Stewart W. Schneller

Enantiospecific Synthesis of 5′-Noraristeromycin and its 7-Deaza Derivative and A Formal Synthesis of (-)-5′-Homoaristeromycin

Abstract Beginning with the treatment of the diacetate of cis-3,5-cyclopentenediol (5) with Pseudomonas cepacia lipase, (-)-5′-noraristeromycin (1) and (-)-7-deaza 5′-noraristeromycin (3) have been prepared. Subjecting 5 to treatment with porcine liver esterase led to an efficient preparation of a substituted cyclopentane precursor which, following literature precedence, can be converted into (-)-5′-homoaristeromycin (4).

S-Adenosyl-L-homocysteine Hydrolase Inhibitors as Anti-Viral Agents: 5′-Deoxyaristeromycin

Abstract (-)-5′-Deoxyaristeromycin (-)-(3) has been prepared in 13 steps beginning with cyclopentadiene. Compound (-)-3 showed an antiviral activity spectrum characteristic of that of S-adenosyl-L-homocysteine hydrolase inhibitors (such as carbocyclic 3-deazaadenosine and neplanocin A), and, in that regard, (-)-3 was found to possess an IC50 of 3.28 /pm 0.48 μM towards this enzyme.

Chemoenzymatic synthesis of (-)-carbocyclic 7-deazaoxetanocin G

Abstract The enantioselective snthesis of (-)-(1 R ,2 S ,3 S )-2-amino-7-[2,3-bis(hydroxymethyl)-cyclobutyl]pyrrolo[2,3- d ]pyrimidin-4(3 H )-one ( 5 ) as the 7-deaza analogue of carbocyclic oxetanocin G is described in 13 steps from trans -3,3-diethoxy-1,2-bis(hydroxymethyl)cyclobutane ( 8 in an overall yield of 6%. Included in this route is the use of Pseudomonas cepacia lipase for enzymatic resolution.

Enantiospecific synthesis of the fluoro and epimeric derivatives of 5′-noraristeromycin

The synthesis of derivatives of 5′-noraristeromycin 1 in which its C-4′ hydroxy group has been (i) replaced by a fluorine atom (5) and (ii) inverted (6) is described starting from the diacetate of (Z)-cyclopentene-3,5-diol.

4-homopyrazofurin and an acyclic analogue

Abstract The synthesis of 4-hydroxymethyl-3(5)-(β- d -ribofuranosyl)pyrazole-5(3)-carboxamide ( 2 , 4-homopyrazofurin) is described via a pathway that commences with the dipolar cycloaddition reaction of 2,5-anhydro-3,4,6-tri- O -benzyl-1-deoxy-1-diazo- d -allitol ( 4 ) and methyl 4-benzyloxy-2-butynoate ( 5 ). Preparation of 3(5)-[(2-hydrox,-ethoxy)methyl]-4-(hydroxymethyl)pyrazole-5(3)-carboxamide ( 3 ) as a derivative of 2 possessing the truncated acyclic side chain of acyclovir has been accomplished in a similar manner beginning with the reaction of 5 with 1-diazo-2-[(2-benzyloxy)ethoxy]ethane ( 13 ). Neither compound 2 nor 3 showed any in vitro antiviral activity against human immunodeficiency virus (HIV-1), sandfly fever, Punta Toro, Japanese encephalitis, yellow fever, Venezuelan equine encephalomyelitis, and vaccinia viruses. Both compounds were also nontoxic. These results suggest that direct bonding of the hydroxyl group to the pyrazole ring is important for pyrazofurin based agents to demonstrate biological activity.

Synthesis of indoles and carbazoles: Diels–Alder reactions of nitrovinyl-pyrroles and -benzindoles

Diels–Alder reaction conditions have been employed to prepare indoles, benz[e]indoles, benzo[a]carbazoles, naphth[e]indoles, dibenzo[a,i]carbazoles, dibenzo[a,g]carbazoles, benzo[a]naphtho[i]carbazoles, and benzo[a]naphtho[g]carbazoles from nitrovinylpyrroles and nitrovinylbenzindoles with various dienophiles.

(±)-7-deazaaristeromycin lacking the hydroxymethyl substituent

Abstract As part of a plan to uncover new nucleoside based inhibitors of S-adenosyl- l -homocysteine (AdoHcy) hydrolase that are incapable of undergoing competing nucleotide formation, a derivative of 7-deazaaristeromycin (carbocyclic tubercidin) (5) has been prepared that lacks the C-5′ hydroxymethyl side-chain. This compound did not exhibit appreciable cytotoxicity or activity against a number of DNA and RNA viruses and was not inhibitory towards AdoHcy hydrolase.

(±)-7-deazacarbovir as a compound with potential anti-hiv and anti-hcmv properties

Abstract (±)-7-Deazacarbovir ( 2 ), which was conceived as an agent that could potentialy possess activity against both human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV), has been prepared in 3 steps from (±)-(3α,5α)-3-acetamido-5-(acetoxymethyl)cyclopentene ( 3 ) and 2-(2-amino-4,6-dichloropyrimidin-5-yl)acetaldehyde ( 4 ) in an overall yield of 36%. While non-cytotoxic, 2 was inactive towards inhibiting these target viruses as well as a variety of other viruses.

(±)-3′-deoxyaraaristeromycin via a surprising rearrangement

Abstract Hydrolysis of (+)-3β-acetoxy-4α-benzamido-1α- cyclopentanemethyl acetate ( 5 ) with 6 N hydrochloric acid has been found to give an amine in which the configuration at C-3 has been inverted. This conclusion was reached following conversion of the amine into (+)-3′-deoxyaraaristeromycin ( 8 ) by following a standard adenine formation process of (i) reaction with 5-amino-4,6-dichlocopyrimidine, (ii) ring closure with diethoxymethyl acetate, and (iii) ammonolysis. Use of basic hydrolysis conditions with 5 led to the expected (+)3′deoxyaristeromycin ( 7 ).

Carbocyclic 7-Deazaguanosine Nucleosides as Antiviral Agents

Nucleosides in which the ribofuranosyl oxygen is replaced by a methylene to result in a cyclopentane ring are referred to as carbocyclic nucleosides.1 The first such compound was carbocyclic adenosine (1, aristeromycin), which was synthesized in its racemic form2 prior to isolation of the (-)-enantiomer from Streptomyces citncolor.3 The antiviral activity of 14 has stimulated the search for other carbocyclic nucleosides that would display a more favorable therapeutic index.5