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. Author manuscript; available in PMC: 2008 Jul 9.
Published in final edited form as: Tetrahedron Lett. 2007 Jul 9;48(28):4809–4811. doi: 10.1016/j.tetlet.2007.05.079

Carbocyclic Sinefungin

Xueqiang Yin 1, Guoxia Zhao 1, Stewart W Schneller 1,*
PMCID: PMC2031829  NIHMSID: NIHMS26022  PMID: 18612331

Abstract

(3aS,4S,6R,6aR)-Tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta[d][1,3]-dioxol-4-ol, itself available from ribose, provided a convenient entry point for an 18-step preparation of carbocyclic sinefungin. This procedure is adaptable to a number of carbocyclic sinefungin analogs with diversity of heterocyclic base and in the amino acid bearing side chain.

Keywords: stereospecific allylboration, pyrazine protected aminoacid, Horeau method

Sinefungin (1)1 is an amino acid-containing nucleoside isolated from the cultures of Streptomyces griseolus2a and Streptomyces incarnatus.2b The C-6′ primary amino center renders sinefungin structurally similar to S-adenosylmethionine (2, AdoMet). This resemblance has served as the mechanistic focal point for rationalizing sinefungin’s in vivo and in vitro biological activities, including antiviral,3–5 antifungal,2,6 amoebicidal,7 and antiparasitical,8 through inhibition of, primarily,3 AdoMet-dependent methyltransfrases.4 However, the clinical promise of 1 is restricted by its in vivo toxicity.9

In our antiviral drug discovery program sinefungin represents an important target for structural modification in order to improve its therapeutic index. Among the many compounds, which have been synthesized and evaluated in the sinefungin series,10 carbocyclic sinefungin (3) has been proven to be elusive.11 This communication discloses a practical synthesis of 3 that is adaptable to analog development.

A retrosynthetic analysis of carbocyclic sinefungin led us to a convergent approach involving a purine base and an appropriately crafted (stereochemically and functionally) cyclopentane. Thus, protection of the secondary alcohol of 412 to 5 was followed by hydroboration to provide the primary alcohol 6. Oxidation of 6 by a modified Swern procedure gave aldehyde 7. Calling on the Brown allylboration13 7 produced 8 in consistent yields (de 90% by NMR).

The side-chain stereochemistry of 8 was clarified by a modified Horeau method14 using 2-phenylbutryl chloride, pyridine and DMAP as reagents. The recovered optically active 2-phenylbutanoic acid was levorotatory. Thus,14b the homoallylic configuration of 8 is S. This result is consistent with the si face selectivity for the Brown allylboration conditions used.13

Mesylation of 8 followed by sodium azide nucleophilic substitution produced 9. Transformation of 9 into the azide-alcohol 10 was accomplished by sodium periodate glycolization/cleavage with, subsequent, Luche reduction (NaBH4/CeCl3·7 H2O).15 (It is to be noted that use of NaBH4 alone in the last step of the 9 to 10 conversion led to an intractable mixture of two products.16)

Derivative 10 was readily converted into the iodide 11 using the reagent obtained from iodine-imidazole. The lithium salt of (3R)-3,6-dihydro-2,5-dimethoxy-3-isopropylpyrazine reacted with 11 in the presence of Cu(I)17 to provide the requisite 12 as one diastereomer (by NMR). Oxidative deprotection of the PMB ether group of 12 yielded 13.

Use of the Mitsunobu reaction18 to construct the purine conjugate (that is, with 13 and 6-chloropurine) was successful but the subsequent ammonolysis at the purine C-6 center yielded mostly decomposed materials. Thus, a more traditional nucleophilic coupling process was undertaken by derivatizing 13 as its triflate that was, in turn, treated with the sodium salt of adenine to yield 14. Hydrolytic (acidic) removal of the pyrazine and isopropylidene units followed by azide reduction and saponification (of the methyl ester made available by breakdown of the pyrazine ring) led to achievement of carbocyclic sinefungin (3).19

Figure.

Figure

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Scheme.

Scheme

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Reagents and conditions: a, PMBCl, NaH, DMF, 95%; b, (i) 9-BBN, THF; (ii) MeOH, H2O2, NaOH, 98% for two steps; c, SO3·py, DMSO, DIPEA, CH2Cl2, 94%; d, (i) (+)-B-methoxydiisopinocampheylborane, CH2=CHCH2MgBr, Et2O/THF; (ii) MeOH, H2O2, NaOH, 96% for two steps; e, (i) MsCl, Et3N, DMAP, CH2Cl2; (ii) NaN3, DMF, 85% for two steps; f, (i) NaIO4, OsO4, MeOH/H2O; (ii) NaBH4, CeCl3·7 H2O, MeOH, 77% for two steps; g, TPP, imidazole, I2, toluene/MeCN, 90%; h, (3R)-3,6-dihydro-2,5-dimethoxy-3-isopropylpyrazine, BuLi, CuCN, THF, 87%; i, DDQ, CH2Cl2/H2O, 88%; j, (i) Tf2O, pyridine, CH2Cl2; (ii) adenine, NaH, DMF, 45% for two steps; k, (i) 0.5 N HCl MeOH; (ii) Pd(OH)2/C, cyclohexene; (iii) LiOH, MeOH/H2O, 55% for three seps.

Acknowledgments

This research was supported by funds from the NIH (AI 56540). The preliminary investigations of Tetyana Shulyak and Minmin Yang of the Auburn group assisted in the design of the successful synthesis described here.

Footnotes

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