1′-Homonucleosides and their structural analogues: A review

Accepted Manuscript 1′-Homonucleosides and their structural analogues: A review Andrzej E. Wróblewski, Iwona E. Głowacka, Dorota G. Piotrowska PII:

S0223-5234(16)30327-0

DOI:

10.1016/j.ejmech.2016.04.034

Reference:

EJMECH 8549

To appear in:

European Journal of Medicinal Chemistry

Received Date: 10 December 2015 Revised Date:

12 April 2016

Accepted Date: 12 April 2016

Please cite this article as: A.E. Wróblewski, I.E. Głowacka, D.G. Piotrowska, 1′-Homonucleosides and their structural analogues: A review, European Journal of Medicinal Chemistry (2016), doi: 10.1016/ j.ejmech.2016.04.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Graphical abstract

Syntheses and biological activity of 1′-homonucleosides and their structural analogues

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were reviewed.

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1′-Homonucleosides and their structural analogues: A review Andrzej E. Wróblewski, Iwona E. Głowacka and Dorota G. Piotrowska* Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, 90-151

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Lodz, Muszyńskiego 1, Poland

Corresponding author: Tel: +48 42 677 92 35; fax: +48 42 678 83 98. E-mail address:

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[email protected]

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Keywords: Homonucleosides / Nucleosides / Antiviral activity / Cytotoxicity /

Abstract

Nucleoside analogues belong to an important class of antiviral and anticancer drugs. Insertion

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of a methylene fragment between the anomeric carbon and pyrimidine or purine bases transforms nucleosides into 1′-homonucleosides. When compared with nucleosides this modification lengthens the separation between HO–C5′ of pentofuranoside fragments and nitrogen (N1 or N9) atoms of nucleobases, lowers the steric and electronic interactions

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between nucleobases and sugar rings, introduces greater flexibility around a CH2–Base bond and thus allows for more rotational freedom, and since the anomeric effect no longer operates

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any sugar or pseudosugar moiety exists in its unique conformation and experiences specific conformational mobility and hydrolysis of the C1′–CH2Base bond by cellular enzymes is no longer feasible. This review covers 1′-homonucleosides with a tetrahydrofuran ring and its nitrogen and sulfur analogues as well as those containing a cyclopentane moiety as a sugar replacer. Achievements in syntheses of sugar or pseudosugar scaffolds are of primary interest since pathways to install nucleobases are well recognized. Whenever possible, the biological activity, mostly antiviral and antitumor but sometimes as inhibitors of specific enzymes, will be presented and discussed to help identify structural features responsible for the particular mode of action and thus possible therapeutic significance.

ACCEPTED MANUSCRIPT 1. Introduction

In search for drugs to treat viral infections or tumors analogues of nucleosides were identified as a very important class of active compounds. Naturally occurring aristeromycin 1 [1–3],

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neplanocin A 2 [4] and oxetanocin 3 [5,6] (Fig. 1) are effective as antibiotics endowed also with antiviral and anticancer properties.

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Figure 1.

However, approved antiviral drugs were obtained by chemical synthesis and majority of them belongs to nucleoside/nucleotide analogues (Fig. 2). When compared with the natural

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nucleosides 4 they contain canonical nucleobases (adenine, guanine, uracil, thymine, cytosine) but also their close structural analogues (e.g. 2,6-diaminopurine, hypoxanthine or 5substitited uracil). The fundamental structural differences between natural nucleosides and their active analogues could be noticed in a sugar part which was successfully modified by replacing with e.g. 2′,3′-dideoxyfuranose, cyclopentane, cyclopentene, 1,3-dioxolane, 1,3-

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oxathiolane rings or acyclic systems. In all analogues a terminal hydroxymethyl group was preserved to allow sequential phosphorylation to active triphosphates. In cyclic analogues this group is positioned cis to nucleobases, thus resembling the HO–C5′ functionality of the natural nucleosides 4. A significant number of compounds lack a HO–C3′ function and after

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Figure 2.

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incorporation into oligonucleotides they serve as chain terminators.

A search for new antiviral compounds among nucleoside analogues was not limited to scaffolds closely resembling N-nucleosides having pseudosugar parts of D- (5, 6, 8–13) or Lconfiguration (7, 14) but was extended on several other frameworks including homologues. Insertion of a methylene unit between a sugar moiety and a nucleobase transforms nucleosides into 1′-homonucleosides as exemplified by adenosine 17 and 1′-homoadenosine 18 [48,49] (Fig. 3). This simple modification affects structural features of new molecules as well as their biological activity. When compared with natural nucleosides addition of a methylene linker lengthens the separation between HO–C5′ of pentofuranoside fragments and nitrogen (N1 or N9) atoms of nucleobases. 1′-Homonucleosides can be phosphorylated by cellular enzymes

ACCEPTED MANUSCRIPT and interact with other nucleosides to form Watson-Crick pairs. After incorporation of 1′homonucleosides into double-stranded oligonucleotides sugar or pseudosugar rings are slightly relocated in space due to the base pairing which seems to be more efficient because of greater flexibility anticipated to a CH2–Base unit.

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Figure 3.

The anomeric carbon atom characteristic of nucleosides loses its unique reactivity when it becomes a member of a tetrahydrofuran or any other cyclic scaffold installed in 1′-

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homonucleosides or their analogues. In fact, the C1′–CH2Base bond is resistant to hydrolysis by cellular enzymes opposite to the C1′–Base glycosidic bond which is readily hydrolyzed. Furthermore, since the anomeric effect does not operate in 1′-homonucleosides any five-

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membered ring replacing a pentofuranoside framework exists in its unique conformation and experiences specific conformational mobility.

The installation of the methylene group in 1′-homonucleosides lowers the steric and electronic interactions between nucleobases and sugar rings, allows for more rotational freedom and slightly increases lipophilicity of compounds, an important factor in transport to central

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nervous system (CNS).

In general, any 1′-homonucleoside is composed of nucleobases or their analogues and a sugar or pseudosugar (cyclic or alicyclic) mimetics linked with a methylene subunit. Since efficiency of the termination of the oligonucleotide propagation depends on the structure of a

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sugar moiety, the major interest in designing new potential antiviral agents was focused on modifications of a sugar part and led to numerous replacements. Installation of nucleobases within a framework of 1′-homonucleosides 19 requires a special approach because they lack

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the anomeric carbon atom. Known synthetic strategies to 1′-homonucleosides relied on the formation of the CH2–Base bond starting from sugars or sugar (cyclic or alicyclic) mimetics containing a hydroxymethyl group 20 (Scheme 1). Although this transformation was frequently completed directly by the Mitsunobu reaction [50], the most common ways to 1′homonucleosides 19 employed alkylation of sodium or potassium salts of substituted pyrimidines or purines with activated species 21a [49] which was supplemented by the de novo construction of the pyrimidine [51–53] or purine [54–56] skeletons from the intermediate 21b in a well-established manner. Further functionalizations of uracil at C5 (chlorination, bromination or iodination) [57–59] as well as of purines at C2 or C6 (ammonolysis or hydrolysis) belong to standard transformations in the nucleoside chemistry.

ACCEPTED MANUSCRIPT Scheme 1.

Because the installation of a nucleobase part in 1′-homonucleosides 19 can be implemented according to standard protocols, syntheses of sugar or pseudosugar moieties 20 will be

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discussed in some detail to expose the impact of the studies on 1′-homonucleosides on the synthetic organic chemistry in general. We aim to review achievements in the synthesis and biological activity of various 1′-homonucleosides 22 (Scheme 1) in which a pseudosugar scaffold is limited to five-membered carbocyclic and heterocyclic rings with one heteroatom

2. 1′-Homocarbanucleosides

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discussed to highlight a therapeutic potential.

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(N, O, S). Whenever available their biological (e.g. antiviral, anticancer) activity will be

The oxygen for carbon replacement in a sugar part leads to a subclass of nucleosides based on a cyclopentane scaffold. The interest in 1′-homocarbanucleosides arose from the known

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activities of natural products 1 and 2 as well as of several synthetic compounds including approved drugs carbovir 11a, abacavir 11b and entecavir 12 (Fig. 2). Many structural alterations within a cyclopentane ring are allowed which are not possible in a tetrahydrofuran moiety. The carbon atom replacing the furanose oxygen can be substituted to modify steric

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environment and polarity of an analogue. The 1,3-substitution pattern characteristic of natural nucleosides (HOCH2–C5′–O–C1′) can now be changed to a 1,2 mode by attaching a hydroxymethyl group to the already introduced endocyclic carbon atom (HOCH2–C–C1′).

