Wu, Yong-Jin (1991) Spiro-annulation strategy in the total synthesis of terpenes and a steroid. Doctoral (PhD) thesis, Memorial University of Newfoundland.
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Kuwajima et al. reported that the Lewis acid-catalysed reaction of a ketal with 1,2-bis(trimethylsiloxy)cyclobutene (109) followed by rearrangement of the resulting cyclobutanone derivative with trifluoroacetic acid (TFA) can provide a 2,2-disubstituted cyclopentane-1,3-dione in a reasonable yield. Our model studies with a variety of ketals revealed that a large excess of BF₃Et₂O and a longer reaction time can give cyclopentane-1,3-diones directly, and in better yields. This improved spiro-annulation procedure has been applied to the total synthesis of (±)-isokhusimone (65), (±)-3-methoxyestra-1,3,5,8,14-pentaen-17-one (161), (±)-epi-pentalenene (279), and (±)-pentalenene (230). -- Our synthesis of (±)-isokhusimone (65) began with norcamphor. 4,4-DimethyI-2-oxabicyclo[3.2.1]octan-3-one (114) readily available from norcamphor was converted to 3-(1,1-dimethyl-2-oxopropyl)cyclopentanone (112) in three steps, and then selectively ketalized. The ketal function underwent Lewis acid-catalysed spiro-annulation with 1,2-bis(trimethylsiloxy)cyclobutene (109) affording 7-(1,1-dimethyl-2-oxopropyl)spiro[4.4]nonane-1,4-dione (106), and intramolecular titanium-induced ketone-ketone coupling and oxidation provided (±)-isokhusimone in an overall yield of 35% from norcamphor. In an alternative approach, 7-(1-carbomethoxy-1-methylethyl)-1,4-dioxaspiro[4.4]nonane (149) was prepared from 4,4-dimethyl-2-oxabicyclo[3.2.1]octan-3-one (114) in three steps. Spiro-annulation proceeded in good yield, but subsequent titanium-induced ketone-ester coupling failed to provide the desired tricyclic product, 7,7-dimethyltricyclo[220.127.116.11¹,⁵]undecane-2,6-dione (147). -- Our synthesis of (±)-3-methoxyestra-1,3,5,8,14-pentaen-17-one (161) was designed so that the D ring was generated by the Lewis acid-catalysed reaction of 1,2-bis(trimethylsiloxy)cyclobutene (109) with a ketal prepared from 6-methoxy-1-tetralone (220) via an ultrasonically induced Barbier reaction with 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane (224). -- Our total synthesis of (±)-epi-pentalenene and of (±)-pentalenene was started with dimedone (446), which was converted to 7-ethyl-9,9-dimethyl-1,4-dioxaspiro[4.5]dec-7-ene (448) in three steps. The spiro-annulation of this ketal proceeded smoothly to produce 7-ethyl-9,9-dimethylspiro[4.5]dec-7-en-1,4-dione (444). Monoaddition of methyllithium and ozonolysis, followed by intramolecular aldol condensation provided 4,8,8-trimethyl-6-(1-oxopropyl)spiro[4.4]nona-3,6-dien-1-one (443). The stereochemical outcome at C-9 depended on the order in which the double bonds of enone 443 were reduced. Catalytic hydrogenation and intramolecular aldol condensation provided a 1 : 5 mixture of rel-(4R,8R,9R)- (439) and rel-(4R,8R,9S)-2,6,6,9-tetramethyltricyclo[18.104.22.168⁴,⁸]undec-1-en-3-one (440) in good yield, but, Birch reduction and catalytic hydrogenation followed by aldol condensation produced a 4 : 1 mixture of 439 and 440, which were transformed into (±)-pentalenene (230) and (±)-epi-pentalenene (279) in a straightforward fashion. -- Two model reactions pertaining to the synthesis of (±)-pentalenolactone (233) and some factors affecting geminal acylation reactions were investigated. We discovered that the geminal acylation reactions of ketals with 1,2-bis(trimethylsiloxy)cyclopentene (543) proceed in the same fashion as with 1,2- bis(trimethylsiloxy)cyclobutene (109) to provide 2,2-disubstituted cyclohexane-1,3-diones in good yields. Our results were at variance with those reported by Pattenden and Teague.
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Bibliography: leaves 271-284.|
|Department(s):||Science, Faculty of > Chemistry|
|Library of Congress Subject Heading:||Pentalenene|
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