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Notes: About the Stereospecific α-Alkylation of β-HydroxyestersIt was found, that dianions derived from β-hydroxyesters with lithium diisopropylamide (LDA) at -50 to -20° were alkylated stereospecifically (Scheme 1). The stereospecificity was 95-98%, the threo-compound (threo-2, -3 and -4) being the main product. This was proved for threo-2 and -3 by preparing the β-lactones 7 and 8, respectively, which were pyrolyzed to trans-1, 4-hexadiene (9) and trans-1-phenyl-2-butene (10), respectively (Scheme 2). Moreover, the acid threo-6 from threo-3 was converted by dimethylformamide-dimethylacetal to cis-1-phenyl-2-butene (11) (s. footnote 6).The alkylation of α-monosubstituted β-hydroxyesters also turned out to be stereospecific. Reduction of 16 and 18 with actively fermenting yeast furnished (+)-17 and (+)-2. respectively (Scheme 4), which were each mixtures of the (2R, 3S)- and the (2S, 3S)-isomers. Alkylation of (+)-17 with allyl bromide yielded after chromatography (2S, 3S)-19 and of (+)-2 with methyl iodide (2R, 3S)-19, the oxidation of which finally gave (S)-(-)-20 and (R)-(+)-20, respectively.

Notes: Stereospecific Synthesis of (+)-(3R, 4R)-4-Methyl-3-heptanol, the Enantiomer of a Pheromone of the Smaller European Elm Bark Beetle (Scolytus multistriatus)Reduction of 2 with actively fermenting baker's yeast gave (-)-3. Stereospecific alkylation [3] of (-)-3 with propyl iodide furnished ethyl (+)-(2R, 3R)-2-propyl-3-hydroxypentanoate ((+)-4, 58%) which was converted to the tetrahydropyranyl ether (-)-5, then the alcohol 6, the p-toluenesulfonate 7 and the thiophenyl ether 8 to give the title compound (+)-1. The latter consisted of 97% of the threo- and 3% of the erythro-isomer. The above synthesis also correlates the absolute configuration of (-)-(R)-3 with that of (+)-(R)-citronellic acid (see [2]).

Notes: The Stereoselectivity of the α-Alkylation of (+)-(1R, 2S)-cis-Ethyl-2-hydroxy-cyclohexanecarboxylateIn continuation of our work on the stereoselectivity of the α-alkylation of β-hydroxyesters [1] [2], we studied this reaction with the title compound (+)-2. The latter was prepared through reduction of 1 with baker's yeast. Alkylation of the dianion of (+)-2 furnished (-)-4 in 72% chemical yield (Scheme 1) and with a stereoselectivity of 95%. Analogously, (-)-7 was prepared with similar yields. Oxidation of (-)-4 and (-)-7 respectively furnished the ketones (-)-6 (Scheme 3) and (-)-8 (Scheme 4) respectively, each with about 76% enantiomeric excess (NMR.). It is noteworthy that yeast reduction of rac-6 (Scheme 3) is completely enantioselective with respect to substrate and product and gives optically pure (-)-4 in 10% yield, which was converted into optically pure (-)-6 (Scheme 3).The alkylation of the dianionic intermediate shows a higher stereoselectivity (95%) from the pseudoequatorial side than that of 1-acetyl- or 1-cyano-4-t-butyl-cyclohexane (71% and 85%) [9] or that of ethyl 2-methyl-cyclohexanecarboxylate (82%). The stereochemical outcome of the above alkylation is comparable with that found in open chain examples [1] [2].Finally (+)-(1R, 2S)-2 was also alkylated with Wichterle's reagent to give (-)-(1S, 2S)-9 in 64% yield. The latter was transformed into (-)-(S)-10 and further into (-)-(S)-11 (Scheme 5). (-)-(S)-10 and (-)-(S)-11 showed an e.e. of 76-78% (see also [11]). Comparison of these results with those in [11] confirmed our former stereochemical assignment concerning the alkylation step.