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The cyclopentane ring can be much easier incorporated into fused frameworks to refine structure and lipophilicity of analogues.

2.1. 1,2-Disubstituted cyclopentanes

2-(Aminomethyl)cyclopentylmethanol 23 [60] was used as a starting material in the synthesis of several 1,2-substituted 1′-homocarbanucleosides (Fig. 4) employing the de novo approach.

Figure 4.

ACCEPTED MANUSCRIPT Although a racemic cis-cyclopentane-nucleoside 24 showed appreciable potency (EC50 = 12.5 µg/mL) in inhibition of HIV-1 and HIV-2, neither racemic cis-1′-homonucleosides containing uracil 25a nor 5-iodouracil 25b were found active [61]. In a series of racemic cis-1′homonucleosides bearing a purine scaffold 26 only compound with a 2-amino-6-chloropurin-

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9-yl group 26a appeared active towards two strains of cytomegalovirus (IC50 > 5 µg/mL), while it did not affect varicella-zoster virus. Other 1′-homonucleosides (26b and 26c) were inactive towards both viruses [62]. On the other hand, several analogues in this series displayed anticancer activity. Thus, cis- and trans-25b were active towards L1210/0,

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Molt4/C8 and CEM/0 cell lines (IC50 = 65.8–158 µg/mL) at the same level as 24 [63]. 6Chloropurin-9-yl analogues cis- and trans-27a were the most potent towards these cell lines (IC50 = 6.5–48.7 µg/mL) and cis isomers slightly superseded trans isomers in potency [63].

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However, compounds cis- and trans-27c devoid of a methylene linker were only slightly less active in the same assay (IC50 = 19–62.8 µg/mL). A marginal activity was noticed for cis-27b (IC50 = 100–108 µg/mL), while cis and trans hypoxanthin-9-yl analogues 27d appeared

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inactive [63].

2.2. 1,3-Disubstituted cyclopentanes [1-(hydroxymethyl)cyclopentanes substituted at C3]

Isomeric 1,3-disubstituted 1′-homocarbanucleosides were synthesized by the de novo protocol

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starting from racemic cis-3-(aminomethyl)cyclopentylmethanol 28 which was prepared from norbornene 29 via a diacid 30 and discrimination between two carboxyl groups was executed

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by the formation of the respective anhydride (Scheme 2) [64].

Scheme 2.

The key intermediate 28 was transformed into the analogues 31 [64], 32 [65] and 33 [65] (Scheme 2), but none of them was found active against a panel of DNA and RNA viruses at subcytotoxic concentrations [64,65]. However, compounds 31a and 33c were cytotoxic to all host cells (CC50 = 1–40 [64] and 80 µg/mL [65]) while compound 31a was also cytotoxic to human T-lymphocyte CEM/0 cells (CC50 = 16 µg/mL) [64]. Two other compounds (32b and 33c) inhibited proliferation of L1210/0 and Molt4/C8 cells with IC50 = 73–105 µg/mL [65]. Higher conformational flexibility of the cyclopentane ring as well as greater mobility of the

ACCEPTED MANUSCRIPT guanine residue separated from the ring by the methylene linker account for major structural differences between carbovir 11a (Fig. 2) and 31b and they seem sufficient to explain the lack of antiviral activity by the saturated 1′-homocarbovir analogue 31b.

A justified modification of 1′-homocarbanucleosides 31–33 involved substitution at C2 with

trimethylcyclopentylmethanol

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and

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hydrophobic groups [66–70]. This was secured by synthesis of (1R,3S)-3-aminomethyl-1,2,2(1S,3R)-3-aminomethyl-2,2,3-

trimethylcyclopentylmethanol 35 from α-camphidone [71] and (+)-camphoric acid [72], respectively. Among 1′-homonucleosides prepared from 34 compounds 36a–36c, 37b–37c

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and 38 (Fig. 5) were inactive against several DNA and influenza viruses at subtoxic concentrations, although 37a showed some potency towards influenza virus (MIC = 10 µg/mL) [68]. Compounds 36a and 36c were effective against HIV-1 and HIV-2 (EC50 = 4–14

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µg/mL) but they were also cytotoxic (CC50 = 17.5 and 28 µg/mL) to the host cells [67]. Proliferation of L1210/0 cancer cells was inhibited by compounds 36a [67] and 36d [69] (IC50 = 16.2 and 13.9 µg/mL) while 36a [67] and 37a [68] were active against Molt4/C8 cells (IC50 = 13.2 and 3.8 µg/mL). Also 1′-homonucleosides 39a–39c and 40a–40c prepared from 35 (Fig. 5) appeared inactive against a broad panel of viruses at subtoxic concentrations [70], however, 39a inhibited proliferation of CEM, Molt4/C8 and L1210/0 cell lines at

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Figure 5.

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concentrations 14, 9 and 13 µg/mL, respectively [70].

The furanose for 1,3-disubstituted indan replacement markedly changes spatial relationships in a sugar part of a nucleoside since in addition to lack of an oxygen atom the benzene ring is

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introduced thus restricting conformational freedom of the cyclopentane ring. Synthesis of a relevant indan framework begins with the cycloaddition of benzyne and cyclopentadiene to give benzonorbornadiene 41 which was first transformed into the diol 42a and later into a mesylate 42c and a tosylate 42d to be used in alkylation of various nucleobases (Scheme 3) [73–75].

Scheme 3.

Moderate cytostatic activity assayed on L1210/0, Molt4/C8 and CEM/0 cells (IC50 = 24–100 µg/mL) was found for purine 1′-homocarbanucleosides 43a–43h, while among pyrimidine

ACCEPTED MANUSCRIPT analogues 44 only compound 44c containing a thymine moiety was slightly active (IC50 = 81– 112 µg/mL) [75]. On the other hand, when the purine ring in 43a was functionalized at C6 with p-substituted phenyls the respective 1′-homonucleosides 45 were endowed with significant cytostatic activity and the most active compounds 45b and 45d inhibited the proliferation of L1210/0, Molt4/C8 and CEM/0 cells at IC50 = 1.4–5.7 and 0.63–3.3 µg/mL,

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respectively [75].

To learn how the hydroxymethyl for hydroxyl group replacement affects the biological activity 1′-homocarbanucleosides 49–51 (Scheme 4) were synthesized [76‒77]. The key

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intermediate 48a was prepared from the anhydride 46 while in the synthesis of the mesylate 48e standard protective group manipulation was applied [76]. 1′-Homonucleosides 49a–49e, 50a–50d and 51a–51e (Scheme 4) were found inactive in inhibiting various viruses in

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concentrations as high as 400 µg/mL [76‒77].

Scheme 4.

1′-Homocarbanucleosides based on the cis-1,3-indandimethanol framework in which the

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benzene ring was replaced with selected heteroaromatic systems were designed to broaden a pool of potentially active compounds while aiming at modification of polar interactions as well as lipophilicity in this region of analogues. Compounds having a cyclopenta[b]pyrazine scaffold 56 were synthesized from N,N-diacetylimidazolone 52 and cyclopentadiene followed

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by a C=C bond dihydroxylation to afford the bicyclic diol 53 (Scheme 5) [78]. Its further transformations included the construction of a pyrazine ring by condensation of an intermediate diamine with benzil and aromatization in the presence of DDQ as the most

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important steps. No data on biological activity of 1′-homonucleosides 56a–56c have been disclosed so far.

Scheme 5.

Following this idea isomers of 56 equipped with a cyclopenta[d]pyridazine skeleton 59 and 60 were synthesized (Scheme 6) [69,79]. Reaction of 2,3-dibenzoylbicyclo[2.2.1]hepta-2,5-diene with hydrazine gave a compound 57 in which a norbornadiene part served as a precursor to a fused cis-1,3-cyclopentanedimethanol-the pyrazine ring framework 58. Compounds 59a–59e appeared inactive against a broad panel of viruses at concentrations up to 400 µg/mL [79]. On

ACCEPTED MANUSCRIPT the other hand the analogue 60b was a moderate inhibitor of L1210/0 cancer cells (IC50 = 65.7 µM) while the derivative 60a was found inactive (IC50 > 200 µM) [69].

Scheme 6.

