The New Method for Introduction of an Allyl Group into the Angular Position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one and Its Application to Chiral Wieland-Miescher Type Compound Synthesis

Abstract

Triterpenoid compounds are of interest because they occur widely in nature and have unique biological activities. Recently, Naganuma and his colleagues found that three natural triterpenes, betulin (1), uvaol (2), and soyasapogenol B (3), have reducing effects against the toxicity of cadmium chloride in HepG2 cells (Fig. 1). 1) They also reported that betulin induced certain proteins, though not metallothionein, which is the representative protein in reducing heavy metal toxicity. 1)To clarify the reduction mechanism of cadmium toxicity, we investigated the relationship between expression of activities and structures, with particular focus on the functional groups of betulin, using its analogues. The results showed that both the polar functional group, found at either the C3 or C28 positions, and the isopropenyl group play important roles in reducing cadmium toxicity and the cytotoxicity of betulin (1).2) However, it is difficult to carry out further investigation into the bioactivities of betulin because the only functional groups of this compound are hydroxyl and isopropenyl, both of which are crucial for its activity. Therefore, we decided to synthesize analogues of betulin, which could not be otherwise derived from natural products. Our synthetic strategy is summarized in Fig. 2, which shows the pentacyclic ring system being divided into two fragments: the AB fragment 4 and the DE fragment 5. Since our focus was on the angular substituents between the D and E rings, the starting material for 5 needed to be the optically pure bicyclo[4.4.0]decaline derivative 6b, and the starting material for 4 the Wieland-Miescher ketone 6a.The optically active Wieland-Miescher type bicyclic ketone 6a was effectively synthesized from the prochiral tricarbonyl compound 7a, using chiral proline as a chiral catalyst (Fig. 3).3-6) The optically pure 6a can be obtained by a single recrystallization, and can be utilized for subsequent syntheses of many natural products.7-11) However, the cyclization reaction of compounds with side chains other than a methyl group (e.g., allyl group 7b) was observed to have serious depreciation of the optical yield.12) In addition, proline did not work as a catalyst for this reaction, meaning a stoichiometric amount of proline is required to complete the reaction. If expensive synthetic proline has to be used, this presents a serious economic obstacle. Therefore, before starting the synthesis of the betulin analogues, it was decided to develop an efficient method for synthesizing optically pure bicyclo[4.4.0]decaline derivatives. Results and DiscussionThe essential features of the synthesis reaction are illustrated in Figs. 4 and 5. When the optically active diketone 8 was treated under acidic conditions, a mixture of the two diastereomers 9a and 9b resulted. However, by using an acidcatalyzed dehydration reaction, the mixture of 9a and 9b was converted to the single enantiomer 10. Using a dissolvingmetal reduction reaction with 10, it was expected that 11a The stereoselective introduction of an al...

Efficient Solvent‐Free Robinson Annulation Protocols for the Highly Enantioselective Synthesis of the Wieland–Miescher Ketone and Analogues

“…[45] The NMR data obtained for 4, [12,22,23] 6, [12,13] 8, [12,29] and 12 [12] are identical to those previously reported. Values were assigned on the basis of gCOSY and gHSQC spectra.…”

“…[23] Using Hanselmans procedure, [22] with l-Pro in DMSO, compound (+)-4 was prepared on a large scale in 72% yield and 84% ee (Table 1, entry 1). However, the cumbersome work-up and the laborious process for increasing the enantiopurity prompted us to optimize the synthesis of 4.…”

Multicomponent Reactions of 1,3‐Cyclohexanediones and Formaldehyde in Glycerol: Stabilization of Paraformaldehyde in Glycerol Resulted from using Dimedone as Substrate

“…[12] During our investigation, we found that some active substrates, such as 1,3-cyclohexanediones, cannot be used in these MCRs under aqueous conditions owing to a lack of selectivity. In view of the fact that derivatives of 1,3-cyclohexanediones are often used in the total synthesis of natural products, such as steroid hormones, [13] triterpenoid compounds, [14] guaianolides [15] and other chemicals, [16] a three-component reaction of 1,3-cyclohexanediones, formaldehyde and alkenes would be, if realized, capable of significantly maximizing the synthetic efficiency. In order to realize this MCR, we thought that the solvent might play a crucial role in controlling the selectivity.…”

Development of Diastereoselective Birch Reduction−Alkylation Reactions of Bi- and Tricyclic β-Alkoxy-α,β-unsaturated Ketones

“… a All products shown in the above figure were isolated as a single diastereomer. b The yield of 24a is from ref . c The numbers in parentheses are the yields of the product based on the consumed starting material 12b or 13b . d BOM is (benzyloxy)methyl. …”

“…In the course of our continuous investigation to establish a general method for constructing an asymmetric quaternary carbon center, we previously published the strong Brønsted acid promoted cyclization reaction of the acetal 1 to β-alkoxy-α,β-unsaturated ketone 2a , followed by the introduction of an allyl group at the angular position in the corresponding TBS (tert-butyldimethylsilyl) ether 2b by a diastereoselective Birch reduction−alkylation reaction. , Moreover, we succeeded in the synthesis of two diastereomers, (7a S )- 4 and (7a R )- 5 , whose absolute configurations at the angular position were opposite to each other, from 3 as a common intermediate (Scheme ) …”