Naturalproductman’s Blog

Hey, is that a natural product?!

Chromodorolide B synthesis

Posted by naturalproductman on February 24, 2016

Larry Overman and co-workers reported in JACS on the synthesis of chromodorolide B.

JACS paper


2 Responses to “Chromodorolide B synthesis”

  1. yuriy slutskyy said

    The stereoselective construction of quaternary carbons remains one of the most challenging tasks faced by the synthetic community. The challenge is illustrated by the structural motifs of existing pharmaceutical agents. Stereogenic quaternary carbons are only found in 5% of the 200 top-selling pharmaceuticals in 2012. Nearly all of these brand-name drugs are opioid or steroid derivatives, prepared by semisynthesis. The shortage of efficient methods to generate quaternary carbon stereocenters resulted in the recent decrease of discovering and introducing new drug candidates to the market, which is undoubtedly a serious concern for public health. Introducing novel ways to increase the sp3 content – and accordingly the three-dimensional character – of pharmaceutical lead compounds is recognized as an important objective to rectify the problem. Despite the recent progress in the development of catalytic enantioselective methods to generate quaternary-carbon stereocenters, the scope of these reactions remains limited.1 It can be attributed to the fact the majority of current methodologies rely on secondary sp3 carbons to obtain the desired functionality. Much less explored are methods to engage tertiary carbons in C–C bond formation reactions. As a result, expanding the repertoire of methods for stereoselective coupling of tertiary carbons to forge C–C bonds and new quaternary stereocenters is of particular importance.
    Recent reports from our laboratory suggest that bimolecular combination of tertiary carbon radicals with carbon-centered electrophiles (eq. 1) can be utilized to construct quaternary-carbon stereocenters. It is surprising that the above strategy is not mentioned in any reviews of stereoselective synthesis of quaternary carbons. To our knowledge, this approach has not be utilized in target-directed synthesis prior to our recent report.5 Construction of sterically demanding carbon bonds by the reaction of nucleophilic carbon radicals with electron-deficient alkenes is attractive for several reasons: (1) the forming bond is unusually long in calculated transition state (2.2−2.5 Å); (2) tertiary radicals add faster than Me, primary, and secondary counterparts to electron-deficient partners; (3) stereoselectivity in the addition of tertiary radicals to prochiral alkenes is higher than that of primary or secondary radicals; (4) radical additions proceed under mild conditions, thus a wide variety of functionalities (e.g., alcohols, ketones) can be tolerated without making recourse to protecting groups. Although these advantages have been recognized for many years, no examples of the stereoselective formation of quaternary carbon stereocenters by intermolecular additions of prochiral trialkyl-tertiary carbon radicals to alkenes are shown the reviews. Recent work from the Stephenson and Movassaghi laboratories attests to the logical nature of constructing quaternary carbon stereocenters via coupling reactions of tertiary carbon radicals.
    Convergent synthesis strategies are essential for efficient construction of complex organic molecules. As a result, reactions that are capable of coupling two polyfunctional fragments in excellent yields are of high importance in the preparation of structurally intricate molecules. The classical Diels-Alder reaction and recently described metal-catalyzed transformations such as Pd(Ni, Fe, etc.)-catalyzed cross couplings, Nozaki-Hiyama-Kishi coupling, as well as olefin metathesis are some of the most useful methods available to realize desired bond forming reactions in complex setting. Particularly demanding reactions involve coupling fragments that result in the formation of sp3-sp3 σ-bonds and two stereocenters, especially when these two stereocenters are found in different rings. Molecules such as aplyviolene (1), tyrinnal (2), and cheloviolene (3) are great examples of complex natural products possessing such structural motifs. The usual strategy for the construction of bonds shown in red often involves intramolecular reactions, most notably Claisen and Claisen-type [3,3]-sigmatropic rearrangements. Much less common is the application of bimolecular reactions to forge the bond between two complex fragments, resulting in the formation of two new stereocenters, at least one of which is quaternary.