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Further extension of this concept led to 1′-homocarbanucleosides containing a cyclopenta[c]pyrazole framework 64 and 65 [80]. Starting from the bicyclo[2.2.1]heptan-2one derivative 61 the key intermediate 63a was obtained as shown on Scheme 7. Compounds 64a, 64b and 65a–65d were found inactive against many viruses except the silyl ethers 64b

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and 65d which proved highly inhibitory to cytomegalovirus and varicella-zoster virus. The inhibition of cytomegalovirus AD169 and DAVIS 07/1 strains by compounds 64b (EC50 = 0.50 and 0.50 µM) and 65d (EC50 = 0.44 and 0.39 µM) matched those of ganciclovir (EC50 =

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0.25 and 0.40 µM). For VZV TK– strain the activities of 64b and 65d (EC50 = 1.5 and 2.1 µM) significantly exceeded that of a reference acyclovir (27 µM) [80].

Scheme 7.

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Isomeric 1′-homocarbanucleosides incorporating a cyclopenta[d]pyrazole framework 66–69 (Fig. 6) were synthesized in a way similar to that shown on Scheme 7 [81–82]. Evaluation of their cytostatic activity on L1210/0, Molt4/C8 and CEM cell lines showed significant potency

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Figure 6.

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(IC50 = 3.2–11 µg/mL) of compounds 66a, 67, 68a and 69a.

2.3. Other substituted cyclopentanes

To construct 2,3-dihydroxycyclopentane-1,4-dimethanol, a parent framework for the synthesis of 1′-homocarbanucleosides which would contain all hydroxyl groups present in a ribofuranoside, the protected cis-cyclopentane-1,3-dimethanol 70 was obtained from norbornadiene (Scheme 8) [83]. The aminoalcohol 71, a key intermediate to install all canonical nucleobases, was then prepared employing a four-step reaction sequence which started from monoacetylation. So far synthesis of 1′-homocarbanucleoside containing an uracil moiety 72 has been disclosed [83].

ACCEPTED MANUSCRIPT Scheme 8.

1′-Homocarbanucleoside analogues lacking the hydroxymethyl group at C4′ but decorated with secondary hydroxyl groups at C3′ and/or C4′ were synthesized from 4-

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tosyloxymethylcyclopentene 73 (Scheme 9) [84]. Alkylation of 2-amino-6-chloropurine with 73 gave the key compound 74 which was subjected to hydroxylation or epoxidation followed by an acid-catalyzed epoxide opening or cis-dihydroxylation to provide intermediates which were transformed into the respective 1′-homocarbanucleosides 75a–75b, 76 and 77.

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Compounds 75–77 were found inactive (IC50 > 500 µM) against a variety of DNA and RNA viruses. This may be due to the presence of a secondary hydroxyl group which is expected to be phosphorylated, however, this process is significantly less efficient than that of the primary

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one. Simultaneously it was found that antiviral activity of acyclovir 15a (Fig. 2) towards HSV-1 infected cells could be increased in the presence of a guanine derivative 76; a case of synergism to be considered for future applications.

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Scheme 9.

A search for 1′-homocarbanucleosides containing three hydroxyl groups in the cyclopentane ring culminated in the synthesis of both enantiomers of the adenine analogue 81 starting from 1-acetoxy-4-(nitromethyl)cyclopent-2-ene 78 (Scheme 10) [85]. Enantiospecific hydrolysis of

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racemic 78 brought about (–)-79 which was re-acetylated to (–)-78 and then subjected to cisdihydroxylation. The nitromethyl group was then transformed into the hydroxymethyl group by the Nef reaction followed by the aldehyde reduction to provide a compound 80. Coupling

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of 80 with 6-chloropurine was accomplished employing a Mitsunobu protocol, and three standard steps finally gave the 1′-homocarbanucleoside 81. Neither 81 nor its enantiomer were active against a panel of viruses and they were not cytotoxic as well [85].

Scheme 10.

An interesting group of 1′-homocarbanucleosides 82–86 (Fig. 7) was obtained from iridoids [86–88]. It is worth noting the structural resemblance of 82b and 83 to neplanocins B and C. Compounds 84 and 85 were assayed against HIV and HSV-1 but appeared inactive; they were also not cytotoxic.

ACCEPTED MANUSCRIPT Figure 7.

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2.4. Substituted cyclopentenes

Studies on 1′-homonucleosides which incorporate a cyclopentene ring were stimulated by the clinical application of carbovir 11a and abacavir 11b (Fig. 2). The 1,3-substitution pattern present in parent compounds was modified to the geminal one and a methylene linker was

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installed to provide 1′-homocarbanucleosides 87a–87d (Scheme 11) [89]. The synthesis of [(1-hydroxymethyl)cyclopent-3-enyl]methanol 88 originated from diallylation of diethyl malonate and included the Grubbs metathesis and reduction of the ester groups. After

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temporary protection of the hydroxyl group the other one was activated by mesylation to make the installation of nucleobases facile. The adenine analogue 87a which is isomeric to carbovir 11a (Fig. 2) inhibited HCMV at EC50 = 78.1 µM, while compound 87d was active (EC50 = 56.4 µM) against HIV-1.

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Scheme 11.

To synthesize 1′-homocarbovir 91a a strategy similar to that shown on Scheme 2 was employed.

racemic

into

cis-[4-(hydroxymethyl)cyclopent-2-enyl]methanol

cis-[4-(aminomethyl)cyclopent-2-yl]methanol

90

89

employing

was a

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transformed

Thus,

monoacetylation–tosylation sequence, modified Gabriel reaction followed by hydrolysis (Scheme 12) [90]. Compound 90 served as a key intermediate in the de novo installation of

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selected nucleobases. The guanine analogue 91a together with 91b and 91c showed no appreciable cytotoxicity (IC50 > 200 µM) against L1210/0 cell line [69].

Scheme 12.

In studies on aminocyclopentitols as glycosidase inhibitors a close structural analogue of neplanocin A 92 (Fig. 8) was synthesized but appeared inactive against several glucosidases and galactosidases [91].

Figure 8.

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3. 1′-Homonucleosides

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3.1. 1′-Homoadenosine and related compounds

The first syntheses of 1′-homoadenosine 18 (Fig. 3) were accomplished by the de novo pathway. A bromide for cyanide exchange in 2,3,5-tri-O-benzoylribofuranosyl bromide 93a was achieved by the action of mercury(II) cyanide to afford the β-anomer which was partially

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deprotected and after isopropylidenation and reduction 1-amino-2,5-anhydro-1-deoxy-3,4-Oisopropylidene-D-allitol 94b was obtained and later transformed into 18 (Scheme 13) [48]. A simplified procedure to prepare 1′-homoadenosine 18 was simultaneously elaborated using 1-

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amino-2,5-anhydro-1-deoxy-D-allitol 94a as a starting material [92]. Thus, upon ammonolysis of the intermediate 6-chloropurinyl derivative 96a homoadenosine 18 was obtained while its hypoxanthine analogue 96b was produced after hydrolysis (Scheme 13) [92]. These efforts were preceded by the synthesis of 1′-homouridine 97 and 1′-homocytidine 98 (Scheme 13) employing the aminotriol 94a as a starting material [93]. No inhibition against E. coli was

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detected for 1′-homouridine 97 and 1′-homocytidine 98 at concentrations 100 µg/mL [93], while for 1′-homoadenosine 18 and 1′-homoinosine 96b – at concentrations up to 1 mg per 1 mL [92].

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Scheme 13.

α-Pseudoanomers of 1′-homonucleosides 18, 96b, 97 and 98 were synthesized by the same

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approach from 1-amino-2,5-anhydro-3,4,6-tri-O-benzyl-1-deoxy-D-altritol 95 which was formed together with 1-amino-2,5-anhydro-3,4,6-tri-O-benzyl-1-deoxy-D-allitol 94c (as a separable 1:2 mixture) upon reduction of a nitrile prepared from 2,3,5-tri-Obenzylribofuranosyl bromide 93b (Scheme 13) [94].

A recent and general method for the synthesis of 1′-homonucleosides 18 and 97–99 (Scheme 13) relied on the substitution of a tosylate with lithium salts of nucleobases [49]. When 2,3-Oisopropylidene-D-ribofuranose 100 was subjected to Wittig olefination the stereospecific tetrahydrofuran ring closure occurred to form the respective ester which was reduced to the TBDPS-protected alcohol 101 (Scheme 14). In a five-step reaction sequence an extra carbon

ACCEPTED MANUSCRIPT atom was removed to give a key intermediate 102a which was readily transformed into a tosylate 102b (Scheme 14) [49].

