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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 September 9.
Published in final edited form as:
PMCID: PMC2754317
NIHMSID: NIHMS140082

A Concise Total Synthesis of Saliniketal B

Abstract

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We report a concise, enantioselective, and highly efficient synthesis of the marine actinomycete-derived natural product saliniketal B. Our approach was motivated with an eye on future structure-function studies of this inhibitor of phorbol ester-mediated ornithine decarboxylase induction via an unknown mechanism. Our strategy highlights the utility of Pt(II)-mediated cycloisomerization of alkynediols developed in our laboratory to construct the dioxabicyclo[3.2.1]octane ring system, a highly selective aldol fragment coupling of which the stereochemical outcome is influenced by a γ-stereogenic methyl group, and an interesting one-pot desilylation/dihydropyranone fragmentation/amidation sequence. As such, saliniketal B was obtained in 11 steps and 23% overall yield from commercially available starting material via a convergent coupling of two equally complex fragments assembled in 7 and 8 steps (39% and 45%) respectively.

Due to the groundbreaking work of Fenical and coworkers, obligate marine actinomycetes were shown to be a rich source of novel bioactive natural products.1 In 2007, they reported the isolation of the polyketides saliniketals A (1) and B (2) from the marine actinomycete Salinispora arenicola,2 the structure of which was confirmed by a total synthesis of Paterson and coworkers.3 Besides unusual structural features, including a dioxabicyclo[3.2.1]octane ring system, an E,Z-dienamide unit reminiscent of the ansa chain of rifamycin, and nine stereocenters (eight of which are contiguous), saliniketals are of biological interest due to their ability to inhibit ornithine decarboxylase (ODC) induction. The first enzyme in the polyamine biosynthesis pathway and direct transcriptional target of the oncogene MYC, ODC was shown to be a potential target for chemotherapeutic or chemopreventive intervention.4 Unlike α-DFMO, saliniketals do not inhibit ODC enzyme activity, but attenuate tumor promoter-mediated induction of ODC.2 Herein, we report a concise and flexible synthesis of saliniketal B (2) featuring a strategy aimed at enabling future structure-function and mode-of-action studies.

Our synthetic strategy is based on a convergent aldol coupling of fragments 3 and 4 following an anti-selective reduction of β-hydroxyketone 2 (Scheme 1). We envisioned a late stage installation of the E,Z-dienamide via an interesting but rarely utilized fragmentation of a dihydropyranone.5 The 2,8-dioxabicylo[3.2.1]octane moiety will be assembled via cycloisomerization of alkynediol 5 exploiting methodology developed in our laboratory.6

Scheme 1
Structure of saliniketals and synthetic strategy

An efficient synthesis of coupling partners 3 and 4 is depicted in Scheme 2. Reagent-controlled aldol reaction of the stannyl enolate derived from known oxazolidinone 87 with aldehyde 7, obtained from oxidation of commercially available alkynol 6 (92% yield), provided aldol product 9 in 82% yield and >16:1 dr. Anti-selective reduction with Na(OAc)3BH (>20:1 dr)7a followed by desilylation (74% yield, 2 steps) set the stage for a cycloisomerization of alkynediol 5. Using 5 mol% of Zeise’s dimer,6 2,8-dioxabicyclo[3.2.1]octane 10 was obtained in quantitative yield and processed to ketone 3 via Weinreb amide formation and Grignard reaction with EtMgBr (87%, 2 steps).8

Scheme 2
Synthesis of fragments 3 and 4a

Dihydropyranone 4 was synthesized from ester 11 ($). According to a sequence by Nicolaou and coworkers, p-methoxybenzyl ether formation (87%) was followed by semi-reduction to aldehyde 12 (93%) and allylation with Brown’s reagent (90%).9 The resulting syn-homoallylic alcohol 139,10 was esterified with acid 14, a material prepared from methyl acrylate via Baylis-Hillman reaction,11 silylation, and saponification (73%, 3 steps). Dihydropyranone formation (→ 15) was accomplished via ring-closing metathesis with Grubbs’ second generation catalyst under high dilution conditions in 67% yield (15% starting material was recovered).12 Final oxidative deprotection (DDQ, 91%) and oxidation with Dess-Martin periodinane13 (quantitative) delivered aldehyde 4 in seven steps and 36–39% overall yield.

The final aldol coupling between ethyl ketone 3 and aldehyde 4 yielded the anti-Felkin adduct 2 with high selectivity (>11:1 dr) in 81% yield (Scheme 3). The stereochemical outcome of this reaction deserves some comment. The Z(O)-lithium enolates of syn α-Me, β-alkoxy-substituted ethyl ketones typically yield the 1,3-syn-1,4-syn aldol adducts,14 a situation that is mismatched with the inherent anti-Felkin bias of aldehyde 4.10 We surmise that the observed high selectivity for our reaction can be attributed to the presence of the additional γ-Me stereocenter. As shown in eq 1, the Si-enolate face is normally exposed via conformation A minimizing A1,3-strain in the TTS, whereas the additional γ-Me group disfavors this conformation (A′, eq 2) due to unfavorable syn-pentane interactions. This exposes the enolate Re-face via B′ for a matched reaction with aldehyde 4.15 Next, reduction of β-hydroxy ketone 2 delivered anti-diol 16 (89%, >20:1 dr).16,17 Finally, combining a fluoride-mediated desilylation and concomitant fragmentation5d of dihydropyranone 16 with an in situ amidation of the liberated carboxylic acid provided saliniketal B (2) in 72% for this one-pot operation.18

