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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 July 20.
Published in final edited form as:
PMCID: PMC3401040

A New Total Synthesis of the Polycyclic Fungal Metabolite Communesin F**

In 1993, Numata et al. isolated two unique natural products from a Penicillium mold found growing on the marine alga Enteromorpha intestinalis.[1] The structures of these compounds, communesin A (1) and communesin B (5), were established by spectroscopic analysis (Figure 1). Notable features of these complex, highly functionalized polycyclic metabolites are the two contiguous quaternary centers at C-7/8, and the presence of two aminal moieties. The communesins were found to have cytotoxic activity against P-388 lymphoid leukemia cells in vitro. In 2001, Hemscheidt and coworkers described an alkaloid called nomofungin, which was isolated from an unidentified fungus growing on the bark of Ficus microcarpa in Hawaii.[2] This material was found to have cytotoxic activity against LoVo and KB cells, which was shown to be due to the ability of the metabolite to cause microfilament disruption. The initial structural assignment of this metabolite, however, was incorrect, and nomofungin was in fact found to be communesin B (5). It should be noted, however, that the Hemscheidt work did serve to establish both the configuration at C-21 of 5 as well as the absolute configuration of the molecule, which were not originally determined by the Numata group. More recently, several other structurally modified communesin derivatives have been isolated[3,4] including communesin C (6), D (7), E (2), F (8), G (3) and H (4). Some of these new compounds were found to have significant biological activity. For example, communesins D, E and F are insecticidal, and communesins C and D are moderately active against various leukemia cell lines.

Figure 1
The communesin family of natural products.

Several groups have reported studies on synthesis of the communesins.[5] In 2007, Qin and coworkers reported the first successful construction of a communesin in the form of a total synthesis of racemic communesin F (8).[6] Herein we report a new stereoselective synthesis of this metabolite which employs a pivotal intramolecular Heck reaction of a tetrasubstituted olefin to construct the B,C,E,F-ring system as well as the C-7 quaternary center.

The synthesis commenced with the known[7] enol triflate 9 (easily prepared from the corresponding commercially available N-benzylpiperidine β-ketoester) which was coupled with 2-nitrobenzeneboronic acid (10) in a Suzuki-Miyaura reaction to afford the arylated product 11 (Scheme 1). Basic hydrolysis of ester 11 gave the acid which was transformed to the acid chloride and then coupled with readily prepared iodo aniline 12 (see Supporting Information) to yield amide 13. At this point the benzyl group of 13 was replaced by an ethyl carbamate moiety in a one-pot procedure using ethyl chloroformate, and the resulting amide was alkylated to form the N-methyl compound 14. We were pleased to find that tetrasubstituted alkene 14 underwent a clean intramolecular Heck reaction,[8] followed by β-hydride elimination, to afford tetracyclic enamide 15 in high yield bearing the C-7 quaternary center of the alkaloid. It should be pointed out that intra-[9a] or intermolecular[9b] Heck reactions involving tetrasubstituted olefins are rare.

Scheme 1
a) Pd(PPh3)4, DME, H2O, Na2CO3, 80°C, 10, 98%; b) LiOH, H2O, MeOH, 50°C, 86%; c) SOCl2, reflux; i-Pr2NEt, CH2Cl2, rt, 12, 87%; d) ClCOOEt, CH2Cl2, 0°C-rt, 96%; e) NaH, THF, MeI, 0°C-rt, 92%; f) Pd(OAc)2, PPh3, DMA, K2CO ...

To continue the synthesis, the nitro group of 15 was reduced by catalytic hydrogenation and the resulting aniline was protected as the Boc derivative 16 (Scheme 2). It was then found that lactam 16 can be partially reduced with alane-dimethylethylamine complex, followed by in situ cyclization to produce the lower aminal 17 having the requisite stereochemistry at C-6/7.[10]

Scheme 2
a) 5% Pt/C, H2 (40 atm) PhMe, rt; b) Boc2O, K2CO3, THF, H2O, 60°C, 87% (2 steps); c) AlH3·Me2NEt, THF, 0°C-rt, 74%; d) 1 N KOH, EtOH, 94°C; e)NCN3, MeCN, rt, 93% (2 steps); f) 1 N KOH, EtOH, 94°C, 60%; g) Boc2O, ...

After some exploration, it was decided that the best approach for introduction of the C-8 quaternary center would be to alkylate a Bring lactam. To implement this strategy, enamide 17 was first hydrolyzed to the enamine 18, which reacts with in situ-generated cyanogen azide to afford N-cyanoamidine 20.[11] This transformation presumably occurs via an initial [3+2]-dipolar cycloaddition of the enamine to afford adduct 19, which rearranges spontaneously to 20. Basic hydrolysis of this amidine gave the corresponding lactam, and acylation subsequently led to N-Boc lactam 21 (3:1 mixture of epimers).