Scheme 14.

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Early synthesis of α-pseudoanomers of 1′-homonucleosides of the D-arabino-configuration 103 and 104a–104c took advantage of the 3,4-O-diacetyl-2,5-anhydro-6-O-tosyl-D-mannose dimethyl acetal 105 readily prepared from 2-amino-2-deoxy-D-glucose (Fig. 9) [95]. Compounds 103–104 were not cytostatic against L1210 leukemia, however, 103, 104b and

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104c showed significant cytotoxicity [95].

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Figure 9.

The epoxide ring opening–tetrahydrofuran ring closure sequence was successfully employed in the synthesis of several 1′-homonucleosides [96,97]. Thus, when bis-epoxides 106 and 108, both prepared from D-mannitol, were treated with nucleobases 1′-homonucleosides 107a– 107d [96,97] and 109a–109e [97] as well as 110 were obtained to structurally diversify a

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class of 1′-homoadenosine or 1′-homouridine stereoisomers (Scheme 15).

Scheme 15.

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These achievements found immediate application in the synthesis of a homologue 111b of the recently identified potent inhibitor 111a (Fig. 10) [98,99]. Treatment of the epoxide 108 with the silylated uracil provided an intermediate 110 (Scheme 15) which was further subjected to

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glycosylation and reductive deprotection to give the compound 111b which at final 2 mM concentration inhibited bacterial transferase MraY (IC50 = 580 µM) [99]. Several derivatives of 111b at the aminomethyl terminus were prepared to study SAR but it appeared that they were less active [99].

Figure 10. 2,3-O-Isopropylidene derivatives of 1′-homoadenosine 18 and its N6-phenyl counterpart 96c (Scheme 13) were also obtained from the protected alcohol 102a (Scheme 14) under Mitsunobu protocol to be later transformed into potential inhibitors of tRNA synthethases

ACCEPTED MANUSCRIPT 112a–112f (Fig. 11) [100]. Compounds 112c and 112f acted as a marginal inhibitors of isoleucyl-tRNa synthethase from E. coli (IC50 > 128 µM). However, other compounds inhibited methionyl-tRNa synthethase (IC50 = 3.6–63 µM) from E. coli with 112a being the most active. The methylene linker had no significant influence on the activity since for the parent 112g and the next homologue 112h very close values of IC50 were assayed (5.0 and 8.3

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µM, respectively) [100].

Figure 11.

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In studies on A3 adenosine receptor ligands an innovative one-carbon homologation at the anomeric center in 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose was elaborated via a Co2(CO)8-catalyzed silyloxymethylation to secure the formation of the compound 113a

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(Scheme 16) [101]. The respective alcohol 113b was transformed into the key intermediate 114a employing the Mitsunobu reaction. Installation of the 3-iodobenzylamino functionality at C6 was followed by oxidation of the hydroxymethyl group and coupling with methylamine or dimethylamine to provide 1′-homonucleoside analogues 115a and 115b, respectively. Their binding affinities at A3 subtype adenosine receptor were very low when compared with that of

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the parent compound 115c (Ki = 1.0 nM) which acted as A3 AR agonist. This is probably due to conformational freedom inherent in compounds 115a and 115b which enabled the favorable interactions with the enzyme binding site.

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Scheme 16.

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3.1.1. Phosphates of 1′-homonucleosides

Studies on interactions between DNA/RNA strands containing 1′-homonucleosides in defined positions required prior elaboration of synthetic routes to protected phosphates. Besides that, the activity of various 1′-homonucleosides and in particular their phosphates in enzymatic processes is of interest.

When 1′-homouridine 97 became available [93] its 2′,3′-cyclic phosphate 116 and 5′phosphate 117 (Fig. 12) were prepared to study their interactions with nucleolytic enzymes [102]. Even in the presence of high excess of pancreatic ribonuclease A cleavage of 116 was

ACCEPTED MANUSCRIPT not observed. Furthermore, although ribonuclease T2 cleaved 116, the reaction was slow in comparison to that with uridine 2′,3′-cyclic phosphate. On the other hand, the 5′-phosphate 117 remained intact when put in contact with the snake venom 5′-nucleotidases [102].

In a thorough study on eleven substrates for adenosine kinase it was found that the relative

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rate of phosphorylation of 1′-homoadenosine 18 is negligible (< 3) in comparison with that of adenosine itself (100) [103]. Compound 18 is also significantly less active as inhibitor of neurotransmission in rat vas deferens when compared with most potent adenosine [104].

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1′-Homonucleotide dimers 118a and 118b were prepared from 1′-homoadenosine 18 as well as from its 2′-deoxy counterpart employing a phosphoramidate chemistry and later incorporated into oligonucleotides to study cross-pairing with complementary oligomers,

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natural or modified [105]. Based on CD data and detailed NMR studies a left-handed conformation was established for the dimers 118 and their oligomers (single- or doublestranded). On the other hand, right-handed helices exist for the duplexes of homo-type dimers with nucleic acids or natural oligomers. The dimers and homooligomers of the 2′-deoxy series were found resistant to digestion by two phosphodiesterases (snake-venom and calf-spleen)

EP

Figure 12.

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and nuclease S1 [105].

3.2. 2′-Deoxy-1′-homonucleosides

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To study interactions in altDNA–DNA and altDNA–RNA hybrids 1′-homonucleosides 120 and 121a were designed by modelling studies. Since the methylene linker aids flexibility they may also be considered as conformational probes. These compounds were efficiently synthesized from methyl 2-deoxy-D-ribofuranoside by cyanation of the protected furanosyl chloride followed by reduction of the easily separable α- and β-cyanides to amines 119a and 119b (Scheme 17) [106,107]. The thymine framework was later constructed in a de novo fashion. Before incorporation into an oligonucleotide chain 1′-homonucleosides 120 and 121a were converted into the phosphoramidate derivatives. It was found that affinity of the altDNA oligomer containing 1′-homonucleoside 120 at the predetermined positions to its

ACCEPTED MANUSCRIPT corresponding RNA sequence is greater than that within altDNA–complementary DNA hybrid [107].

Scheme 17.

composed

of

canonical

nucleobases

were

efficiently

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2′-Deoxy-1′-homonucleosides

synthesized by a mesylate displacement [108,109]. Starting from 2-deoxy-D-ribose the hydroxyl groups at C3 and C5 in the methyl ribofuranoside were protected as benzyl ethers and an one-carbon unit was added by the Wittig methylenation to produce the respective

SC

olefin 122 which was subjected to epoxidation (Scheme 18) [108]. Under acidic reaction conditions the intermediate epoxide was opened by an intramolecular attack of the oxygen atom to give protected isomeric tetrahydrofuranes 123a (β-pseudoanomer) and 124 (α-

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pseudoanomer) in nearly equimolar ratios. A mesylate 123b was a key compound to produce thymine, cytosine, adenine and guanine containing 2′-deoxy-1′-homonucleosides 121, 125, 126, and 127, respectively after deprotection of hydroxyl groups. The 1′-homonucleosides were incorporated into the specific sites in DNA employing a phosphoramidate methodology. Duplex destabilization was noticed when even one modified nucleoside was present and destabilization progressed after introducing the next ones. 1′-Homonucleosides 126 and 127

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containing purine skeletons showed significant activity (MIC = 5–20 µg/mL) against several viruses including HSV-1 and HSV-2 while the pyrimidine analogues 121 and 125 were found

Scheme 18.

EP

inactive [109].

AC C

2′-Deoxy-1′-homothymidine 121a (Scheme 17) was also synthesized from 2,3,5-tri-O-benzylD-arabinofuranosyl

chloride (Scheme 19) [110,111]. Vinylation at C1 was followed by

dihydroxylation, diol cleavage and reduction to prepare a compound 128 as a mixture of pseudoanomers. The required isomer having β-oriented hydroxymethyl group at C1′ was separated via the isopropylidene derivative 129a which after protection at C3 and C5 and hydrolysis furnished a compound 129c. Its deoxygenation at C2 was accomplished by the standard Barton-McCombie sequence to give the protected alcohol 130, a substrate for installation of a thymine residue according to the Mitsunobu protocol to give 121a.

