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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2010 August 12.
Published in final edited form as:
PMCID: PMC2756578

Total Synthesis and Structural Revision of (±)-Tricholomalides A and B


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The neurotrophic diterpenoids, tricholomalides A (1) and B (2), were synthesized in a concise fashion. Key transformations include a ketene [2+2] cycloaddition and a Grignard-type reaction. In the course of the synthesis, it was determined that the structures of tricholomalides A and B had originally been mis-assigned.

A focus of our laboratory is on the total synthesis and evaluation of small molecule natural products possessing neurotrophic activity.1 Such compounds may serve as promising lead agents in the treatment of neurodegenerative disease, the progression of which is marked by diminishing levels of neuronal support.2 In this context, we took note of a report by Ohta et. al. of a class of neurotrophically active diterpenes, termed the tricholomalides. Isolated from the mushroom tricholoma sp., tricholomalides A-C were found to induce neurite outgrowth in rat pheochromocytoma cells at micromolar levels.3 The promising neurotrophic activity and complexity of the target structures prompted us to undertake the syntheses of tricholomalides A and B. As shown below, in the course of our total synthesis effort, we found that the structures of tricholomalides A (1′) and B (2′) had been mis-assigned. Our revised assignments are shown in formulas 1 and 2 (Scheme 1). We describe below the total syntheses of tricholomalides A (1) and B (2) using chemistry recently developed in our laboratory.

Scheme 1
Original and Revised Tricholomalide Structures.

Our synthetic strategy, outlined in Scheme 2, centered around a homo-Robinson annulation to construct the hydroazulene core (45). We envisioned installing the lactone moiety of 6 through a sequence initiated by [2+2] dichloroketene cycloaddition. Finally, Grignard-type reaction of 6, or a suitable derivative thereof, would provide tricholomalide B, and subsequent Michael reaction was expected to furnish tricholomalide A.

Scheme 2
Synthetic Strategy Toward Tricholomalides A and B.

As described previously,4 the synthesis of 10 was accomplished through a progression involving homo-Robinson annulation (48), followed by DIBAL-H mediated ketone reduction, to afford a diastereomeric mixture of alcohols 9 and 10 (1:3.8).5 Isomer 10 was protected as a TIPS ether (11) and subjected to [2+2] addition with dichloroketene, which occurred at the more reactive olefin to afford cyclobutanone 12 as a single diastereomer.6 As anticipated, ketene addition occurred from the less hindered α-face of the olefin.7 Next, dechlorinated product, 13 was advanced to 15 in a straightforward manner.8 The latter was subjected to hydroxyl-directed epoxidation to furnish 16 in 93% yield. The structure assignment of 16 was confirmed by X-ray diffraction. Finally, Dess-Martin oxidation, followed by base-promoted β-elimination of the resultant ketone and TES protection of the γ-hydroxyl enone, as shown, afforded 17 (Scheme 3).

Scheme 3
Synthesis of Intermediate 17.a

As outlined in Scheme 4, 17 was subjected to Grignard-type conditions to provide 18 (31-66% yield).9 The latter was advanced to 20 as shown. Surprisingly, X-ray crystallographic analysis of 20 showed that the isopropenyl group had approached from the β-face of the molecule, syn to the α-angular methyl group. Although, at the time, we were disappointed in this stereochemical outcome, we nevertheless decided to continue with the synthesis, with the intention of exploring conditions for allylic oxidation. Thus, upon exposure to SeO2, 20 was converted to diol 2 in 53% yield. To our surprise, the 1H and 13C NMR spectra of synthetic 2 matched those reported for tricholomalide B. Furthermore, attempts to transform 2 to tricholomalide C under basic conditions afforded compound 1 (72% yield), which exhibited 1H and 13C NMR spectra identical to those reported for tricholomalide A. The structures of 2 and 1 were confirmed by X-ray diffraction, although the assignment of the hydroxyisopropenyl group in 2 was based on NMR data, due to the disorder of the hydroxyisopropenyl in the crystal.

Scheme 4
Synthesis of Tricholomalides A and B.a

Comparative analysis of the tricholomalides and their structurally close relatives, the trichoaurantianolides (21-24), led us to hypothesize that tricholomalides A and B may actually have the same stereochemistry at C2 as tricholomalide C and the trichoaurantianolides.3, 10 Since natural samples of the tricholomalides were not available to us, we decided to synthesize the originally proposed tricholomalide B (2′) for further structural clarification.

Our unoptimized route to 2′ is presented in Scheme 6. Thus, 6 was advanced to 25 as shown.11 Ketone 25 was converted to its vinyl triflate, and a modified Stille coupling served to append the isopropenyl moiety, providing 26.12 Following deprotection,13 the intermediate was subjected to a hydroxyl directed epoxidation/oxidation/β-elimination sequence to furnish 28.14 Finally, allylic oxidation of 28 gave 2′, whose structure was unambiguously confirmed by X-ray diffraction.

Scheme 6
Synthesis of the Originally Proposed Tricholomalide Ba

As expected, the 1H and 13C NMR of 2′ were clearly different from those reported for tricholomalide B. Thus, we can conclude that the structure of tricholomalide B is 2, rather than 2′. Furthermore, since the Ohta group reported that tricholomalide B could be transformed into tricholomalide A (in DMSO at 4 °C), we may infer that the two compounds possess the same stereochemistry at C2; and based on the NOE data shown by the Ohta group (as well as our own observation), the stereochemistry of C1 and C11 of tricholomalide A should be as originally reported. Thus, the structure of tricholomalide A is 1, rather than 1′. We note that the tetrahydrofuran-cycloheptane system of 1 is, surprisingly, in a trans junction. This may reflect thermodynamic control in the cyclization of 2.

In summary, a concise synthesis of the neurotrophically active tricholomalides A and B has been accomplished, and the structures of these natural products have been reassigned. We are confident that an enantiopure synthesis of 1 and 2 is achievable, since substantially enantiopure 7 has been synthesized in our laboratory.15 The biological evaluations of the tricholomalides will be disclosed in due course.

Scheme 5
The Trichoaurantianolides.

Supplementary Material








Support was provided by the NIH (HL25848 to SJD). ZW thanks Eli Lilly for a graduate fellowship. Aaron Sattler, Wesley Sattler, and Kevin Yurkerwich from Prof. Parkin group (Columbia University) are thanked for their help with X-ray diffraction experiments (CHE-0619638 from the NSF). We thank Prof. Tsukamoto (Chiba University) for providing 1H NMR spectra of the tricholomalides, Mr. Mingji Dai for helpful discussions, and Dr. Fay Ng and Ms. Rebecca Wilson for preparation of this manuscript.


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