Notes: Thermal Rearrangement of 2-Oxa-bicyclo [3.3.1]-non-7-en-3-ones; a Novel Lactone RearrangementLactone (+)-2 was prepared by iodolactonisation and subsequent elimination in 51% yield from the known acid (+)-1 (Scheme 1). Alkylation of (+)-2 furnished (+)-3a, (+)-3b and (+)-3c, respectively (Scheme 2). Heating of (+)-3a in boiling DMF racemized the compound ((+)-3a ⇆ (-)-4a). Heating of (+)-3b and (+)-3c, respectively, equilibrated them with (-)-4b and (-)-4c, respectively. This results are interpreted as a [3.3]-sigmatropic rearrangement with a transition state as depicted in a.

Notes: Synthesis of (±)-α-ChamigreneCis- and trans-β-ionol (cis and trans-1) underwent acid catalysed dehydration to a mixture of the tetraenes 2-5 in 70-80% yield (Table 1). Irradiation of this mixtures made the 6-(Z), 8-(Z)-isomer 5 accessible (columns 3 and 4 in Table 1). Pyrolysis of the different mixtures at 170° showed, that both isomers, 3 and 5 respectively undergo electrocyclization to dehydrochamigrene (6). The latter was reduced to α-chamigrene (7) by hydrogen on Lindlar catalyst.

Notes: Photochemistry of tricyclic β, γ-γ′, δ′-unsaturated ketonesThe easily available tricyclic ketone 1 (cf. Scheme 1) with a homotwistane skeleton yielded upon direct irradiation the cyclobutanone derivative 3 by a 1,3-acyl shift. Further irradiation converted 3 into the tricyclic hydrocarbon 4. However, acetone sensitized irradiation of 1 gave the tetracyclic ketone 5 by an oxa-di-π-methane rearrangement. Again with acetone as a sensitizer the ketone 5 was quantitatively converted to the pentacyclic ketone 6. The conversion 5 → 6 represents a novel photochemical 1,4-acyl shift. The possible mechanisms are discussed (see Scheme 7). The tricyclic ketone 2 underwent similar types of photoreactions as 1 (Scheme 2). Unlike 5 the tetracyclic ketone 9 did not undergo a photochemical 1,4-acyl shift. The epoxides 10 and 14 derived from the ketones 1 and 2, respectively, underwent a 1,3-acyl shift upon irradiation followed by decarbonylation, and the oxa-di-π-methane rearrangement (Schemes 3 and 4). The diketone 18 derived from 1 behaved in the same way (Scheme 5). The tetracyclic diketone 21 cyclized very easily to the internal aldol product 22 under the influence of traces of base (Scheme 5). Upon irradiation the γ, δ-unsaturated ketone 24 underwent only the Norrish type I cleavage to yield the aldehyde 25 (Scheme 6).

Notes: New Mechanistical Details Concerning the Synthesis of Seychellen [1]In the last step of our synthesis of Seychellen (2) [1], the solvolysis of 1, only one side-product was formed, namely 3 (Scheme 1). Now the structure of 3 has been elucidated, mainly by spectroscopic studies of its derivatives 7 and 9 (Scheme 2). In order to differentiate between two different solvolytic pathways from 1 to 3 (see Scheme 1 and 3) d3-1 was prepared. Solvolysis of d3-1 proved the mechanism shown in Scheme 1. Solvolysis of 1 and of 2-epi-1, respectively, furnished the same product distribution, which makes a common intermediate a very probable. In both cases 10 is an intermediate, which is slowly converted into 2 and 3. 2-epi-1 was prepared from 1 (Scheme 5).Kinetic measurements with 1, d3-1 and 2-epi-1 are also in agreement with the mechanism drawn in Scheme 4: k1(72°) = (5,2±0,5) · 10-5 sec-1, k1(H)/k1(D)(72°) = 1,4±0,15; k2(H)/k4(H) = 0,66 and k2(H)/k2(D) = 2,2 if k4(H) ≈ k4(D) is assumed.

Notes: A four step synthesis of Seychellene (1) is described. Intramolecular Diels-Alder reaction of dienon 2 furnished the tricyclic ketones 3 and 4 in good yield. Hydrogenation of 3 gave 5 and 6. The higher reactivity of 6 with methyllithium compared to 5 allowed the selective preparation of 8, which, on subsequent acid-catalyzed rearrangment afforded Seychellen in 57,5% yield. In an analogues manner epi-Seychellene was synthetized via the intermediates 5 and 7.