Scheme 19.

ACCEPTED MANUSCRIPT A series of the known 2′-deoxy-1′-homonucleosides [108,109] was extended on uracil and 6mercaptopurine containing compounds 131b and 132, respectively (Fig. 13) by employing the mesylate 123b (Scheme 18) [112]. Protected 1′-homo-2′-deoxy-thymidine 121b and -uridine 131b were additionally transformed into their 4-thio counterparts 133 and 131c (Fig. 13) after

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treatment with phosphorus pentasulfide (P4S10). During studies on their oxidation several new compounds were synthesized to collect a library of 27 2′-deoxy-1′-homonucleosides. Some of them showed moderate activity against the influenza A virus and compounds having the hypoxanthine residue 134a and 134b were the most potent (IC50 = 25.2 and 24.3 µg/mL)

SC

while devoid of cytotoxicity. These studies revealed several examples of very close antiviral activities of parent compounds (series a – 3′,5′-dihydroxy) and their dibenzyl ethers (series b) which were not limited to a pair of 134a and 134b but were also found for the substituted

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thymines 121a (70.4 µg/mL) and 121b (70.3 µg/mL), cytosines 125a (67.3 µg/mL) and 125b (57.4 µg/mL), adenines 126a (49.2 µg/mL) and 126b (39.9 µg/mL) as well as uracils 131a (94.2 µg/mL) and 131b (108.2 µg/mL) [112]. It is highly likely that both series of compounds exert their antiviral activity by different mechanisms and detailed studies should clarify the

Figure 13.

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issue.

In search for inhibitors specific for viral UDG (uracil-DNA glycosylase) enzymes but with

EP

little or no impact on human ones 2′-deoxy-1′-homouridine 131a was incorporated into a 25mer. It appeared that this oligomer binds specifically to the viral UDG (HSV-1) with affinity of Kd = 160 nM and does not bind to the respective human enzyme. However, it is still

AC C

significantly lower when compared to a 25-mer tagged with 2′-deoxy-2′-β-fluorouridine (Kd = 4 nM) [113].

3.3. 1′-Homonucleosides devoid of the HOCH2–C4 group Although cellular enzymes readily catalyze phosphorylation at the HO–C5′ terminus a subclass of 1′-homonucleosides containing secondary hydroxyl groups is of interest as potential chain terminators. The synthesis of adenine [114,115], cytosine [114,115], uracil [114,115] and 5-fluorouracil [116] containing analogues 135, 136, 137a and 137b was

ACCEPTED MANUSCRIPT accomplished by either the oxetane ring opening in 1,4;3,5-dianhydro-DL-xylitol 138 or substitution of chloride or bromide in 5-chloro(bromo)-5-deoxy-1,4-anhydro-DL-xylitols 139 with sodium salts of nucleobases (Fig. 14). Cytotoxicity of 137b was found to be significantly lower than that for tegafur [5-fluoro-1-(tetrahydro-2-furanyl)uracil] [116].

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Figure 14.

Similar strategy was applied in the synthesis of 5-(adenin-9-yl)-5-deoxy-1,4-anhydro-D-ribitol 140 (Scheme 20) [117]. 2,3-O-Isopropylidene-D-ribofuranose was protected as a 5′-O-trityl

SC

derivative and later reduced to the diol 141 which under basic conditions of tosylation underwent intramolecular cyclization to produce the compound 142a. Acid-catalyzed hydrolysis of the trityl ether 142a was followed by the reprotection of a 2′,3′-diol again as an

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acetonide which was transformed into the tosylate 142b, a precursor to homonucleoside 140. The latter compound was inactive in inhibiting the growth of E. coli at concentration up to 1 mg/mL [117] as well as against VSV (vesicular stomatitis virus) and VV (vaccinia virus) showing IC50 > 400 µg/mL [118].

TE D

Scheme 20.

Synthesis of ent-140 was accomplished by the de novo protocol from 1-amino-2,5-anhydro-1deoxy-3,4-O-isopropylidene-D-ribitol 144 which was obtained from 2,5-anhydro-D-ribose

AC C

Scheme 21.

EP

diisobutyl dithioacetal 143 in six straightforward steps (Scheme 21) [119].

1′-Homonucleosides 145 and 146 were originally designed as components of locked nucleic acids [120]. They were synthesized from 3,5-di-O-benzyl-1,2-O-isopropylidene-4-Chydroxymethyl-α-D-ribofuranose 147 which was transformed into a tosylate 148 in a series of standard reactions (Scheme 22) [120]. Acetylation of 148 preceded nucleophilic substitution of a tosylate with sodium salt of thymine to obtain final 145 after removal of the protecting groups. To synthesize 1′-homonucleoside 146, a deoxy analogue of 145, the compound 148 was deoxygenated to provide a protected tosylate 149 which after reaction with thymine and deprotection gave 146. After phosphorylation 1′-homonucleosides 145 and 146 were incorporated into oligonucleotide chains to study conformational changes and duplex

ACCEPTED MANUSCRIPT stabilization. It was found that oligomers equipped with either 145 or 146 destabilize duplexes because of unfavorable conformations of the tetrahydrofuran ring in the monomers.

Scheme 22.

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Locked nucleic acids (LNA) are of interest in studies of biological functions of modified RNA and DNA oligomers since the tetrahydrofuran ring is forced to adapt a single and well defined conformation. This idea stimulated interest in the synthesis and activity of analogous 1′-homonucleosides. Annulation of a 7-oxabicyclo[2.2.1]heptane framework with benzene or

SC

naphthalene rings fulfills this requirement. To synthesize this group of compounds anthranilic acid (or its naphthalene counterpart) as a source of benzyne (naphthyne) and 2-furaldehyde or 5-(acetoxymethyl)-2-furaldehyde were subjected to the Diels-Alder reaction as shown on

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scheme 23 [121]. Installation of purine bases in 150a and 150b was accomplished by the Mitsunobu reaction while C=C bond hydrogenations, dihydroxylations, epoxidations and hydroboration followed by alkaline hydrolysis were conducted according to the standard protocols to provide compounds 151–158 (Scheme 23).

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Scheme 23.

It was found that 1′-homonucleoside analogues 151–154 possess noticeable anti-HCV activity (EC50 = 45.1–68.7 µM) but also marked cytotoxicity (CC50 = 89.3–100 µM) [121].

EP

Replacement of the 6-chloropurin-9-yl component in 151 for the adenine-9-yl group produces an inactive analogue. However, compounds 155–158 appeared more potent against HCV (EC50 = 6.31–16.1 µM) while being also cytotoxic (CC50 = 11.1–72.4 µM) [121]. In addition,

AC C

the growth of CCRF-CEM cancer cells was reduced (IC50 = 5.73 µM) by 155 [121]. Undoubtedly, origin of anti-HCV activity for this group of compounds requires further studies.

3.4. 1′-Homonucleosides derived from 2,5-dihydrofuran

The interest in 1′-homonucleosides containing a 2,5-dihydrofuran framework has been evoked by clinical application of stavudine 10 (Fig. 2). 1′-Homostavudine 159 was synthesized from a compound 129c (Scheme 19) by silylation followed by debenzoylation and reprotection of the

ACCEPTED MANUSCRIPT primary hydroxyl as a trityl ether to form a diol 160 (Scheme 24) [110,111]. BartonMcCombie deoxygenation and desilylation provided the alcohol 161 which was transformed into 159 employing the Mitsunobu reaction.

4. 1′-Homonucleosides having a pyrrolidine ring

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Scheme 24.

SC

The oxygen for nitrogen replacement in a sugar moiety provides a class of nucleosides containing a pyrrolidine skeleton. It significantly modifies spatial and electronic environment around the heteroatom in the five-membered ring since depending on the substitution at the

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nitrogen atom its hybridization may switch from tetrahedral (in amines and ammonium salts) to trigonal (in amides). Substituents at the nitrogen atom can have profound impact on the activity of pyrrolidine analogues and their lipophilicity. Polyhydroxylated pyrrolidines are well recognized for their biological activity primarily as inhibitors of glycosidases. Consequently, this stimulates the interest in the synthesis and studies on various aspects of

TE D

biological activity of, among others, 1′-homonucleosides having a pyrrolidine ring substituted with hydroxyl groups in a pento- or 2′-deoxypentofuranoside manner to eventually improve or

EP

at least make comparisons with structurally related compounds of well-established activities.