    In our recent report on the formal synthesis of 1, a convergent strategy, utilizing a radical intermediate, was used to form the central carbon-carbon bond between the two characteristic bicyclic fragments of the natural product. Common bromide and iodide radical precursors were not a viable option, as preliminary results showed that the access to these tertiary halides was plagued by facile elimination to the corresponding 1,3-diene. Another class of common radical precursors, Barton esters, was also unsuited for the application due to the difficulties associated with its preparation and storage. Instead, Okada’s general method for generating radical intermediates, employing (N-acyloxy)phthalimide precursors, in combination with photoredox catalysis was used to form the central C8-C14 σ-bond via the fragmentation of 2 and subsequent addition of the radical intermediate to enone 5. Prior to this example, (N-acyloxy)phthalimides have not been utilized as radical precursors in conjugate additions since their initial disclosure. In concurrent studies, postdoctoral associate Dr. Michelle Garnsey has also employed the aforementioned strategy to achieve the first asymmetric synthesis of 3 in five steps from an enantiopure radical coupling of a known intermediate 4 and butenolide 83.
    While the above key fragment coupling strategy was found to be successful in uniting the bicyclic fragments of 1 and 3, one unattractive aspect was the requirement for the incorporation of structural carbon-carbon bond in the carboxylic acid-derived radical precursor 4 that was cleaved in subsequent radical couplings. Due to recent advances in selective C–H oxidation, our group recognized that tertiary alcohols would be more viable tertiary radical precursors in complex synthesis applications. A recent report by our group has identified analogous substrate alkyl N-phthalimidoyl oxalates 7 as effective alternative precursors for generating tertiary radicals. Addition of these nucleophilic radicals to electron-deficient olefins resulted in the formation of the desired products in high yields that ranged from 36-92%. The broad scope of the reaction revealed that this methodology could be applied to the construction of complex molecules. Oxalates derived from commercially available natural products, sclareolide and estrone, underwent efficient coupling with methyl vinyl ketone to award desired products 8 and 9 in 85% and 68% yields, respectively. Excellent diastereoselectivity was observed, with the addition of the radical to methyl vinyl ketone occurring exclusively from the less hindered face of the molecule. In his efforts towards the total synthesis of 2, postdoctoral associate Dr. Kyle Quasdorf utilized the developed methodology to achieve radical coupling of sclareolide-derived N¬-phthalimidoyl oxalate 11 with butenolide 12. As expected, the reaction proceeded with a high degree of diastereoselectivity, resulting in the addition of the tertiary carbon radical to butenolide 12 from the less sterically congested face of the acceptor.
    Our initial communication, described interesting results in the case of adamantyl oxalate. The desired coupling product 10a was obtained in low yield, with the major product 10b deriving from coupling of the intermediate alkoxycarbonyl radical with methyl vinyl ketone. The observation was explained by the relative instability of the resulting atypical radical, leading to the lower rate of second decarboxylation. Consequently, it was reasoned that the utilization of secondary and primary oxalates, as radical precursors, would also lead to trapping of the alkoxycarbonyl radical intermediates with a variety of electron-deficient olefins, providing access to a number of structural motifs, including 4-oxoesters, 4-oxonitriles, and 4-oxoamides. In preliminary studies, we were able to construct secondary, primary, and methyl oxalates in 32-97% yield. These radical precursors underwent addition to electron-deficient alkenes, awarding desired 4-oxoester products in 55-65% yields.
    II. Approach
    Specific Aim 1: Construction of 4-Oxoesters, 4-Oxonitriles, and 4-Oxoamides by Radical Addition of Alkoxyacyl Radicals to Alkenes
    While there generally exist a variety of means, either direct or indirect, to access particular functional motifs, the formation of 1,4-dicarbonyl moieties remains a hurdle to be surmounted by the synthetic community. This functionality is ubiquitous and is exhibited in a wide range of seemingly unrelated structurally complex natural products. While these molecules illustrate great chemical diversity, they are all linked through 1,4-dicarbonyl structural element, found in these and other countless natural and medicinal agents. The complexity of the structures presented reveals just how valuable a direct method of generating 1,4-dicarbonyl architectures could be in complex molecule synthesis.
    The extant methods for construction of 1,4-dicarbonyl functionalities from intermolecular coupling of simple precursors are limited. One of the approaches, pioneered by the Boger group, utilizes acyl radicals, generated via a reaction between tri-n-butyltin hydride with phenyl selenoesters, and electron-deficient alkenes to achieve desired carbon-carbon bond formations. This methodology works well with aryl precursors, however it fails with selenocarbonate analogues where the major observed product is derived from the addition of tri-n-butyltin to the acceptor. Byproduct formation is explained by relatively low rate of generation of alkoxycarbonyl radical from phenyl selenocarbonates in comparison to phenyl selenoesters. Only other existing method utilizes Pd-catalyzed carbonylative coupling of methyl esters of α,β-unsaturated acids with alcohols to achieve the desired transformation. While this method provides great control over the regioselectivity of the reaction, through ligand modifications, it suffers from generally low yields, due to the parallel formation of oligomeric materials.
