Lipase I Mountain pine beetle I Asymmetric synthesis I Pheromones I Natural products (-)-exo-Isobrevicomin {( lS,5R,?S)-( -)-5-ethyl-?-methyl-6,8-acetal7 as the common intermediate and by using the Sharpdioxabicyclo[3.2.l]octane (1)) and its (-)-endo isomer less asymmetric dihydroxylation and Iipase-catalyzed acety-[ (lS,5R,?R)-2] were synthesized by employing the acetylenic lation as the key reactions.Both the exo and endo isomers of isobrevicomin (1 and Scheme 1. Retrosynthetic analysis of 1 and 2 2) were isolated in 1996 by Francke et al. as the components of the volatiles obtained from male mountain pine beetles, Dendroctonus ponderosae['I. The exo isomer (1) was far more abundant in the volatiles. Francke et al. synthesized (1S,5R,7S)-1 by starting from (+)-tartaric acid, and their coinjection experiments by chiral G C of the natural and synthetic 1 revealed the natural exo-isobrevicomin to be the (lS,5R,7$) isomer of at least 90% e.e.['l. The naturally occurring endo-isobrevicomin may share the same, stereochemically equivalent (1 S,5R)-6,8-dioxabicyclo[3.2. lloctane skeleton as shown in 2, but this has yet to be proved. According to the suggestion of Francke, we undertook our project to synthesize both (lS,5R,7$)-1 and (lS,5R,7R)-2 by employing a chemical or an enzymatic asymmetric reaction.Scheme 1 shows our retrosynthetic analysis of 1 and 2. Isobrevicomins 1 and 2 can be prepared by deprotection and intramolecular acetalization of the dihydroxy acetals A and B, respectively. The diols A and B are obtained by the Sharpless asymmetric dihydroxylation (AD)[2331 of the (aand (2)-olefinic acetals C and D. If the enantiomeric purity of A and B is low and unsatisfactory, it may be improved by either chemical or enzymatic purification. Both C and D can be prepared by selective reduction of the acetylenic acetal E.Two different syntheses of the building block 7 (= E) are summarized in Scheme 2. Commercially available 3-pentyn-1-01 (3) was converted to the corresponding iodide 4 via the tosylate. Alkylation of methyl 3-oxopentanoate with 4 (1 S,5R,7S)-l exdsobrevicorninLo] Part CLXXVII: M. Takenaka, H. Takikawa, K. Mori, Liebigs yielded the b X 0 ester 5, which was hydrolyzed and decarboxylated to give 7-nonyn-3-one (6). Acetalization of 6 with

In 1991, 5,ll-dimethylheptadecane (1) and 2S-dimethylheptadecane (2) were identified by Gries et a1.121 as the major and minor components of the female-produced sex pheromone of the eastern hemlock looper, Lumbdinufiscelluriufiscelluriu Guen. It then became clear that the western hemlock looper, Lumbdina fiscelluriu lugubrosu Hulst, also employs 1 as the major pheromone component, while 2 and 7-methylheptadecane are the minor and synergistic components of the These geometrid moths are important pests against balsam fir in Canada especially in Newf~undland [~,~]. The absolute configuration of the natural 1 was shown to be 5R,llS, because (5R,llS)-1 was the only stereoisomer eliciting electrophysiological responses by male L. fiscelluriu fiscelluriu and L. fiscelluriu lugubrosu antennaeL41. Subsequently, the (53-isomer of 2 was proved to be the synergistic sex pheromone component of L. fiscellavia lugubro.~a[~I. This paper describes a new synthesis of (5R,119-1 and that of (S)-2.Scheme 1 shows the retrosynthetic analyses of (5R,1153-1 and (9-2. In analogy to the previously reported synthesis of the stereoisomers of 13,23-dimethylpentatria~ontane[~I, (5R,119-1 was dissected into the three building blocks, A, B and C. These three blocks can be connected by alkylation of B with A and C. The optically active iodides A and C were to be prepared from the enantiomers of methyl 3-hydroxy-2-methylpropanoate (3) like in other cases of the synthesis of pheromone hydrocarbon^[^-"1. The second target molecule, (53-2, can be prepared by assembling the two building blocks D and E, the former of which may be synthesized from (9-citronellol (4).