4.1. Nitrogen analogues of 1′-homoadenosine and related compounds

AC C

The elegant synthesis of a nitrogen analogue of 1′-homoadenosine 162 and its hypoxanthine 163 and guanine 164 containing counterparts applied protected 1,4-dideoxy-1,4-imino-Dribitol 165 as a source of the imine 166 (Scheme 25) [122]. The hydroxymethyl group was introduced employing an 1,3-dithiane chemistry to form protected 2,5-dideoxy-2,5-imino-Dallitol 167 which after activation as sulfonates was transformed into 1′-homonucleosides 162– 164 in a standard way.

Scheme 25.

ACCEPTED MANUSCRIPT Compounds 162–164 belong to a library of inhibitors of nucleoside hydrolases (NH) from protozoan parasites and they were assayed on IU-NH and IAG-NH [122,123] to show the inhibitory power toward both enzymes with Ki = 5.4–22 µM and 3.6–13 µM, respectively. However, it was still approximately three orders of magnitude lower than that observed for the most active C-nucleoside 168 (Ki = 7 and 3 nM) [123]. Since these enzymes are involved

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in the hydrolysis of N-glycosyl bonds one may conclude that the presence of a methylene linker is in a significant part responsible for lower affinity of 1′-homonucleoside 162 to the enzymes active sites in comparison with that of the C-nucleoside 168. Later on compound 162 was also found inactive (Ki > 10 µM) as an inhibitor of TvPNP (Trichomonas vaginalis purine

SC

nucleoside phosphorylase), while compound 168 was endowed with potency in low picomolar concentrations in the same assay [124].

synthesized

from

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In search for other stereoisomers of pyrrolidine-based 1′-homonucleosides compound 169 was (2S,3R,4R,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)pyrrolidine

170

(Scheme 26) [125]. Highly stereoselective formation of the 1,2-carbamate of 170 preceded the benzylation of three hydroxyl groups and was followed by the carbamate hydrolysis and protection at the nitrogen atom to give the pyrrolidine 171. Introduction of a guanine residue

Scheme 26.

TE D

was accomplished by substitution of a tosylate with 2-amino-6-chloropurine.

EP

To synthesize 1′-homonucleosides (2S,3R,4R,5S)-172 and (2S,3S,4R,5S)-173 a protected pyrrolidine 174 was selected (Scheme 27) [126]. First, an adenin-9-yl substituent was installed in three steps by substitution of the tosyloxyl group to form a compound 175 which

AC C

was deprotected to give 172a. Synthesis of the N-methyl derivative 172b required prior removal of the N-tosyl group to produce a bicyclic intermediate 176 after reaction with formaldehyde. Regioselective cleavage of the C–O bond in the oxazolidine ring secured the formation of the Me–N fragment and restored the hydroxymethyl group to give compound 177 which was transformed into 172b in a standard manner (Scheme 27). Removal of benzyl groups from 175, isopropylidenation and formation of a triflate afforded the intermediate 178. Upon hydrolysis of an acetonide a tetrahydrofuran ring closure occurred which was followed by the Ts–N bond cleavage and thus a bicyclic locked 1′-homonucleoside 173 became available for the first time (Scheme 27) [126].

ACCEPTED MANUSCRIPT Scheme 27.

Protected 1′-homo-2′-deoxynucleoside 179 containing the pyrrolidine ring was obtained to study binding to the DNA adenine glycosylase MutY, since it was found that oligomer containing unsubstituted pyrrolidine (devoid of adenine) 180 extremely strongly (Kd in a pM

RI PT

range) binds to BER (base-excision DNA repair) enzymes [127]. Synthesis of 179 began with allylation of Garner aldehyde prepared from D-serine followed by partial deprotection and silylation of both hydroxyl groups to give compound 181 (Scheme 28) [127]. After epoxidation of 181 the protected pyrrolidine 182 was formed and it was further reacted with

SC

6-chloropurine following the Mitsunobu protocol. Removal of all protecting groups and installation of N-Fmoc moiety gave the diol 179 ready for incorporation into a 25-mer oligonucleotide. Finally, the transformation of the 6-chloropurin-9-yl group into the adenin-9-

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yl moiety was accomplished in a standard manner. Indeed, the presence of the (adenin-9yl)methyl residue in the 25-mer 183 improved the binding as much as 50-fold in comparison with the 25-mer in which unsubstituted pyrrolidine moiety was included 180.

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Scheme 28.

4.2. 3,4-Dihydroxypyrrolidine-based 1′-homonucleosides

EP

When 1′-homonucleosides containing a pyrrolidine framework lacking the hydroxymethyl group are of interest dehydro-DL-proline can be considered as a starting material of choice [128]. A sequence of standard transformations gave the protected 2,5-dihydropyrrole 184

AC C

(Scheme 29). The most efficient way to the 1′-homonucleoside 185 required cisdihydroxylation to be performed before installation of the adenin-9-yl group. As expected dihydroxylation occurred in a trans fashion to the existing tosyloxymethyl group.

Scheme 29.

4.3. Monohydroxypyrrolidine-based 1′-homonucleosides

ACCEPTED MANUSCRIPT Synthesis of 1′-homonucleoside 186 was readily accomplished in a standard manner from the intermediate 187 which was obtained from ethyl N-Boc-trans-4-hydroxy-D-prolinate after protection, ester reduction and tosylation (Scheme 30) [129]. Compound 186 was found inactive against HIV-1 and HSV-1 [129].

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Scheme 30.

An interesting approach to 1′-homonucleosides bearing a pyrrolidone moiety 188 exploited 1,3-dipolar cycloaddition of nucleobase-derived nitrones and acrylates and is based on a

SC

reduction-recyclization sequence (Scheme 31) [130]. Reaction of a nitrone 190a with methyl acrylate produced the 1:1 mixture of cis-189 and its trans counterpart. Hydrogenolysis of cis189 resulted in the cleavage of an isoxazolidine ring and triggered cyclization to the trans

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isomer of 188.

Scheme 31.

TE D

5. 1′-Homonucleosides containing thiolane rings

In search for A3 adenosine receptor ligands [101] a sulfur analogue 191 of the compound 115c (Scheme 16) was also identified as a powerful agonist (Ki = 0.38 nM) and this observation

AC C

Figure 15.

EP

prompted studies on a nucleoside 192 and 1′-homonucleosides 193 (Fig. 15) [131].

The latter compounds were obtained from 2,3;5,6-di-O-isopropylidene-D-mannofuranose 194 which after reduction and mesylation was treated with sodium sulfide to give the thiolane 195 (Scheme 32) [131]. A series of standard reactions began with terminal acetonide hydrolysis and finally led to the formation of compounds 196, key intermediates in the synthesis of final 1′-homonucleosides 193. While nucleoside 192 acted as a selective antagonist at A3 AR (Ki = 4 nM), none of the homologues 193 showed appreciable affinity to any subtype of adenosine receptors [131].

Scheme 32.

ACCEPTED MANUSCRIPT

Conclusions

To the best of our knowledge this review is the first comprehensive coverage of synthesis

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[132] and biological activities of 1′-homonucleosides containing in addition to the pentofuranose ring the cyclopentane, pyrrolidine and thiolane moieties and their unsaturated counterparts as pseudosugars. Since the installation of the nucleobases or their mimetics could be achieved according to standard protocols the major interest was focused on the

SC

construction of pseudosugar scaffolds. These efforts resulted in designing of several elegant syntheses which were later successfully executed. Unfortunately, biological activities of a significant number of the synthesized compounds were not studied.

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Despite that a few active compounds were discovered. Thus, compounds 45b and 45d inhibited the proliferation of L1210/0, Molt4/C8 and CEM/0 cells at IC50 = 1.4–5.7 and 0.63– 3.3 µg/mL, respectively [75]. The silyl ethers 64b and 65d inhibited cytomegalovirus AD169 and DAVIS 07/1 strains with EC50 = 0.50 and 0.50 µM and EC50 = 0.44 and 0.39 µM, respectively and their potencies matched those of ganciclovir (EC50 = 0.25 and 0.40 µM) [80]. Furthermore, for VZV TK– strain the activities of 64b and 65d (EC50 = 1.5 and 2.1 µM)

TE D

significantly exceeded that of a reference acyclovir (27 µM) [80]. Although the ester of 1′homoadenosine 112a significantly (IC50 = 3.6 µM) inhibited methionyl-tRNa synthethase from E. coli the respective esters of a nucleoside and the next homologue showed similar

EP

potencies (5.0 and 8.3 µM, respectively) [100].

