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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Biomol Chem. Author manuscript; available in PMC 2010 November 21.
Published in final edited form as:
PMCID: PMC2830907

Efficient synthesis of the C7–C20 subunit of amphidinolides C and F


Synthesis of the C7–C20 subunit of amphidinolides C and F has been accomplished utilizing a Me3Al-mediated ring opening of a vinyl iodide/allylic epoxide to establish the C12,13 anti stereochemistry, an organolithium coupling/olefination sequence to construct the C9–C11 diene moiety and a sulfone alkylation/hydroxylation strategy to join the C7–C14 and C15–C20 fragments.

The amphidinolide natural products have generated considerable attention since their initial discovery in the 1980’s by Kobayashi and co-workers.1 Two of the most complicated members of this family are amphidinolides C (1) and F (2) (Scheme 1).2 While most of the amphidinolides have attracted sizable synthetic interest from numerous researchers, macrolides 1 and 2 have been significantly underexplored and remain unconquered synthetic targets.3 We were drawn particularly to amphidinolide C (1) as it is one of the most potent members of this natural product family against a range of cancer cell lines.2 Additionally, the macrocyclic core of both 1 and 2 possesses significant synthetic challenges: (a) 11 stereogenic centers, (b) two separate substituted THF rings, (c) the sensitive C15,C18-diketone moiety and (d) the C9–C11 highly substituted diene. Herein, we detail a unified synthesis of the entire C7–C20 western portion of amphidinolides C and F.

Scheme 1
Retrosynthesis of amphidinolides C and F.

Our retrosynthetic strategy for macrolides 1 and 2 is shown in Scheme 1. The three main disconnections are at the C25,26 alkene sidearm, the C-O bond of the macrolactone and the C14,15 bond. The C25–C26 alkene should be accessible via a Julia-Kocienski olefination—thereby allowing access to both natural products 1 and 2 through a common intermediate. The C-O linkage of the macrolactone could be constructed via standard Yamaguchi-type cyclization.4,5 The most difficult of these three dissection points is the C14–C15 bond. The proposed route requires a challenging alkylation of an α-branched halide6 followed by hydroxylation of the resultant sulfone coupled product with in situ decomposition to the corresponding ketone.7 While these types of oxidative desulfurizations have been known for some time, this transformation has found only limited application in complex molecule synthesis.8,9 Any strategy must also take care to avoid furan formation between the C15 and C18 carbonyl motifs. Finally, the C9–C11 diene moiety should be accessible via an organolithium addition of vinyl iodide 6 to Weinreb amide 7 followed by methylenation.

The C9–C11 diene motif is worthy of additional comment. These types of highly substituted dienes have proven challenging to construct. One illustration of this point is the fact that no method for preparing the C9–C11 diene in amphidinolides C and F has been reported. A structurally related diene is present in amphidinolides B, G and H. While these compounds have attracted significantly more synthetic attention,1012 proportionally limited success has been achieved for accessing the key diene motif—likely due to the challenging nature of the metal-mediated cross coupling reaction (e.g. Suzuki or Stille reaction) commonly envisioned to form dienes.12,13 While both Fürstner and Nelson have separately disclosed the ability to construct highly substituted dienes via Suzuki couplings, it is important to note that these conditions require extremely high catalyst loadings (up to 70 mol% Pd).11m,12,14 Consequently, our group has invested considerable effort to develop alternate pathways for constructing these types of structures.10

The synthesis of the Weinreb amide subunit is shown in Scheme 2. Amide 7 was readily accessible from the known Ley ester 10, which in turn was constructed from D-mannitol (8).15 Ley has shown that these diacetal derivatives of glyceraldehyde are significantly more robust than traditional acetonide analogues. We did find that the order of addition (LDA was added to the ester 9) for the key epimerization of equatorial ester 9 into axial ester 10 was critical to the success of the experiment—use of the alternate order of addition led to a significant reduction in yield (<20%).

Scheme 2
Synthesis of the Weinreb amide.

Synthesis of the C7–C14 subunit is shown in Scheme 3. The vinyl iodide 12 was available from diester 11 through a known procedure.16 After Sharpless epoxidation to cleanly provide the epoxide 13,17 the first major challenge in this sequence was selective opening of the epoxide at C12 with inversion by a methyl nucleophile. Despite the wealth of research on the reactivity of allylic electrophiles, surprisingly few examples of this type of transformation have been reported.18 Furthermore, no reported examples of accomplishing this transformation on an allylic vinyl iodide have been disclosed. After some experimentation, we were pleased to find that Me3Al-mediated epoxide ring opening19 at C12 cleanly provided product 15 in good diastereoselectivity (>20:1 dr) at −78 °C. The temperature proved to be critical to the success of this transformation. If the epoxide opening was conducted at −50 °C, significant erosion in the C12 stereochemistry was observed (3.5:1 dr).20 The absolute stereochemistry of 15 was established by degradation to a known compound and by matching the optical rotation data.21 With the key vinyl halide 15 in hand, silylation followed by halogen-metal exchange and addition to the Weinreb amide 7 cleanly generated the enone 16. Methylenation of ketone 16 using the Petasis reagent generated the diene. Alternate methylenation conditions (e.g. Wittig, Lombardo’s reagent) were unsuccessful. Finally, selective desilylation at C14 OTBS ether followed by conversion to the iodide generated the key coupling subunit 5.

Scheme 3
Synthesis of the C7–C14 subunit

The synthesis of the sulfone subunit 4 is detailed in Scheme 4. Starting from the known iodide 18,22 halogen/metal exchange followed by addition of the aldehyde 1923 generated the alcohol 20 as an inconsequential mixture of isomers at C18. TPAP oxidation24 of the C18 alcohol followed by Noyori ketalization25 generated the dimethyl ketal 21. Careful debenzylation with Freeman’s LiDBB reagent26 followed by sulfide formation provided compound 23. Finally, sulfide oxidation using TPAP27 provided the C15–C20 subunit 4.

Scheme 4
Synthesis of the C15–C20 subunit

With the subunits in hand, efforts turned towards the critical coupling sequence (Scheme 5). Treatment of sulfone 4 with LiHMDS followed by the addition of iodide 5 smoothly provided the C14,15 coupled material.6 Next, treatment of sulfone 24 under our previously developed hydroxylation conditions28 (NaHMDS, TMSOOTMS, THF) led to no reaction. Fortunately, modification of the base to LDA led to clean formation of the ketone 3 via the presumed intermediate 25. Key to these reactions is the relative stability of silyloxy sulfone 25 to decomposition to the ketone 3. This two-step sequence (sulfone alkylation/oxidation) circumvents any problematic furan formation (between C15 and C18) and can be viewed as a viable alternative to traditional dithiane chemistry.29

Scheme 5
Completion of the C7–C20 fragment of amphidinolides C and F.

In conclusion, synthesis of the C7–C20 fragment of amphidinolides C and F has been disclosed. A diastereoselective ring opening of vinyl iodide/allylic epoxide provided access to the anti-stereochemistry. An efficient Weinreb amide coupling/methylenation sequence was used to access the key C9–C11 diene motif. Sulfone alkylation was used to join the C7–C14 and C15–C20 subunits. Finally, a hydroxylation/desulfurization process incorporated the C15 ketone. Further application towards the synthesis of amphidinolides will be reported in due course.

Supplementary Material




Financial support was provided by the National Institutes of Health (NIH) (GM63723). National Science Foundation (CHE-0722319) and the Murdock Charitable Trust (2005265) are acknowledged for their support of the NMR facility. Mr. Jun Xie (OSU) is acknowledged for his early work towards the synthesis of amide 7. The authors would like to thank Professor Max Deinzer and Dr. Jeff Morré (OSU) for mass spectra data. Finally, the authors are grateful to Dr. Roger Hanselmann (Rib-X Pharmaceuticals) for their helpful discussions.


Electronic supplementary information (ESI) available: Complete experimental procedures are provided, including 1H and 13C spectra, of all new compounds. See DOI: 10.1039/b916744g

Notes and references

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