The key alkylation step could be effected by treating N-Boc lactam 21 with potassium t-butoxide and allyl iodide to afford the desired product 23 as a single C-8 stereoisomer in high yield. This alkylation proceeds via attack of the iodide on lactam enolate 22 from the least hindered convex face. In order to prepare for construction of the upper aminal system, after selectively removing the Boc group on the lactam nitrogen of 23 by basic hydrolysis, the allyl group was oxidatively cleaved and the resulting aldehyde was manipulated via a straightforward sequence to form mesylate 24.

The BOM protecting group of 24 was next removed by catalytic hydrogenolysis, and the resulting benzylic alcohol was oxidized with Dess-Martin periodinane to yield aldehyde 25 (Scheme 3). Following conversion of mesylate 25 to the azide 26 with sodium azide in DMF, we investigated conversion of this aldehyde to the α,β-unsaturated ketone 27. Surprisingly this transformation could not be effected via Wittig chemistry, but we were gratified to find that the aldehyde underwent a clean mixed aldol reaction with acetone using aqueous sodium hydroxide as catalyst to produce the desired (E)-unsaturated ketone 27 in excellent yield. After reinstalling a Boc group on the δ-lactam nitrogen of 27, azide reduction using trimethylphosphine in aqueous THF caused an in situ rearrangement to form spiro-γ-lactam 28.

Scheme 3
a) Pearlman’s catalyst, H2, THF, rt; b) Dess-Martin reagent, CH2Cl2, rt, 75% (2 steps); c) NaN3, DMF, 90°C, 61%; d) Me2CO, 10% NaOH/H2 O, 60°C, 93%; e) Boc2O, LiHMDS, THF, rt, 81%; f) PMe3, THF, H2O, 70°C, 88%. Dess-Martin ...

In order to expedite construction of the remaining B- and G-rings of the alkaloid, the unsaturated ketone 28 was first treated with methyllithium to produce allylic alcohol 29 in high yield (Scheme 4). The remaining steps of the synthesis were then patterned on the work of Qin, et al.[6] Thus, exposure of 29 to PPTS in chloroform at room temperature leads to hexacycle 30 in 62% yield via a stereoselective allylic substitution reaction to form the G-ring with the requisite configuration at C-11. In addition, a small amount of the diene resulting from dehydration of starting alcohol 29 is produced. The stereochemical outcome of this cyclization is undoubtedly due to attack of the NHBoc group on the isopentenol side chain through the preferred conformation shown in 29. This conformation is enforced by minimization of steric interactions with the lactam A-ring.

Scheme 4
a) MeLi, THF, −78°C, 73%; b) PPTS, CHCl3, rt, 62%; c) Me3OBF4, i-Pr2NEt, CH2Cl2, rt, 86%; d) 5% TFA/CH2Cl2, rt, 88%; e) NaBH4, Ac2O, HOAc; f) 40% TFA/CH2Cl2, rt, 66% (2 steps). PPTS = pyridinium p-toluenesulfonate; TFA = trifluoroacetic ...

To complete the synthesis, γ-lactam 30 was treated with trimethyloxonium tetrafluoroborate in the presence of Hunig’s base to generate imidate 31. The upper Boc protecting group was then selectively removed with 5% trifluoroacetic acid in methylene chloride and upon neutralization of the resulting amine salt cyclization occurred to form the heptacyclic amidine 32. Reduction of this amidine with sodium borohydride in acetic acid containing acetic anhydride occurred stereoselectively from the least congested face to yield the N-acetyl aminal 33. Finally, removal of the Boc protecting group on the lower aminal with 40% TFA in methylene chloride afforded racemic communesin F (8) which had spectral data identical to that reported by the Qin group for the natural product.[6]

In summary, we have achieved a stereoselective total synthesis of the heptacyclic alkaloid communesin F (8) in racemic form in approximately 30 operations from known enol triflate 9. Key reactions include a novel intramolecular Heck cyclization of a tetrasubstituted alkene to generate a tetracycle with a quaternary carbon center, a reductive cyclization of an N-Boc aniline onto an oxindole moiety to form the pentacyclic framework containing the lower aminal, a stereoselective lactam C-allylation to introduce the second quaternary carbon center, and an azide reduction-N-Boc-δ-lactam opening cascade leading to the upper aminal functionality. We are currently investigating methodology for effecting the pivotal Heck reaction of 14 enantioselectively to produce natural (−)-communesin F.


**We are grateful to the National Institutes of Health (CA-34303) and the National Science Foundation (CHE-0806807) for financial support of this research

Supporting information for this article is available on the WWW under or from the author


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