Alkylation of Cyclic 1,3-Diketones

Rajamannar, T.; Palani, N.; Balasubramanian, K. K.

doi:10.1080/00397919308011168

Cited by 20 publications

(9 citation statements)

References 14 publications

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“…[14][15][16][17][18][19] The resulting hydroxyl group was converted to bromine under standard conditions (CBr 4 , PPh 3 , Et 3 N, CH 2 Cl 2 , rt, 2 h, 86%), producing 24. Unfortunately, efforts using the alkylation reactions 20) to produce 26 failed, with the isolable compounds consisting either of a mixture of the alcohol 23 and the methyl ether 27, or the enol ether 28. Thus, our focus shifted from synthesizing 26 from the alkylation reaction of 1,3-cyclohexanedione (25) to the construction of the substituted 1,3-cyclohexanone-ring system from d-keto-ester derivative 29 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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

Hiroya

Takahashi

Shimomae

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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Section: Resultsmentioning

confidence: 99%

“…Based on the concept described above, a chiral side chain unit, 24, synthesized from commercially-available (S)-malic acid (20), was introduced to 1,3-cyclohexanedione (25). The results are summarized in Chart 1.…”

Section: Resultsmentioning

confidence: 99%

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

Hiroya

Takahashi

Shimomae

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…At the beginning of the project very little literature on the enantioselective preparation of C-8a Wieland-Miescher ketone analogues was available, 54 and consequently, there had been little utilization of these types of compounds in total synthesis. 55 Key to accessing these types of ana-logues is the synthesis of the corresponding 2-substituted cyclohexane-1,3-dione starting materials for which there are three main approaches (Scheme 5): (a) direct alkylation of cyclohexane-1,3-dione (33) with activated alkyl groups (such as methyl or allyl halides) using bases such as KOH 56 or Triton B; 57 (b) coupling of cyclohexane-1,3dione (33) with an aldehyde followed by trapping with thiols 58 or pyrrolidines, 59 or reduction with the Hantzsch ester; 54e or (c) alkylation of the dimethoxy compound 34 with unactivated alkyl halides utilizing t-BuLi in HMPA. 60 Scheme 5 Methods for the preparation of 1,3-diketone starting materials When deciding which substituent to introduce, we reflected on our model work 61 in which stepwise elaboration of an abridged side chain had proved lengthy and problematic.…”

Section: Background To Developing a New Wmk Synthesismentioning

confidence: 99%

The Wieland-Miescher Ketone: A Journey from Organocatalysis to Natural Product Synthesis

Bradshaw¹,

Bonjoch²

2011

Synlett

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The Hajos-Parrish-Eder-Sauer-Wiechert reaction can be considered as the origin of asymmetric organocatalysis, giving rise to the Wieland-Miescher ketone 1 (WMK), a versatile building block. Although 40 years have passed since its discovery, a highly enantioselective and scalable synthesis of the WMK has remained elusive. This account details a solution to that problem that came about in the development of methodology towards C-8a WMK analogues as part of the total synthesis of complex diterpene natural products. The work has been placed in the context of the historical background and reactivity of this important building block, highlighting the challenges faced by organocatalysis in large-scale reactions.

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“…The VAT substrates were prepared by either of two methods ( A or B ), as outlined in Scheme ; both methods conclude with enol triflation of the requisite 2-alkyl-dione using our standard procedure . Alkylation of cyclic 1,3-diones (Method A ) is notoriously difficult, but we were able to achieve modest yields in cases where the alkylating agent was either allylic or benzylic (VATs 1 , 3 , and 5 ) . In general, however, it was more convenient (and effective in terms of overall yield) to condense the appropriate aldehyde with excess 1,3-cyclohexanedione using proline catalysis, followed by conjugate reduction of the intermediate 2-alkylidene-dione (Method B , Scheme ). , …”

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confidence: 98%

Generation of Medium-Ring Cycloalkynes by Ring Expansion of Vinylogous Acyl Triflates

Tummatorn

Dudley

2011

Org. Lett.

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Reductive cyclization of aryl and vinyl iodides tethered to vinylogous acyl triflates (VATs) induces a ring-expanding fragmentation to provide cyclic alkynyl ketones, including strained nine-membered cycloalkynes, in fair to excellent yield. The tandem cyclization/C-C bond-cleavage is initiated under carefully optimized conditions by halogen-metal exchange in the presence of carbonyl and vinyl triflate functionality. A modified protocol for alkylation of 1,3-cyclohexanedione is described for preparing the relevant VAT substrates.

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Alkylation of Cyclic 1,3-Diketones

Cited by 20 publications

References 14 publications

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

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

The Wieland-Miescher Ketone: A Journey from Organocatalysis to Natural Product Synthesis

Generation of Medium-Ring Cycloalkynes by Ring Expansion of Vinylogous Acyl Triflates

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