    It is our goal to gain further experience with utilizing renewable energy, visible light, to perform coupling reactions between alkoxyacyl radical species, derived from oxalate precursors, and electron-deficient alkenes to gain access to various structural motifs. Our initial studies demonstrated successful formation and coupling of secondary, primary, and methyl alkoxyacyl radicals to electron-deficient acceptors. Our further studies will focus on: (1) optimization of synthesis of oxalate radical precursors by varying reaction conditions (e.g., temperature, time, amine base). (2) Isolation of methyl oxalate as a crystalline solid that can be produced on industrial scale and made commercially available. (3) Improvements to radical coupling reactions by screening different solvents, hydrogen atom donors, and photoredox catalysts. (4) Establishing the scope of the coupling with respect to the acceptor – it is our ultimate goal to expand this methodology beyond simple α,β-unsaturated esters to forge 4-oxoesters, 4-oxonitriles, and 4-oxoamides in a complex molecule synthesis setting.
    General Approach to Fragment Coupling at the Tertiary Alcohol Carbon of Natural Products
    It is the objective of the proposed research to examine the feasibility of elaborating terpenoid tertiary alcohols to append a functionalized carbon fragment and form a new quaternary-carbon stereocenter. In general terms, the proposed investigations will focus on determining how best to accomplish the fragment coupling reactions outlined schematically in eq 2. As an arena to initially examine the potential of fragment couplings of this type, we have chosen a structurally remarkable family of natural products, isolated largely from plants of the genus Eucalyptus, that contain a diformylated phloroglucinol unit linked to polycyclic sesquiterpene moiety. These natural products and their analogs are largely chosen as targets for three reasons: (1) reported anticancer and antiretroviral activity, through c¬-Met tyrosine kinase and HIV-RTase inhibition, respectively. (2) Initial structure-activity relationship studies revealed that both a phloroglucinol and a sesquiterpenoid fragments are essential for their medical relevance. (3) Linking the fragments by forming the -bond depicted in red in Figure 3 using radical reactions would capitalize on the well-known compatibility of radical reactions with protic functionality.
    While there have been several reported syntheses of sesquiterpenoid fragments, including elegant triple-cascade catalytic approach recently developed by the MacMillan group, only two total syntheses of natural products from this series, macrocarpal C and G, have been described by the Tanaka group to date. Both syntheses are based on the same approach – stereoselective coupling of the sesquiterpenoid fragment 13 with a benzyl cation 14, that obtains face chirality upon coordination to chromium tricarbonyl ligand. While the coupling reaction proceeds with good yield and diastereoselectivity, it is greatly hampered by the requirement for protecting groups on all of the polar functionalities of the phloroglucinol fragment 14. The use of radical-based approach to unite fragments of similar complexity and polarity would circumvent this requirement and allow for faster, more efficient access to these complex natural products and their analogues, enabling potential expansive studies on their biological activity.
    Specific Aim 2: Explore utility of tert-Alkyl N-phthalimidoyl oxalates for fragment coupling of various terpenoid tertiary alcohols.
    Initial studies will be aimed at preparation of terpenoid-derived oxalates from commercially available/simple to prepare tertiary alcohols. 1-azulenol will be accessed from a readily available biosynthetic precursor, α-gurjunene, following previously reported method. 4,10-aromadendranediol, prepared by the MacMillan group, is a vital substrate for the study, as it represents the sesquiterpenoid core of macrocarpal A and B. In addition, reported synthesis contains several intermediates that can be elaborated to give rise to a variety of analogs for future biological studies. Tertiary alcohols, shown in red, will be acylated in accordance with our previous report. Substrates possessing additional tertiary alcohol functionalities, trans-terpin and 4,10-aromdendranediol, will be converted to corresponding benzoate esters to prevent unwanted reactivity. Our previous studies, indicate that the latter are inert to radical coupling reaction conditions.
    With terpenoid-derived oxalates in hand, our investigations will focus on subjecting these tertiary radical precursors to visible-light catalyzed coupling reaction conditions in the presence of simple electron-deficient olefins. Our recent report demonstrates that methyl vinyl ketone and acrylonitrile are outstanding coupling partners, awarding desired products in excellent yields. The reactions are expected to proceed with a high degree of diastereoselectivity, with addition occurring from the least sterically congested face of tertiary radical intermediates.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: