Internal aldolization synthesis

The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172 The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem... 

The 3.8-nonadienoate 91, obtained by dimerization-carbonylation, has been converted into several natural products. The synthesis of brevicomin is described in Chapter 3, Section 2.3. Another royal jelly acid [2-decenedioic acid (149)] was prepared by cobalt carbonyl-catalyzed carbonylation of the terminal double bond, followed by isomerization of the double bond to the conjugated position to afford 149[122], Hexadecane-2,15-dione (150) can be prepared by Pd-catalyzed oxidation of the terminal double bond, hydrogenation of the internal double bond, and coupling by Kolbe electrolysis. Aldol condensation mediated by an organoaluminum reagent gave the unsaturated cyclic ketone 151 in 65% yield. Finally, the reduction of 151 afforded muscone (152)[123]. n-Octanol is produced commercially as described beforc[32]. 

An ingenious new method for the preparation of Woodward s intermediate (97) by Pearlman70 constitutes another formal synthesis of reserpine. The essence of this new approach is an adaptation of the de Mayo reaction which allows the introduction of vicinal aldehyde and acetic ester functions on to a double-bond (Scheme 13). An internal [2tt + 27r] photocyclization of the diene (98) gave the tetracyclic cyclobutane derivative (99), which was converted into the ester (100) by standard procedures. Methanolysis of the acetate function with concomitant retro-aldol fission completed the introduction of the vicinal aldehyde and acetic ester functions obvious manipulation then gave the desired intermediate (97). 

The transformation of cyclododecanone via IX/9 to the bicyclic intermediate, IX/10 is possible through an internal enamine reaction. Cleavage of the central ketone bridge gives the 14-membered product IX/11 [3]. This reaction was a key step in the synthesis of ( )-muscone (IX/15), Scheme IX/2, [4]. On treatment with base, the bicyclic intermediate, IX/13, prepared from 2-nitrocyclotri-decanone (IX/12), was quantitatively (R=H) [5] (or in 47 % yield (R=CH3) [4]) converted into the enlarged product IX/14. The retro aldol reaction was not... 

As mentioned above, treatment of the aldol adducts 150 a/b with NMO produced the phenol 152. The interesting oxidation properties of NMO had previously been investigated by Sulikowski et al. on the model compound 157 [85] (Scheme 40). They observed the formation of the hemiacetal 159 in 60% yield and assumed attack of the nucleophilic N-oxide on the quinonemethide tautomer 158 (or on the anion of 158). A related reaction was observed in our group in which the diol 94 was methoxylated at C-6 to 95 by treatment with methoxide ions [82] (Scheme 27). An internal redox step is postulated to account for the reductive 0-N-bond cleavage with concomitant oxidation of the hydroquinone back to the quinone. Without the presence of perruthenate, aromatization with formation of a C-5 phenolic hydroxy group was observed, a reaction later exploited in the synthesis of angucycline 104-2 [87] (see Scheme 49). Thus, based on similar mechanistic principles, the chemical results of the NMO oxidations were quite different compound 147 gave the C-6 phenol 152 [86] whereas 157/158 were converted to the C-5 phenol 160 [85]. 

The important intermediate 66 of the steroid synthesis has been prepared by the application of the same reaction sequence to 2-methyl-1,3-cyclohexanedione (65) (Scheme 22). A synthesis of (+) 19-nortestosterone (69) starts with the Michael addition of the optically active oxo ester 67 to 1,7-octadien-3-one (59) catalyzed by sodium hydride, the ester group being removed by heating in aqueous HMPA with sodium iodide to give the dione 68. The aldol condensation catalyzed by sodium hydroxide proceeds in 90% yield. The terminal double bond is oxidized with PdCl2/CuCl to the methyl ketone and the internal olefinic double bond subsequently hydrogenated. The final reaction step involves aldol condensation in refluxing... 

Evans, D.A., Janey, J.M., Magomedov, N. and Tedrow, J.S. (2001) Chiral salen-aluminum complexes as catalysts for enantioselective aldol reactions of aldehydes and 5-alkoxyoxazoles an efficient approach to the asymmetric synthesis of syn and anti P-hydroxy-a-amino acid derivatives. Angewandte Chemie - International Edition, 40, 1884—1888. 

When the aldol reaction furnishes an intermediate oxonium ion, a Prins cydization may ensue in the case where a suitable internal nucleophile is present that intercepts this oxonium ion. Rychnovsky et al. have developed this strategy into a powerful tool for the straightforward synthesis of tetrahydropyrans [7]. Thus, enol ether 15 attached to an allyl silane reacted with various aldehydes under BFj activation to produce 2,6-cis-substituted-4-methylene tetrahydropyrans 16 in good to very good yields (Table 8.2). 

---