Chiral pheromone lactones

Chiral y-iactones (10, 321). Midland3 has extended his synthesis of chiral y-lactones to an efficient synthesis of the sex pheromone (2) of the Japanese beetle. The overall optical yield of (2) from optically pure a-pinene is 97%. 

Both chiral lactones and ketones have been utilized in asymmetric synthesis of bioactive compounds like lipoic acid [175[ and natural products like various insect pheromones [176[. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

Birch reduction-methylation of the 2,3-dialkyl substituted benzamide 85 (Scheme 19) provided the cyclohexa-1,4-diene 86 with diastereoselectivity comparable to that observed with the 2-alkylbenzamides illustrated in Scheme 4. Cyclohexadiene 86 was converted to iodolactone 87 and reduction of 87 with BusSnH occurred with exclusive equatorial delivery of hydrogen to give the axial methoxyethyl derivative 88. Lactone 88 was converted to the Caribbean fruit fly pheromone (+)-epia-nastrephin 90 (> 98% ee) in 9.5% overall yield from the chiral benzamide 85. °... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Chiral lactones. The aldol type condensation of this reagent with an aldehyde has been used to synthesize two chiral five- and six-membered lactones in > 80% ee. The synthesis of the six-membered lactone (R)-( + )-d-n-hexadecanolactone (5), a pheromone of the Oriental hornet, from the /-butyl ester (1) of the sulfoxide is formulated in equation (I).1... 

The [2 + 2]-photocycloaddition chemistry of a,(3-unsaturated lactones has been widely explored. The factors governing regio- and simple diastereoselectivity are similar to what has been discussed in enone photochemistry (substrate class Al, Section 6.2). The HT product is the predominant product in the reaction with electron-rich alkenes [84]. A stereogenic center in the y-position of ot,P-unsaturated y-lactones (butenolides) can serve as a valuable control element to achieve facial diastereoselectivity [85, 86]. The selectivity is most pronounced if the lactone is substituted in the a- and/or P-position. The readily available chiral 2(5H)-furanones 79 and 82 have been successfully employed in natural product total syntheses (Scheme 6.30). In both cases, the intermediate photocycloaddition product with 1,2-dichloroethylene was reductively converted into a cyclobutene. In the first reaction sequence, the two-step procedure resulted diastereoselectively (d.r. = 88/12) in product 80, which was separated from the minor diastereoisomer (9%). Direct excitation (Hg lamp, quartz) in acetonitrile solution was superior to sensitized irradiation (Hg lamp, Pyrex) in acetone, the former providing the photocycloaddition products in 89% yield, the latter in only 45%. Cyclobutene 80 was further converted into the monoterpenoid pheromone (+)-lineatin (81) [87]. In the second reaction... 

The sex pheromone of the scarabaeid beetle Popillia japonica is a chiral lactone (379) with a (Z)-unsaturated side chain 218). Optically active (/ )(—)-glutamic acid 357, which is converted by retention of configuration via three steps into the Wittig synthon 377, serves as the starting material. Reaction of the latter with the ylide 378 yields the lactone 379 with the desired (R)(Z)-configuration 218) (Scheme 67). 

The (S)-(+)-y-butyrolactone-Y-carboxylic acid is a useful Intermediate for the synthesis of pheromones,4 natural lignans,5 and other derivatives.6 In the same manner, but starting with D-glutamic acid, the (R)-(-)-lactone acid may be prepared. Lactonization occurs with full retention of configuration at the chiral center.8 9 Recently, authors have described an efficient method which allows the formation of derivatives of the (R)-(-)-lactone from the more available (S)-(+) counterpart.10... 

It is not only drugs that have to be manufactured enantiomerically pure. This simple lactone is the pheromone released by Japanese beetles (Popilia japonica) as a means of communication. The beetles, whose larvae are serious crop pests, are attracted by the pheromone, and synthetic pheromone is marketed as Japonilure to bait beetle traps. Provided the synthetic pheromone is the stereoisomer shown, with the Zdouble bond and the R configuration at the stereogenic centre, only 25 jug per trap catches thousands of beetles. You first met this compound in Chapter 32, where we pointed out that double bond stereocontrol was important since the -isomer of the pheromone is virtually useless as a bait (it retains only about 10% of the activity). Even more important is control over the configuration at the chiral centre, because the S-enantiomer of the pheromone is not only inactive in attracting the beetles, but acts as a powerful inhibitor of the R-enantiomer—even 1% S-enantiomer in a sample of pheromone destroys the activity. 

