Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol.

Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (-)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control.

The mandelalides constitute a family of unusual, variously glycosylated polyketide macrolides isolated by McPhail et al.[1] via bioassay guided fractionation of the cytotoxic extracts of a rare species of Lissoclinum ascidian collected from Algoa Bay, South Africa. Among this family, (−)-mandelalide A (1, Figure ) was reported to exhibit the most potent biological activity, with nanomolar cytotoxicities against both human NCI-H460 lung cancer cells (IC50, 12 nM) and mouse Neuro-2A neuroblastoma cells (IC50, 29 nM), thus rendering (−)-mandelalide A (1) and analogs attractive as lead structures for cancer chemotherapeutics. The inaccessibility of the source organism[2] however precludes ready biological investigation.

Figure 1

Structure of (−)-mandelalide A (1) and originally assigned structure (1a).

Notsurprisingly, this architecturally interesting family of natural products has become of considerable interest to the synthetic community, leading recently to the revision via synthesis[3,4b] of the stereochemical configuration of (−)-mandelalide A (Figure ).[3−7] Interestingly, initial evaluations of the synthetic material against a small panel of cancer cell lines by several investigators yielded contradictory cell toxicity data,[8] pressing the demand for a modular preparative synthesis of (−)-1 for detailed evaluation and future analog development.

Anion relay chemistry (ARC), an effective, multicomponent union protocol, introduced and developed in our laboratory for the rapid elaboration of structurally complex scaffolds in a “single-flask” entails the ability to control the migration of negative charge.[9] Over the past decade, we have reported extensive studies in the area of through-space ARC employing Brook rearrangements, which led to the evolution of types I and II ARC union tactics (Scheme ).[10] The potential of each of the ARC tactics has been demonstrated separately in a number of completed or ongoing synthetic ventures, including those on (+)-spongistatin 1 and 2,[11] (+)-spirastrellolide A and B,[12] (−)-secu’amamine A,[13] and most recently (−)-enigmazole A.[14] Herein, we illustrate the strategic value of both types I and II ARC union tactics with a total synthesis of (−)-mandelalide A (1). In addition we demonstrate for the first time the combination of through-space negative charge migration, followed by a new CuCN-mediated cross-coupling of significant value for complex molecule synthesis.

Scheme 1

Through-Space Types I and II ARC Tactics

From the retrosynthetic perspective (Scheme ), we envisioned the macrocyclic aglycon of (−)-mandelalide A (1) to arise from advanced fragments 2 and 3, which in turn would be united via a Yamaguchi esterification, followed by a ring-closing Heck reaction. Glycosylation with the known 2-O-methyl-α-l-rhamnose-based fragment (+)-4[3] would then yield the natural product 1. The tetrahydrofuran and tetrahydropyran structural motifs embedded in the northern and southern hemispheres in turn would be constructed from advanced intermediates 5 and 6, respectively.

Scheme 2

Retrosynthetic Analysis of (−)-Mandelalide A

Anion Relay Chemistry (ARC) was envisioned to provide access to both 5 and 6 with great stereochemical flexibility for future analog development, employing commercially available and/or readily prepared intermediates or building blocks 7–13 (Scheme ).[15] Importantly, the proposed construction of advanced intermediate 5 would showcase a novel type II ARC tactic featuring the migration of negative charge to a sp-hybridized carbon center capable of undergoing cross-coupling with an electrophilic partner.[16]

The synthesis of (−)-mandelalide A (1) began with the construction of the northern hemisphere (2; Scheme ). Toward this end, nucleophilic attack of the vinyl epoxide linchpin (−)-8[15] with 2-lithio-1,3-dithiane (7), followed by a CuI-triggered Brook rearrangement to what we envisioned to be a sp-hybridized carbon nucleophile 15, then readily underwent Pd-catalyzed cross-coupling reaction with vinyl iodide (+)-9 to furnish advanced intermediate 5 in a “single flask” in excellent yield (81%).

Scheme 3

Type II ARC/Pd Cross-Coupling

Adduct 5 in turn was subjected to the reaction sequence of alcohol deprotection, dithiane removal, and carbonyl reduction to furnish diol (+)-16 (Scheme ), setting the stage to explore the key strategic construction of the required tetrahydrofuran ring. Here we envisioned the 1,3-diol to chelate to a metal catalyst to facilitate a selective, syn-specific oxidative cyclization on the disubstituted alkene of the conjugated diene system to generate 2,5-cis-dihydrofuran 19 in a stereocontrolled fashion, possessing the requisite hydroxyl group at C21. A series of catalytic systems employing various metals (e.g., osmium,[17] ruthenium[18] and chromium[19]) known to facilitate oxidative cyclization of vicinal diols adjacent to alkenes to generate cis-tetrahydrofurans was screened. All attempts toward this end however proved unsuccessful, leading either to very sluggish reactions or to decomposition. We reason that the major reason for this difficulty could be attributed to the inherent planar conformation of the conjugated diene system which inhibits formation of the requisite transition state 18.

