Hexadecanolides

Rj-S-Hexadecanolide (27) is the pheromone produced by the queens of the oriental hornet (Vespa orientalis). Yamamoto synthesized (R)-27 by employing an interesting asymmetric process (A—>B) followed by a multi-step conversion of B to (R)-27 via C (Scheme 40) [65]. 

Scheme 41 summarizes Couladouros s synthesis of the oviposition attractant pheromone of the Southern house mosquito (Culexpipiensfatigans)y (5R,6S)-6-acetoxy-5-hexadecanolide (28) [66]. The key-steps are (i) -selective Schlosser olefination (A B), asymmetric dihydroxylation (B C), and lactonization of carbonate C to the desired 6-lactone with inversion at C-5. 

Four macrolides, 11-undecanolide (12-membered,UDL) [85,86], 12-dodeca-nolide (13-membered,DDL) [86,87], 15-pentadecanolide (16-membered, PDL) [85,86,88,89], and 16-hexadecanolide (17-membered, HDL) [90], were subjected to the lipase-catalyzed polymerization. For the polymerization of DDL, lipases CC, PC, PF, and PPL showed the high catalytic activity and the activity order in the bulk polymerization was as follows lipase PC > lipase PF > lipase CC> PPL. These enzymes were also active for the polymerization of other macrolides. NMR analysis showed that the terminal structure of the polymer was of carboxylic acid at one end and of alcohol at the other terminal. 

Following a report that male P. hybneri were attractive to both sexes [99], males were found to produce a mixture containing the sesquiterpene 6-sesquiphellandrene, (R)- 15-hexadecanolide 114, and methyl (Z)-8-hexade-cenoate [100]. Odors from live males were attractive to adults of both sexes, with males also becoming sexually stimulated. Each component alone had some slight activity, with the 3-component blend being the best attractant in laboratory bioassays. The (S)-enantiomer of the macrolide lactone component was not inhibitory. 

Scheme 16 Synthesis of both enantiomers of 15-hexadecanolide from a single precursor via judicious choice of macrolactonization conditions...

Advent of ring-closing olefin metathesis reaction has influenced the synthetic strategy of pheromones very much. For example, the racemate of a macrolide pheromone such as (5Z,13S)-5-tetradecen-13-olide (29) (aggregation pheromone of the flat grain beetle, Cryptolestes pusillus) could readily be synthesized as shown in Scheme 42 [67]. Unfortunately, ( )-29 prepared by this method was a mixture of c/s, trans-isomers (Z/E=69 31). (S)-5-Hexadecanolide (27) was also synthesized by means of ring-closing olefin metathesis as shown in Scheme 43 [68]. 

S, 5i )-2-methylhexanolide and (i )-hexadecanolide were synthesized as examples of a new protocol for asymmetric reduction of long chain aliphatic ketones. 

Efficient asymmetric total syntheses of naturally occurring insect pheromones, (i )-4-dodecanolide and (5)-5-hexadecanolide have been reported. 

The process starts from tricyclohexylidene triperoxide which is obtained by oxidation of cyclohexanone with hydrogen peroxide. Pyrolysis leads to a mixture of 1,16-hexadecanolide and cyclopentadecane. The latter is oxidized by oxygen under boric acid catalysis to cyclopentadecanol which is subsequently oxidized to cyclopentadecanone [124,124a]. 

Oxa-16-hexadecanolide as well as the stronger smelling 11-oxa (m = 9, n = 5) [3391-83-1], and 10-oxa m = %, n = 6) [1725-01-5] isomers which are obtained in the same way from the corresponding hydroxy-oxa acids, are used as long-lasting musks mainly in fine fragrances. 

Trade Names. 12-Oxa-16-hexadecanolide = Cervolide (Quest), Musk 781 (IFF) ll-Oxa-16-hexadecanolide = Musk R 1 (Quest) 10-Oxa-16-hexadecanolide = Oxalide (Takasago). 

Macrocyclic lactones like ambrettolide (7-hexadecen-l,16-olide) 158, 15-pentadecanolide (cyclopentadecanolide) 159, hexadecanolide (cyclohexa-decanolide) 160 and cyclohexadec-7-enolide 161 (Structure 4.48) are called musks. They are found in a variety of essential oils, e.g. ambrette seed oil and angelica root oil [1-4, 21-23, 62]. 

The nature of the product strongly depends on the length of the hydroxy acid generally when the hydroxyl group is remote the yield of lactone drops significantly. For example, 10-hydroxydecanoic acid [1679-53-4] does not produce any decanolide instead, the reaction proceeds by intermolecular oligomerization, and a complex mixture of di-, tri-, tetra-, and pentalactones results (90). However, when Pseudomonas sp. or Candida cylindracea Upases are incubated with 16-hydroxyhexadecanoic acid [506-15-8]hexadecanolide is the predominant product (91). 

This one-pot, three-component reaction has been successfully applied to the total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 131 (Scheme 9.23). 

Based on the previous work of this group on the three-component aza[4+2]/ allylboration strategy to construct polysubstituted piperidines [62], Gao and Hall developed a catalytic enantioselective version [63] of the corresponding oxygeneous process to construct a-hydroxyalkylated pyrans from 3-boronoacrolein [64], This recent variant of a Vaultier-Lallemand one-pot three-component reaction (see Scheme 12.14) was successfully applied to a concise total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 128 (Scheme 12.20), the oviposition attractant pheromone of the female Culex mosquito [65] capable of transmitting the West Nile virus. 

Kotsuki, H. Kadota, I. Ochi, M. A novel C-C bond-forming reaction of triflates with Cu(I)-catalyzed Grignard reagents. A new concise and enantiospecific synthesis of (+)-e o-brevi-comin, (5 R,6 S) - (-) -6-acetoxy-5 -hexadecanolide, and L-factor. J. Org. Chem. 1990, 55, 4417-4422. 

Compound 33, was allowed to react with BrMg (Ct ) and the syn and anti diastereoisomers so obtained were separated to ultimately yield, (5S,6R) 6-acetoxy-5-hexadecanolide 42 and the... 

R,6R) diastereoisomer (Scheme 7). Again, from 34 the (5R,6R) product 43 was obtained. Products 42 and 43 represent the two enantiomers of the proposed major component of a mosquito oviposi-tion attractant pheromone (18). The enantiomeric forms of 5-hexadecanolide, 44 and 45, the pheromone of Vespa orientalis, were obtained from the enantiomeric aldehydes 34 and 37 (19). All the compounds obtained up to this point have been prepared in both enantiomeric forms, starting from a single chiral material. 

Both y- and 5-keto acids are reduced to hydroxy acids, which directly cyclize to the corresponding lactones in the incubation media. The pheromone (/f)-(+)-hexadecanolide has been prepared in this way by reduction of the corresponding 5-keto acid (eq 7). ... 

V. Alphand, A. Archelas, and R. Furstoss, Microbiological transformations. 13. A direct synthesis of both S and R enantiomers of 5-hexadecanolide via an enantioselective microbiological Baeyer-VUliger reaction, /. Org. Chem., 72 347 (1990). 

Couladouros, E. A., Mihou, A. P. A general synthetic route towards y- and 5-lactones Total asymmetric synthesis of (-)-muricatacin and the mosquito oviposition pheromone (5R,6S)-6-acetoxy-hexadecanolide. Tetrahedron Lett. 1999, 40,4861-4862. 

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