Scheme 3
Synthesis of saliniketal Ba
equation image
(1)
equation image
(2)

In summary, we have achieved a short, highly efficient synthesis of saliniketal B (2) in 11 steps (longest linear) and 23% overall yield. Our approach features the utility of our Pt(II)-catalyzed cycloisomerization methodology for the construction of the dioxabicyclo[3.2.1]octane core, a stereoselective aldol coupling of which the selectivity was positively influenced by the ketone γ-stereocenter, and an unusual one-pot desilylation/dihydropyranone fragmentation/amidation sequence.

Supplementary Material

1_si_001

Acknowledgments

Financial support for was provided by the NIH (CA90349) and the Robert A. Welch Foundation. We thank Christopher F. Bender for helpful suggestions.

Footnotes

Supporting Information Available: Experimental procedures and characterization data for new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

References

1. (a) Mincer TJ, Jensen PR, Kauffman CA, Fenical W. Appl Environ Microbiol. 2002;68:5005–5011. [PubMed] (b) Marris E. Nature. 2006;443:904. [PubMed]
2. Williams PG, Asolkar RN, Kondratyuk T, Pezzuto JM, Jensen PR, Fenical W. J Nat Prod. 2007;70:83. [PubMed]
3. Paterson I, Razzak M, Anderson EA. Org Lett. 2008;10:3295. [PubMed]
4. For reviews: (a) Gerner EW, Meyskens FL., Jr Nat Rev Cancer. 2004;4:781. [PubMed] (b) Basuroy UK, Gerner EW. J Biochem. 2006;139:27. [PubMed]
5. For examples: (a) Corey EJ, Schmidt G. Tetrahedron Lett. 1979;20:2317. (b) Masamune S, Imperiali B, Garvey DS. J Am Chem Soc. 1982;104:5528. (c) Roush WR, Spada AP. Tetrahedron Lett. 1982;23:3773. (d) Nakata T, Hata N, Oishi T. Heterocycles. 1990;30:333.
6. Liu B, De Brabander JK. Org Lett. 2006;8:4907. [PubMed]
7. Oxazolidinone 8 was obtained in two steps from commercially available (4S)-N-propionyl 4-Bn-2-oxazolidinone, see (a) Evans DA, Clark JS, Metternich R, Novack VJ, Sheppard GS. J Am Chem Soc. 1990;112:866. (b) Evans DA, Ng HP, Clark S, Rieger DL. Tetrahedron. 1992;48:2127.
8. The stereochemistry was confirmed by NMR-analysis of the acetonide derived from 5, and comparison of the primary alcohol obtained from reduction of oxazolidinone 10 to the same alcohol prepared independently by Paterson et al.,3 see the Supporting Information.
9. Nicolaou KC, Patron AP, Ajito K, Richter PK, Khatuya H, Bertinato P, Miller RA, Tomaszewski MJ. Chem Eur J. 1996;2:847.
10. Note that the stereochemical outcome is not important as the resulting stereocenter will be destroyed during the final dihydropyranone fragmentation reaction (Scheme 3). However, homogeneous material facilitates characterization, and targeting the syn-stereoisomer ensures maximal stereocontrol during the aldol fragment coupling (Scheme 3) in this double diastereodifferentiating process, see: (a) Roush WR. J Org Chem. 1991;56:4151. (b) Evans DA, Dart MJ, Duffy JL, Yang MG. J Am Chem Soc. 1996;118:4322.
11. Yu C, Liu B, Hu L. J Org Chem. 2001;66:5413–5418. [PubMed]
12. Scholl M, Ding S, Lee CW, Grubbs RH. Org Lett. 1999;1:953. [PubMed]
13. Dess DB, Martin JC. J Am Chem Soc. 1991;113:7277.
14. (a) Gustin DJ, VanNieuwenhze MS, Roush WR. Tetrahedron Lett. 1995;36:3447. (b) Evans DA, Yang MG, Dart MJ, Duffy JL. Tetrahedron Lett. 1996;37:1957.
15. We are currently testing this hypothesis by preparing the corresponding des-γ-methyl and epi-γ-methyl congeners of ketone 3, which are expected to give lower selectivity in the aldol reaction with aldehyde 4.
16. Evans DA, Chapman KT, Carreira EM. J Am Chem Soc. 1988;110:3560.
17. The relative configuration was confirmed via acetonide 17, see: (a) Rychnovsky SD, Skalitzky DJ. Tetrahedron Lett. 1990;31:945. (b) Evans DA, Rieger DL, Gage JR. Tetrahedron Lett. 1990;31:7099.
18. The spectroscopic data and optical rotation of synthetic saliniketal B (2) are in full agreement with literature data reported for natural2 and synthetic3 2. See the Supporting Information for details.