There is, however, a room left especially for new pyrrolidine and thiolane ring-containing frameworks to be proposed and synthesized to broaden the set of the respective 1′-

AC C

homonucleosides. There are a wealth of options to make further progress in this area by rational design of pseudosugars and further exploration of new nucleobase mimetics. 1′Homonucleosides proved to be a promising class of compounds and we hope this review will stimulate further research in this area.

Acknowledgments The authors acknowledge the support of the National Science Centre (grant UMO2013/09/B/NZ7/00729) and the Medical University of Lodz (internal fund 503-3014-01).

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[48] J.A. Montgomery, K. Hewson, J. Heterocycl. Chem. 7 (1970) 443–445. [49] D.C. Pryde, D.S. Middleton, P.T. Stephenson, P. Wainwright, A. Maddaford, X. Zhang, D. Leese, R. Glen, J. Hart, N. Forrest, T. Guyot, Tetrahedron Lett. 52 (2011) 6415–6419. [50] K.C. Kumara Swamy, N.N. Bhuvan Kumar, E. Balaraman, K.V.P. Pavan Kumar, Chem.

TE D

Rev. 109 (2009) 2551–2651.

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EP

[54] J.A. Montgomery, C. Temple, Jr., J. Am. Chem. Soc. 79 (1957) 5238–5242. [55] R. Vince, M. Hua, J. Med Chem. 33 (1990) 17–21. [56] Y.F. Shealy, J.D. Clayton, J. Pharm. Sci. 62 (1973) 1432–1434.

AC C

[57] V. Kumar, J. Yap, A. Muroyama, S.V. Malhotra, Synthesis (2009) 3957–3962 and references cited therein.

[58] R. Rayala, S.F. Wnuk, Tetrahedron Lett. 53 (2012) 3333–3336 and references cited therein.

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ACCEPTED MANUSCRIPT [62] L. Santana, M. Teijeira, E. Uriarte, C. Teran, G. Andrei, R. Snoeck, E. de Clercq, Nucleosides, Nucleotides 16 (1997) 1337–1339. [63] L. Santana, M. Teijeira, E. Uriarte, C. Teran, G. Andrei, R. Snoeck, J. Balzarini, E. de Clercq, Nucleosides, Nucleotides 18 (1999) 733–734. [64] M.C. Balo, F. Fernandez, E. Lens, C. Lopez, Nucleosides, Nucleotides 15 (1996) 1335–

RI PT

1346. [65] C. Balo, F. Fernandez, E. Lens, C. Lopez, G. Andrei, R. Snoeck, J. Balzarini, E. De Clercq, Arch. Pharm. (Weinheim, Germany) 330 (1997) 265‒267.

[66] O. Caamaño, F. Fernandez, G. Gómez, M.I. Nieto, Nucleosides, Nucleotides 14 (1995)

SC

295–297.

[67] J.M. Blanco, O. Caamaño, F. Fernandez, G. Gómez, M.I. Nieto, J. Balzarini, E. Padalko, E. De Clercq, Nucleosides, Nucleotides 16 (1997) 159–171.

M AN U

[68] M.I. Nieto, J.M. Blanco, O. Caamaño, F. Fernandez, X. Garcia-Mera, J. Balzarini, E. Padalko, J. Neyts, E. De Clercq, Nucleosides, Nucleotides 17 (1998) 1255–1266. [69] A.M. Helguera, J.E. Rodriguez-Borges, O. Caamaño, X. Garcia-Mera, M.P. Gonzalez, M.N.D.S. Cordeiro, Molecular Informatics 29 (2010) 213–231.

[70] M.I. Nieto, O. Caamaño, F. Fernandez, M. Gomez, J. Balzarini, E. De Clercq,

TE D

Nucleosides, Nucleotides, Nucleic Acids 21 (2002) 243–255.

[71] O. Caamaño, F. Fernandez, G. Gómez, I. Nieto, Tetrahedron 50 (1994) 2175–2182. [72] M.I. Nieto, J.M. Blanco, O. Caamaño, F. Fernandez, G. Gómez, Tetrahedron 54 (1998) 7819–7830.

EP

[73] F. Abad, F. Alvarez, F. Fernandez, X. Garcia-Mera, J.E. Rodriguez-Borges, Nucleosides, Nucleotides, Nucleic Acids 20 (2001) 1127–1128. [74] F. Fernandez, X. Garcia-Mera, M. Morales, J.E. Rodriguez-Borges, E. De Clercq,

AC C

Synthesis (2002) 1084–1090. [75] S.-W. Yao, V.H.C. Lopes, F. Fernandez, X. Garcia-Mera, M. Morales, J.E. RodriguezBorges, M.N.D.S. Cordeiro, Bioorg. Med. Chem. 11 (2003) 4999–5006. [76] F. Fernandez, X. Garcia-Mera, M. Morales, L. Vilarino, O. Caamano, E. De Clercq, Tetrahedron 60 (2004) 9245–9253. [77] F. Fernandez, X. Garcia-Mera, C. Lopez, M. Morales, J.E. Rodriguez-Borges, Synthesis (2005) 3549–3554. [78] C. Balo, C. Lopez, O. Caamano, F. Fernandez, X. Garcia-Mera, J.E. Rodriguez-Borges, Chem. Pharm. Bull. 56 (2008) 654–658. [79] O. Caamaño, G. Gómez, F. Fernández, M.D. García, X. García-Mera, E. De Clercq,

ACCEPTED MANUSCRIPT Synthesis (2004) 2855–2862. [80] M.D. Garcia, O. Caamano, F. Fernandez, C. Lopez, E. De Clercq, Synthesis (2005) 925– 932. [81] M.D. Garcia, O. Caamano, F. Fernandez, P. Abeijon, J.M. Blanco, Synthesis (2006) 73– 80.

RI PT

[82] M.D. Garcia, O. Caamano, F. Fernandez, X. Garcia-Mera, I. Perez-Castro, Synthesis (2006) 3967–3972.

[83] C. Balo, F. Fernandez, E. Lens, C. Lopez, Chem. Pharm. Bull. 46 (1998) 687–689.

[84] S. Halazy, M. Kenny, J. Dulworth, A. Eggenspiller, Nucleosides, Nucleotides 11 (1992)

SC

1595–1606.

[85] V.P. Rajappan, X. Yin, S.W. Schneller, Tetrahedron 58 (2002) 9889–9895. [86] H. Franzyk, J.H. Rasmussen, R.A. Mazzei, S.R. Jensen, Eur. J. Org. Chem. (1998) 2931–

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[87] H. Franzyk, F.R. Stermitz, J. Nat. Prod. 62 (1999) 1646–1654. [88] A. Bianco, D. Celona, S. Di Rita, M. Guiso, C. Melchioni, F. Umani, Eur. J. Org. Chem. (2001) 4061–4066.

[89] A. Kim, J.H. Hong, Arch. Pharm. 338 (2005) 522–552.

TE D

[90] C. Balo, J.M. Blanco, F. Fernandez, E. Lens, C. Lopez, Tetrahedron 54 (1998) 2833– 2842.

[91] G. Mehta, N. Mohal, Tetrahedron Lett. 42 (2001) 4227‒4230. [92] J. Farkas, Collect. Czech. Chem. Commun. 36 (1971) 3043–3046.

EP

[93] M. Bobek, J. Farkas, Collect. Czech. Chem. Commun. 34 (1969) 1684‒1689. [9]]. M.W. Winkley, Carbohydr. Res. 31 (1973) 245‒254. [95] P. Angibeaud, J. Defaye, H. Franconie, Carbohydr. Res. 78 (1980) 195–204.

AC C

[96] R. Saladino, U. Ciambecchini, S. Hanessian, Eur. J. Org. Chem. (2003) 4401–4405. [97] P. Busca, I. McCort, T. Prange, Y. Le Merrer, Eur. J. Org. Chem. (2006) 2403–2409. [98] A. Clouet, C. Gravier-Pelletier, B. Al-Dabbag, A. Bouhss, Y. Le Merrer, Tetrahedron: Asymmetry 19 (2008) 397–400. [99] D. Lecercle, A. Clouet, B. Al-Dabbagh, M. Crouvoisier, A. Bouhss, C. Gravier-Pelletier, Y. Le Merrer, Bioorg. Med. Chem. 18 (2010) 4560–4569. [100] J. Lee, S.U. Kang, S.Y. Kim, S.E. Kim, M.K. Kang, Y.J. Jo, S. Kim, Bioorg. Med. Chem. Lett. 11 (2001) 961–964. [101] H.W. Lee, W.J. Choi, K.A. Jacobson, L.S. Jeong, Bull. Korean Chem. Soc. 32 (2011) 1620–1624.

