Toward the Total Synthesis of Palhinine A: Expedient Assembly of Multifunctionalized Isotwistane Ring System with Contiguous Quaternary Stereocenters

Zhang, Guobiao; Wang, Fang-Xin; Du, Ji‐Yuan; Qu, Hu; Ma, Xiaoyan; Wei, Meng-Xue; Wang, Chengtao; Li, Qiong; Fan, Chun‐An

doi:10.1021/ol301534r

Cited by 33 publications

(19 citation statements)

References 57 publications

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“…Construction of Isotwistane and Homoisotwistane Skeletons Isotwistane is an all-carbon tricyclic compound, and its structural motif is found in natural products such as pupukeananes, [8][9][10][11][12] palhinines, [13][14][15] and seychellene. [16][17][18] These types of compounds with (homo) isotwistane skeleton were attracted by their potential for perfumery, and the difference of scent derived from their chirality could be an important research target.…”

Section: Resultsmentioning

confidence: 99%

Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate

Harada

Kino

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have developed a new method for synthesizing chiral isotwistane and homoisotwistane skeletons as well as aminocyclitols in a highly stereoselective manner. These results were achieved through the use of a common intermediate, which was derived from the ytterbium-catalyzed asymmetric Diels-Alder reaction of Danishefsky diene.Key words isotwistane; homoisotwistane; aminocyclitol; Diels-Alder; asymmetric catalysis; hetero-DielsAlder Many biologically active compounds possess a cyclic skeleton with center chirality in their structure. Therefore, the stereoselective synthesis of optically active carbon frameworks is in high demand for synthetic and medicinal chemists. The Diels-Alder reaction has been widely used for this purpose to construct six-membered carbocycles, and the catalytic and enantioselective variant of this reaction has been studied for decades. 1) Our group reported the first example of the catalytic and asymmetric Diels-Alder reaction of Danishefsky diene (1) 2,3) (Chart 1). Functionalized cyclohexene 3 was obtained in optically pure form, and 3 could be transformed to cyclohexenone 4 in quantitative yield. Both functionalized compounds could be potential synthetic intermediates, and we have previously demonstrated the synthetic utility of this reaction. 4-7)In the present study, silyloxy-substituted cyclohexadiene 7 derived from 4 was shown to be a key intermediate for two types of synthetically useful chiral building blocks, i.e., the tricyclo[4.3.1.0 3,7 ] decane (isotwistane 8, n=1) and tricyclo[5.3.1.0 3,8 ] undecane (homoisotwistane 8, n=2) skeletons via the intramolecular Diels-Alder reaction, and aminocyclitol 10 via the intermolecular hetero-Diels-Alder reaction with nitrosobenzene (Chart 2). Results and DiscussionConstruction of Isotwistane and Homoisotwistane Skeletons Isotwistane is an all-carbon tricyclic compound, and its structural motif is found in natural products such as pupukeananes, [8][9][10][11][12] palhinines, [13][14][15] and seychellene. [16][17][18] These types of compounds with (homo) isotwistane skeleton were attracted by their potential for perfumery, and the difference of scent derived from their chirality could be an important research target. Due to the unique structure of isotwistanes, the total syntheses of biologically active compounds with isotwistane skeletons have been studied by many research groups. [19][20][21][22][23] Most of these studies have used the intramolecular DielsAlder reaction to build the fused structure of isotwistane. Based on these previous studies, we planned the synthesis of a chiral isotwistane skeleton by two Diels-Alder reactions: our asymmetric Diels-Alder reaction and a sequential intramolecular Diels-Alder reaction.Dienophiles 2a-d with an olefin in the side chain (R) were prepared. We expected that Lewis acidic activation of the dienophile would occur site-specifically only at the acyloxazolidinone moiety, and the Diels-Alder reaction would take place at the adjacent olefin. With the application of our ytterbium catalyst, 3) the asy...

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Section: Resultsmentioning

confidence: 99%

Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate

Harada

Kino

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Later in 2012, Fan and coworkers reported their preliminary efforts towards the functionalized isotwistane cage, along with an IMDA strategy [ 12 ]. Differing from Xie and She’s procedure using two key steps, Fan’s group assembled the tricyclic isotwistane from a monocyclic precursor in a single step ( Scheme 2 ).…”

Section: Synthetic Efforts Reported During 2010–2015mentioning

confidence: 99%

Strategies and Efforts towards the Total Synthesis of Palhinine Alkaloids

Liang

Gong

et al. 2020

Molecules

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The palhinine family of Lycopodium alkaloids were first reported in 2010, which feature an intriguing isotwistane carbon cage and a nine-membered azonane ring. It is noteworthy that the tetracyclic 5/6/6/9 skeleton was unprecedented in Lycopodium alkaloids before their seminal discovery. Over the past decade, extensive synthetic efforts stemming from seven research groups have resulted in two racemic total syntheses to date. This review article takes the opportunity to survey these efforts and achievements so as to promote further research towards the asymmetric total synthesis of palhinine alkaloids.

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“…Recently, two synthetic studies were published by Chinese groups. 2,3 Thus, Xie and She et al utilized an intramolecular Diels-Alder reaction of an ortho-quinone acetal to form the bicyclo[2.2.2]octane core for the synthesis of tricyclic diketone 2. In this case the five-membered ring originated from an intramolecular radical addition to a double bond.…”

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“…2 In another study Fan et al employed an intramolecular Diels-Alder reaction as well. 3 Here the five-membered ring of the isotwistane system was formed in the course of the cycloaddition reaction, eventually leading to core structure 3. As a model study we targeted the partly substituted isotwistane core structure 5 of palhinine A.…”

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confidence: 99%

“…Some selected examples of isotwistane formation are listed in the references. 3 Our retrosynthetic analysis (Scheme 1) features an intramolecular aldol reaction to close the third ring to reach the tricyclic structure 6. The required bicyclo[2.2.2]octane motif 7 could be established via a domino Michael reaction, a transformation which was broadly described in the literature, 4-6 followed by an Arndt-Eistert homologation.…”

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Approach to the Core Structure of the Polycyclic Alkaloid Palhinine A

Gaugele

Maier

2013

Synlett

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A synthesis of the tricyclic partly substituted core structure of palhinine A was achieved. To reach the bicyclo[2.2.2]octane motif a domino Michael reaction was employed as a key step. After Arndt-Eistert homologation and intramolecular aldol reaction the isotwistane core could be obtained after simple functional-group manipulations. LETTER Synlett 2013, 24, 955-958 © Georg Thieme Verlag Stuttgart · New York step with tert-butyldiphenylsilylchloride (TBDPSCl) giving good yields of silyloxyenone 8. Thus, this intramolecular oxo-Michael reaction is reversible under the conditions of the protection reaction.Scheme 2 Grignard addition to vinylogous ester 9 and conversion of the mixture of 10a/10b into silyloxyenone 8 LETTER Synlett 2013, 24, 955-958

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Toward the Total Synthesis of Palhinine A: Expedient Assembly of Multifunctionalized Isotwistane Ring System with Contiguous Quaternary Stereocenters

Abstract: The stereoselective, expedient assembly of the key functionalized isotwistane (bridged tricyclo[4.3.1.0(3,7)]decane) system, 5/6/6 ring, with contiguous quaternary stereocenters in Lycopodium alkaloid palhinine A and its analogues via an intramolecular Diels-Alder strategy is described.

Cited by 33 publications

References 57 publications

Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate

Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate

Strategies and Efforts towards the Total Synthesis of Palhinine Alkaloids

Approach to the Core Structure of the Polycyclic Alkaloid Palhinine A

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