Scheme 4

Planar Conformation Inhibits Oxidative Cyclization

Gratifyingly, a solution to this problem could be achieved exploiting the flexibility of the ARC tactic (Scheme ). Application of the type II ARC/cross-coupling strategy employing 1,3-dithiane, vinyl iodide (+)-9 with the redesigned vinyl epoxide linchpin (−)-20,[15,20] now possessing a terminal olefin, furnished tricomponent adduct (+)-23 in excellent yield (89%) on a gram scale. Dithiane removal revealed 1,3-diol (+)-24, now possessing a skipped diene system which underwent an efficient, albeit slow,[21] stereocontrolled osmium-catalyzed oxidative cyclization[17] to provide the desired advanced intermediate [(−)-25] in good yield with excellent stereoselectivity (88% brsm, >15:1 dr). The great advantage of ARC to readily customize coupling partners [e.g., (−)-8 and (−)-20] with programmable, preloaded functionality and stereochemistry to access a wide variety of scaffolds was thus demonstrated. Particularly important, we identified during this study a copper cyanide-mediated cross-coupling reaction between vinyl iodide (+)-9 and allyl silane 21, activated via what we presume to be a pentavalent silicon-ate (22) derive from an adjacent alkoxide group.[22]Interestingly, attempts to use palladium catalysis to carry out the same ARC/cross-coupling protocol failed to provide the desired adduct in more than 5% yield, demonstrating the unique utility of this CuCN-mediated reaction in a multicomponent union protocol (i.e., ARC). A preliminary study on the substrate scope of this ARC/CuCN cross-coupling strategy is outlined in Scheme . Also of significance in the construction of (−)-25 is the transition-metal-mediated oxidative cyclization of an allylic 1,3-diol, known to be a difficult substrate, due both to the unfavorable chelate ring size and to a variety of possible side reactions (e.g., allylic alcohol oxidation, racemization of allylic alcohol, and product instability).

Scheme 5

Revision of the ARC Tactic and Construction of the Northern Hemisphere

Scheme 6

Multicomponent Union Featuring a Type II ARC/CuCN Cross-Coupling Protocol

Advanced intermediate (−)-25 (Scheme ) was next subjected to bis-hydroxy protection (TBSCl), followed by hydrogenation with Wilkinson catalyst to install the desired stereocenter at C18. Selective desilylation of primary alcohol, Dess-Martin periodinane oxidation, and Stork-Zhao olefination[23] then provided advanced intermediate (−)-27 in 74% yield. Further protecting group manipulations (two steps) completed the construction of the mandelalide A northern hemisphere (−)-2.

We next turned attention to the construction of the mandelalide A southern hemisphere aglycon (3), which as outlined earlier would rely on a type I ARC tactic[24] (Scheme ). Nucleophilic attack of known epoxide (+)-11[15,25] with 2-lithio-2-TBS-1,3-dithiane (10), followed by a solvent-triggered Brook rearrangement generated what we envision to be a carbon nucleophile at the 2-position of the dithiane (29). In the same flask, (S)-epichlorohydrin was added as the second electrophile, to generate chlorohydrin anion 30, which in turn formed a new electrophilic terminal epoxide upon warming the reaction mixture to room temperature. Addition of vinylmagnesium bromide and copper iodide completed the construction of the requisite advanced homoallylic alcohol (−)-6.Pleasingly, this four-component adduct could be generated in a single flask in 87% yield on half-gram scale, with an average yield for each of the three carbon–carbon bond-forming steps over 95%. Mesylation of the free hydroxyl group (Scheme ) then set the stage for ring formation upon TBS group removal, to yield tetrahydropyran (−)-32. Removal of dithiane, followed by reduction with NaBH4 next led with high stereocontrol to alcohol (+)-33 in 82% yield. Further protecting group manipulations and cross-metathesis with methyl acrylate furnished advanced intermediate (+)-34 in 76% yield for the three steps. Alcohol (+)-34 was then subjected to Dess-Martin periodinane oxidation, Julia-Kocienski olefination with known sulfone 35,[26] and ester saponification to complete the construction of the southern hemisphere (−)-3 in 84% yield for the three steps.

Scheme 7

Four-Component Type I ARC

Scheme 8

Construction of the Southern Hemisphere

Having the northern and southern fragments (−)-2 and (−)-3 in hand, final elaboration to (−)-mandelalide A (1) is outlined in Scheme . To this end, (−)-2 and (−)-3 were smoothly united via Yamaguchi esterification, to furnish (−)-36 in 85% yield, without isomerization of the enoate double bond, an issue previously observed both by Furstner[4] and Altmann.[6] Removal of PMB protecting group, followed by Kahne glycosylation[27] with sulfoxide (+)-4[3] then furnished (−)-37 in 83% yield. Macrocyclization employing Heck reaction[28] on (−)-37 then proceeded with remarkable ease. Global desilylation with HF/pyridine completed the synthesis of (−)-mandelalide A (1), which displayed spectral properties identical in all respects to those reported for the natural product.[15]

Scheme 9

Fragments Union

In summary, a highly convergent, modular synthesis of (−)-mandelalide A (1) has been achieved exploiting ARC. The central features of this synthetic venture entailed the development of a novel three-component type II ARC/CuCN cross-coupling protocol and a four-component type I ARC union, both performed on preparative scale employing commercially available and/or readily accessible building blocks. The advantages of the ARC tactic are evident in the short synthetic sequences[29] and the excellent stereochemical control, holding the promise for all possible stereogenicities in the macrocyclic aglycon of mandelalide A (1). Also of significance, we have identified an effective new CuCN-mediated cross-coupling reaction of allyl silanes with vinyl and aryl iodides that is compatible with the ARC multicomponent union protocol. Application of the strategies presented here for the synthesis of other members of mandelalide family and analogs thereof continues in our laboratory.