Notes: Synthesis of new polycyclic compounds by means of intramolecular Diels-Alder reactions of cyclohexa-2,4-dien-1-one derivativesThermal rearrangement of mesityl penta-2,4-dienyl ether (1), consisting of the isomers E (93%) and Z (7%), furnished, besides mesitol, the two mesityl penta-1,3-dienyl ethers 2 (24%) and 3 (3%), and the two tricyclic ketones 4 (4,5%) and 5 (12,5%) (Scheme 1). A probable mechanism for this formation of 2 involves a [1,5]-hydrogen shift in (Z)-1. Isomerisation of (E)-1 to (Z)-1 at 145° occurs via reversible sigmatropic [3,3]- and [5,5]-rearrangements of (E)-1 to the cyclohexadienones 38 and 39 respectively (see Chapter A p. 1710, and Scheme 15). Formation of 3 from either (Z)-1 or 2 is rationalized by a series of pericyclic reactions as outlined in Chapter A and Scheme 16.The tricyclic ketones 4 and 5 are undoubtedly formed by internal Diels-Alder reactions of the 6-pentadienyl-cyclohexa-2,4-dien-1-one 6 (Scheme 2). In fact, at 80° 6 is converted into 4 (5%) and 5 (35%). At 80° the cyclohexadienone derivative 7 furnished the corresponding tricyclic ketones 8 (15%) and 9 (44%) (Scheme 2). 5 and 9 contain a homotwistane skeleton. 8 and 9 are easily prepared by reaction of sodium 2,6-dimethylphenolate with 3-methyl-penta-2,4-dienyl bromide at ambient temperature, followed by heating, and finally separation by cristallization and chromatography.The cyclohexadienones 6 and 7 have mainly (E)-configuration. Here too (E) → (Z) isomerization is a prerequisite for the internal Diels-Alder reaction, and this partly takes place intramolecularly through reversible Claisen and Cope rearrangements (Scheme 17). On the other hand, experiments in the presence of 3,5-d2-mesitol have shown (Table 1) that intermolecular reactions, involving radicals and/or ions, are also operating (see Chapter B, p. 1712).Two different modi (I and II) exist for intramolecular Diels-Alder reactions (Scheme 18). Whereas only modus I is observed in the cyclization of 5-alkenyl-cyclohexa-l,3-dienes, in that of (2)-cyclohexadienones 6 and 7 (Scheme 2) both modi are operating. Only in modus 11-type transitions is the butadienyl conjugation of the side chain retained, so that modus 11-type addition is preferred (Chapter C p. 1716).Analogously to the synthesis of the tricyclic ketones 4, 5, 8 and 9, the tricyclic ketone 15 (Scheme 4) and the tetracyclic ketone 11 (Scheme 3) are prepared from mesitol, pentenyl bromide and cycloheptadienyl bromide, respectively.From the polycyclic ketones derivatives such as the alcohols 16, 17, 18, 19, 23, 24 and 25 (Schemes 9 and 11), policyclic ethers 20, 21, 22 and 26 (Scheme 10), epoxides 30, 32 (Scheme 13), diketones 31, 33 (Scheme 13) and ether-alcohols 35 and 36 (Scheme 14) have been prepared. Most of these conversions show high stereoselectivity.

Notes: Synthesis of the Sesquiterpene Ketone Shyobunon and of its DiastereoisomersShyobunon (12) and 6-epishyobunon (13) as well as their epimers 10 and 11 were synthetized in five steps from geranyl- (1) and nerylsenecionate (2), respectively. Ester enolate rearrangement [5] of 1 and 2 furnished the key intermediates 3 and 4 in high yield and in about 80% stereoselectivity [6] (Scheme 1). Conversion of the acid mixture 3/4 to the cyclohexanone derivatives 7 and 8 succeeded in 35-40% yield by means of cyclization of their acidchlorides with tin tetrachloride to the mixture of 5 and 6, followed by HCl elimination with diazabicyclononene (DBN) (Scheme 2). Selective reduction of 7 to 10 and 11, and 8 to 12 and 13 with triphenyltinhydride completed the synthesis.The relative configuration of 10 and 11 as well as of 12 and 13 were deduced from the 13C-NMR. spectra (Scheme 4, Table 2). The structure of ‘epishyobunone’ is revised: it has the structure 13, and not 11 as described earlier [1]. This is discussed in connection with the rearrangement of acoragermacrone (16) [18] to shyobunone (12) and 6-epishyobunone (13) (Scheme 5).