Kinetic resolution of chiral acetals has been effected by use of some organoaluminum reagents [84], On treating a chiral acetal 88, derived from (2, 4/ )-(-)-pentanediol, with -Bu3A1 at room temperature, one diastereomer was found to react much faster than the other, and the residu enol ether is transformed into optically pure ketone. The efficiency of this method is demonstrated by a concise synthesis of (5)-(-)-5-hexadecan-l,5-lactone (89), the pheromone of Vespa orientalis, as shown in Sch. 56. 

The pheromone 151 possesses an anti-relationship between the two hydroxyl functions built in its structure (Scheme 43). The estabUshment of such an antistereochemistry requires the AD of a (Z)-olefin, a process which usually proceeds with moderate enantiocontrol. To overcome this difficulty, Lohray [120] performed the asymmetric dihydroxylation of the isomeric ( )-alkene 149 and inverted selectively one of the chiral center via an intramolecular lactonization reaction on the derived cyclic sulfate 150. 

Cucujoides. Group of unsaturated macrocyclic lactones with 12 or 14 carbon atoms identified as pheromones of the saw-toothed grain beetles of the genera Cryptolestes and Oryzaephilus. Some of these compounds, which occur in differing mixtures in the different species, are chiral and species-specific. Enantiomer ratios have also been observed, see also ferra-lactone II. 

Reaction of (5)-2-methy1decan-1-y1- 1ithiurn (76) with (3s,4s)-3, 4-dimethyl-Y-butyrolactone (75) has been used to prepare (2s,35,7s)-3,7-dimethylpentadecan-2-ol (77)This alcohol was converted to the acetate and propionate,which are potential pheromones of the European pine sawfly, Neodiprion sertifer. The chiral lactone (75) was obtained from (2S,3S)-trcms-epoxybutane and dimethyl malonate. 

Alkyl 2-acyloxy-3-deoxy-D-eryt7zr o-hex-2-enopyranoside diesters (91) have been converted into chiral 5-hydroxy-2-methylhexanoic acid lactones which constituted the pheromone of the Carpenter bee. Treatment of (90) with boron trifluoride etherate gave (91), which on addition of methylenetriphenylphosphorane gave a most interesting transformation to (92). A further reaction sequence... 

Enantiomerically pure lactonic pheromones 607-611, of the carpenter bee, blacktailed deer, Japanese beetle, rove beetle, and Oriental hornet, respectively, have been synthesized from racemic cyano alcohols of type 612. The key to the success of the overall approach is the facile separation of diastereomeric carbamates derived from cyano alcohols of type 612 by automated multigram LC. The chosen approach also facilitates the assignment of absolute configurations to the lactone enantiomers and their precursors. In the case of 607, direct determination of enantiomeric purity and absolute configuration is also possible using the chiral solvating agent 2,2,2-trifluoro-l-(9-anthryl)ethanol [439]. 

Midland and his co-workers have continued their work on the reduction of acetylenic keto-esters, e.g. (97), with chiral boranes to include a highly efficient synthesis of the insect pheromone (98). Catalytic hydrogenation of the lactone tetra-acetate (99) in the presence of triethylamine gives the triacetate (100) by... 

A review of syntheses of the Prelog-Djerassi lactonic acid includes carbohydrate-based routes,27 and there have been two further reports of syntheses of the P-hydroxy-5-lactone unit (38) of mevinic acid and its congeners.28, 29 jn a synthesis of the mosquito oviposition pheromone (39), the chiral centres were derived from those of 2,3-0-ethylidene-D-erythrose, with this chiron being extended by Wittig reactions, in a similar manner to the use of 2-deoxy-D-ribose in an earlier approach to the same target (S.-K. Kang and I.-H. Cho, Tetrahedron Lett., 1989, 30, 743). 

The insect pheromone (140) has been prepared in an optically pure form by the chiral reduction of the keto-ester (139), followed by lactonization and partial reduction of the acetylene group (Scheme 85). 

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