohexenone) as seen in Functional Groups-11. There are many more tactics that have been developed to accomplish this fundamental strategy in the laboratory. 

Consider the Johnson synthesis of progesterone. The q clization precursor (102) was derived from cyclopentenone 101, which was prepared by an intramolecular aldol-dehydration of 1,4-diketone 100. Johnson did not construct the 1,4-difunctional relationship present in 100. It was purchased in the form of 2-methylfuran (96). This simple heterocyclic compound is at the same oxidation state as the 1,4-dicarbonyl compound, released by hydrolysis of the furan, first in a protected form (98 and 99) and finally ready for use in the aldol dehydration (99 — 100). 

The preparation of 54 (same as 50 and similar to 9) passed through intermediates with only odd-difimctional relationships and used normal carbonyl chemistry (1,2-carbonyl addition, aldol-dehydration, conjugate addition, hydrolysis-decarboxylation). Conditions were also found to coax 54 to undergo the intramolecular conjugate addition to provide 48 (and its epimer a to the ketone). An unselective reduction of the ketone provided 49 after esterification of the intermediate alcohol. 

An intramolecular conjugate addition, followed by an enamine aldol-dehydration reaction provided 274 as a mixture of stereoisomers at C2. Catalytic hydrogenation of the isolated olefin gave 275 and TBAF removal of the silicon protecting group provided 186 after separation from the C2 diastereomer. 

Taber (University of Delaware) described an approach that focuses on the same bond construction used by Mulzer to set the quaternary center, but uses the opposite sense of polarity in construction of this bond. The key transformation was projected to be 100 to 101 via a combination of aldol-dehydration and intramolecular alkylation reactions (not in any particular order). Compound 100 is highly fimctionalized. Perhaps in an attempt to reduce the level of functionality in precursors, it was to be generated in a manner we first saw in Chapter 2, by the oxidative cleavage of a cyclopentene. 

Cascade reactions triggered by the combination of chiral amines and achiral Brpnsted acid were well documented on the basis of enamine and iminium ion formation, while examples with the combination of a chiral amine catalyst and a chiral Brpnsted acid were rare, hi 2(X)7, Zhou and List reported an elegant cascade intramolecular aldol-reduction process to prepare chiral 3-substituted cyclohexyl-amines by combining achiral enamine catalysis and chiral phosphoric acid catalysis [38]. Unusually, achiral aryl primary amine was exploited as an amino catalyst to generate a transient enamine intermediate to facilitate an intramolecular aldolization-dehydration process, while chiral phosphoric acid was harnessed to accelerate the following conjugate reduction-reductive amination cascade. Starting from readily available 2,6-diketones and aryl amines, pharmaceutically relevant 3-substituted cyclohexyamine derivatives were readily produced in satisfactory yield and excellent enantioselectivity (Scheme 9.42). 

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

The next step is an intramolecular aldol reaction leading to closure of a six-membered ring. Subsequent dehydration yields the bicyclic enone 4 ... 

Scheme 2.10 illustrates intramolecular aldol condensations. Entries 1 and 2 are cases of formation of five-membered rings, with aldehyde groups serving as the electrophilic center. The regioselectivity in Entry 1 is due to the potential for dehydration of only one of the cyclic aldol adducts. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

Another related synthesis made use of the intramolecular cycloaddition of co-nitroalkene 243, also derived from geraniol epoxide 237. Generation of the expected nitrile oxide dipole using p-chlorophenyl isocyanate and triethylamine quantitatively gave the annulated isoxazoline 244 as a 2 1 mixture of diastereo-isomers (Scheme 6.94). Reductive hydrolysis of the cycloadduct to the aldol product followed by dehydration provided enone 245, which was used to prepare the sesquiterpene nanaimoal 246 (242). 

Attempts to functionalize the homoallylic alcohol 15 quickly revealed that this product of an intramolecular aldol condensation was sensitive to base. Fortunately, heating with thiocarbonyldiimidazole effected clean dehydration to give predominantly the desired regioisomer of the diene. Methanolysis followed by oxidation then gave the triketone 1, which on epoxidation with MCPBA gave 2 as the minor component of a 3 1 mixture. 

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