We have described the design and synthesis of (E)-N-[17-(cyclopropylmethyl)-4,5a -epoxy-3,14-dihydroxymorphinan6b-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride, TRK-820 ( Fig. 1), and its pharmacological activity.1) TRK-820 exhibited a high k-opioid agonistic activity and effective antipruritic actions in histamine resistant pruritus models using mice.2,3) Now clinical trials of TRK-820 are in progress (Phase III in Europe and Phase IIb in Japan) as an antipruritic agent for uraemic pruritus.In order to investigate pharmacokinetics of TRK-820, it is necessary to synthesize potential metabolites of TRK-820 as standard materials. In general, 17-N-dealkylation and conjugation (3-O-b-D-glucuronide formation) are well known as major metabolic pathways for detoxification in 4,5-epoxymorphinans.4) Therefore, we supposed three kinds of metabolites 2, 3, and 4 of TRK-820 would occur in metabolism (Fig. 2). It is also important to investigate whether these compounds are active or inactive metabolites in pharmaceutical research. Herein we wish to report the syntheses of compounds 2, 3, and 4, and the results of their pharmacological studies and in vitro metabolism on TRK-820. Results and DiscussionNoroxycodone 5, which is a 17-N-dealkylated derivative with a 14b-hydroxy-4,5a-epoxymorphinan skeleton, was used as the starting material to synthesize compound 2 (Chart 1). Protection of the 17-amino group in noroxycodone 5 as a tert-butoxycarbonyl group (Boc), followed by reductive amination of the resulting compound 6 with N-benzylmethylamine using NaBH 3 CN 5) gave compound 7 in 72% yield (2 steps). Stereochemistry of the newly introduced amino group was elucidated to be 6b-configuration by 1 H-NMR spectral analysis of the 5-proton, which was observed at dϭ4.75 with an axial-axial coupling of 7.1 Hz between the 5-and 6-protons. Compound 7 was converted into amide 8 by debenzylation under hydrogenolysis conditions, followed by acylation with (E)-3-(3-furyl)acryloyl chloride in 61% yield (2 steps). The next step was deprotection of the 3-O-methyl and Boc groups of compound 8 to obtain the first target compound 2. For this purpose, the 17-N-Boc group of compound 8 was first converted to a 9H-fluorenylmethoxycarbonyl group (Fmoc) in 96% (2 steps). When compound 6 was directly treated with 1.0 M BBr 3 for removal of the 3-Omethyl and 17-N-Boc groups, the desired compound was obtained in ca. 50% yield concomitant with a significant amount of a 17-N-methylated compound due to side reaction with the resulting methyl bromide under the reaction conditions. Thus, in the case of compound 8, we had to replace the 17-N-Boc group with a 17-N-Fmoc group which is stable in Lewis acidic conditions. The reason why an Fmoc group was not used in the first protection step was due to instability of the Fmoc group in the presence of intramolecular basic amine at the 6-position (6-N(CH 3 )Bn or 6-NHCH 3 ) in the Pharmaceutical Research Laboratories, Toray Industries, Inc.; 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Received Dece...

Syntheses of 10-oxo, 10a a-hydroxy, and 10b b-hydroxy derivatives of a potent k k-opioid receptor selective agonist, TRK-820, are described. These derivatives were supposed to be potential degradation products in formulation of TRK-820 as a result of autoxidation. 10-Oxo-TRK-820 11 was derived from 10-oxo-4,5-epoxymorphinan 14 in 10 steps in 32% overall yield. Reduction of the 10-oxo group in 4,5-epoxymorphinan with NaBH 4 gave 10b bhydroxy-4,5-epoxymorphinan, exclusively. A stepwise inversion method of the 10b b-hydroxy group to produce 10a a-hydroxy-4,5-epoxymorphinan was established. By HPLC analyses, 10a a-hydroxy-TRK-820 12 was confirmed to be one of the degradation products in developing formulation of TRK-820.

A convenient oxidation method of the benzylic 10-position in 4,5-epoxymorphinan to obtain its 10-oxo derivatives is described. The reaction by using potassium permanganate proceeds in good yield and can be performed in large scale.Three types of opioid receptors (µ, δ, κ) are now well established by not only pharmacological studies but also molecular biological studies. 1-3 Especially, the κ-opioid receptor has been of interest because its activation produces analgesia with minimum physical dependence and respiratory depression. 4 Thus, a highly selective κ-opioid agonist may provide a useful analgesic free from abuse potential and the adverse effects of a µ-agonist like morphine. 4,5 Oxo derivatives at the benzylic position of 4,5-epoxymorphinan and benzomorphan were described to possess more κ-receptor selectivity than the corresponding parent compounds, respectively. 6-8 In our research program searching for opioid receptor-type selective compounds, we focused on the 10-oxo derivatives of 4,5-epoxymorphinan compounds. In the field of