A New Route toward 7-Oxo-13-hydroxy-8,11,13-podocarpatrienes from Labdane Diterpenes

Abstract

Trinorlabdane 1,5-diketones (7, 10a,b, 13a,b), which are easily prepared from labdane diterpenes, are directly converted into the corresponding 7-oxo-13-hydroxy-8,11,13-podocarpatrienes, immediate precursors of bioactive compounds, under basic treatment. Utilizing this strategy, the first enantiospecific synthesis of 13-hydroxy-8,11,13-podocarpatriene (20), a constituent of Taiwania cryptomerioides, was achieved starting from (-)-sclareol (5) after a seven-step sequence in 55% overall yield.Podocarpane diterpenes do not occur extensively in nature but are present in several genera, such as Azadirachta, 1 Humirianther, 2 Micrandropsis, 3 and Podocarpus. 4 During recent years, some biologically active podocarpane phenols have been isolated. Representative examples are 1, a highly fungistatic agent, 5,6 and the aminophenol 3, a potent 5-lipoxygenase inhibitor. 7 Recently, some nor-dehydroabietic acid derivatives, such as 4, have been patented as potential antiviral agents. 8 Due to their natural scarcity, the synthesis of these terpenoids has become the object of increased interest. Some enantiospecific syntheses starting from diterpenes have been reported, but these usually involve many steps and low yields. 9,10 A synthesis based on the enantioselective cyclization of homogeranylbenzene derivatives was recently reported. 11In this paper we report a short and efficient route to 7-oxo-13-hydroxy-8,11,13-podocarpatrienes from labdane diterpenes. The key step involves the intramolecular aldol condensation of a trinorlabdane 1,5-diketone, aromatization of the resulting -enone, and benzylic oxidation. Results and DiscussionDuring our research into the C ring construction of pentacyclic quassinoids starting from communic acids (8a-c), 12 via aldol condensation of the corresponding 1,5-diketones, small quantities of phenol derivatives were obtained together with the required -enones. To explore the synthetic usefulness of this side reaction and its utilization in preparing bioactive podocarpatriene derivatives, several diketones bearing different functionalities in the A-and B-rings were prepared. 1,5-Diketones 7, 10a,b, and 13a,b were synthesized from (-)-sclareol (5), the main component of SalVia sclarea, 13 and communic acids (8a-c), widely found in species of the genus Juniperus, 14 respectively (Scheme 1). 7 was obtained by ozonolysis of enone 6. 15 10a,b resulted from the ozonolysis of dienes 9a and 9b, prepared by 1,4-reduction of the conjugated diene in 8a-c. 13a,b were synthesized after allylic oxidation of 11a,b.Next, the reaction of these diketones to different basic reagents was investigated, and K 2 CO 3 in refluxing MeOH was found to be the most favorable medium to obtain phenol derivatives (Table 1). All diketones gave the expected tricyclic -enones resulting from the intramolecular aldol condensation, utilizing a diluted base solution for a short period of time. 13a,b were transformed in good yields into phenols 19a,b when a concentrated base and a prolonged reaction time were utilized. Aromatization and...

Facile Access to Optically Active Ring C Aromatic Diterpenes from (+)-manool. Synthesis of (+)-13-Hydroxypodocarpa-8,11,13-Triene, (+)-7-Deoxynimbidiol and (+)-Nimbidiol

“…Recently, a new route to compound 1 in seven steps via β-enone 7 from (+)-sclareol has been reported. 27 The key step involves the intramolecular aldol condensation of a trinorlabdane 1,5-diketone, aromatisation of the resulting β-enone, and benzylic oxidation. Previously Nakano et al 28 reported the synthesis of β-enone 7 from (+)-manool 4 in three steps.…”

“…29 Ozonolysis of ketone 5 afforded diketone 6. 27,28 Intramolecular aldol condensation utilising a dilute solution of H 2 SO 4 afford the desired compound 7 in 80% yield. 30,31 To synthesise compound 1, we first tried aromatisation of β-enone 7 with DDQ and SeO 2 .…”

“…The spectroscopic properties were similar to those reported in the literature. 27,28 Intramolecular aldol condensation of diketone 6: To a solution of diketone 6 (76 mg, 0.28 mmol) in methanol (5 mL) was added dropwise H 2 SO 4 (0.6 mL) at room temperature. This mixture was refluxed for 2 h. then water was added and extracted with ether.…”

Synthesis of Novel Podocarpa-8,11,13-Triene-7- and 13-Nitriles and Evaluation of their Anti-Inflammatory and Cytotoxic Activity

“…Several natural podocarpanes with an aromatic ring C have been reported to exhibit various biological properties such as antitumoural, [1][2][3][4][5] antifungal, 6 5-lipoxygenase 7,8 and anti-hepatitis C viral (anti-HCV) 9 activities. Furthermore, different synthetic compounds related to podocarpanes with aromatic ring C have shown modulation of large-conductance calcium-activated potassium channels (BK channels), 10,11 antiplasmodial, 12 antiproliferative, 13 anti-inflammatory 14 and gastroprotective 15 activity.…”