ACCEPTED MANUSCRIPT [102] A. Holy, Collect. Czech. Chem. Commun. 35 (1970) 81–88. [103] L.L. Bennett Jr., D.L. Hill, Molecular Pharmacology 11 (1975) 803–808. [104] D.M. Paton, H.-P. Baer, A.S. Clanachan, P.A. Lauzon, Neuroscience 3 (1978) 65–70. [105] K. Ishiyama, G.E. Smyth, T. Ueda, Y. Masutomi, T. Ohgi, J. Yano, J. Am. Chem. Soc. 126 (2004) 7476–7485.

RI PT

[106] C.L. Scremin, J.H. Boal, A. Wilk, L.R. Phillips, S.L. Beaucage, Bioorg. Med. Chem. Lett. 6 (1996) 207–212.

[107] J.H. Boal, A. Wilk, C.L. Scremin, G.N. Gray, L.R. Phillips, S.L. Beaucage, J. Org. Chem. 61 (1996) 8617–8626.

SC

[108] N. Hossain, N. Blaton, O. Peeters, J. Rozenski, P. Herdewijn, Tetrahedron 52 (1996) 5563–5578.

[109] N. Hossain, C. Hendrix, E. Lescrinier, A. Van Aerschot, R. Busson, E. De Clercq, P.

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Herdewijn, Bioorg. Med. Chem. Lett. 6 (1996) 1465–1468.

[110] B. Doboszewski, Nucleosides, Nucleotides 16 (1997) 1049–1052. [111] B. Doboszewski, Nucleosides, Nucleotides, Nucleic Acids 28 (2009) 875–901. [112] R. Saladino, V. Neri, P. Checconi, I. Celestino, L. Nencioni, A.T. Palamara, M. Crucianelli, Chem. Eur. J. 19 (2013) 2392–2404.

TE D

[113] Y. Sekino, S.D. Bruner, G.L. Verdine, J. Biol. Chem. 275 (2000) 36506–36508. [114] E.M. Ioannisyan, V.V. Kolomeitseva, G.E. Ustyuzhanin, N.S. Tikhomirova-Sidorova, Zhurn. Obshch. Khim. 50 (1980) 2146–2147.

[115] E.M. Ioannisyan, V.V. Kolomeitseva, G.E. Ustyuzhanin, N.S. Tikhomirova-Sidorova,

EP

Zhurn. Obshch. Khim. 51 (1981) 2128–2133.

[116] V.V. Kolomeitseva, G.V. Denisov, D.S. Terekhov, L.A. Uvarova, E.A. Pyaivinen, N.S. Sidorova, Zhurn. Obshch. Khim. 58 (1988) 2387–2392.

AC C

[117] A. Holy, Collect. Czech. Chem. Commun. 47 (1982) 2786–2805. [118] A. Holy, I. Votruba, E. De Clercq, Collect. Czech. Chem. Commun. 50 (1985) 245– 261.

[119] J. Defaye, T. Reyners, Bull. Soc. Chim. Biol. 50 (1968) 1625–1635. [120] L. Kværno, R. Kumar, B.M. Dahl, C.E. Olsen, J. Wengel, J. Org. Chem. 65 (2000) 5167–5176. [121] M. Dejmek, H. Hrebabecky, M. Dracinsky, J. Neyts, P. Leyssen, H. MertlikovaKaiserova, R. Nencka, Collect. Czech. Chem. Commun. 76 (2011) 1549–1566. [122] R.H. Furneaux, V.L. Schramm, P.C. Tyler, Bioorg. Med. Chem. 7 (1999) 2599–2606.

ACCEPTED MANUSCRIPT [123] R.W. Miles, P.C. Tyler, G.B. Evans, R.H. Furneaux, D.W. Parkin, V.L. Schramm, Biochemistry 38 (1999) 13147–13154. [124] A. Rinaldo-Matthis, C. Wing, M. Ghanem, H. Deng, P. Wu, A. Gupta, P.C. Tyler, G.B. Evans, R.H. Furneaux, S.C. Almo, C.C. Wang, V.L. Schramm, Biochemistry 46 (2007) 659– 668.

RI PT

[125] C.-H. Wong, L. Provencher, J.A., Jr. Porco, S.-H. Jung, Y.-F. Wang, L. Chen, R. Wang, D.H. Steensma, J. Org. Chem. 60 (1995) 1492–501.

[126] S. Martinez-Montero, S. Fernandez, Y.S. Sanghvi, J. Chattopadhyaya, M. Ganesan, N.G. Ramesh, V. Gotor, M. Ferrero, J. Org. Chem. 77 (2012) 4671–4678.

SC

[127] L. Deng, O.D. Schaerer, G.L. Verdine, J. Am. Chem. Soc. 119 (1997) 7865–7866. [128] V. Nair, R.H. Walsh, J. Org. Chem. 39 (1974) 3045–3047.

[129] T. Yamasaki, M. Abdel-Aziz, N. Kiyota, T. Maruyama, M. Otsuka, Heterocycles 60

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(2003) 1561–1566.

[130] J. Gotkowska, J. Balzarini, D.G. Piotrowska, Tetrahedron Lett. 53 (2012) 7097–7100. [131] H.W. Lee, H.O. Kim, W.J. Choi, S. Choi, J.H. Lee, S. Park, L. Yoo, K.A. Jacobson, L.S. Jeong, Bioorg. Med. Chem. 18 (2010) 7015–7021.

AC C

EP

TE D

[132] C. Lamberth, Org. Prep. Proc. Int. 34 (2002) 149–167.

ACCEPTED MANUSCRIPT FIGURE AND SCHEME CAPTIONS:

Figure 1. (–)-Aristeromycin 1, (–)-neplanocin A 2 and (–)-oxetanocin 3.

Figure 2. Selected antiviral nucleoside analogues (5 – vidarabine [7,8], 6a – idoxuridine; IDU

RI PT

(R = I) [9–11], 6b – trifluridine; TFT (R = CF3) [12], 6c – edoxudine (R = Et) [13], 6d – brivudine; BVDU (R = CH=CHBr) [14–16], 7 – telbivudine; L-dT [17–19], 8 – zidovudine; AZT [20–22], 9a – didanosine; ddI (B = hypoxanthin-9-yl) [23–24], 9b – zalcitabine; ddC (B = cytosin-1-yl) [25–26], 10 – stavudine; d4T [27–28], 11a – carbovir (R = guanin-9-yl) [29],

SC

11b – abacavir; ABC (R = 2-amino-6-(cyclopropylamino)purin-9-yl) [30–31], 12 – entecavir; ETV [32], 13 – amdoxovir; DAPD [33–34], 14a – lamivudine; 3TC (R = H) [35–37], 14b – emtricitabine; FTC (R = F) [38–39], 15a – acyclovir; ACV (R = H) [40–41], 15b –

M AN U

ganciclovir; GCV or DHPG (R = CH2OH) [42–44], 16 – penciclovir; PCV [45–47]. Figure 3. Adenosine 17 and 1′-homoadenosine 18.

Scheme 1. Synthetic approaches to 1′-homonucleosides 19 and the target 1′-homonucleosides

TE D

22.

Figure 4. 2-(Aminomethyl)cyclopentylmethanol-based 1′-homocarbanucleosides 25a (X = H); 25b (X = I); 26a (X = Cl); 26b (X = NH2); 26c (X = OH); 27a (X = Cl, n = 1); 27b (X =

EP

NH2, n = 1); 27c (X = Cl, n = 0); 27d (X = OH, n = 1). Scheme 2. Synthesis of racemic cis-3-(aminomethyl)cyclopentylmethanol 28 and cis-3-

AC C

(aminomethyl)cyclopentylmethanol-based 1′-homocarbanucleosides 31a (X = Cl); 31b (X = OH); 31c (X = NH2); 32a (X = H); 32b (X = I); 33a (X = Cl); 33b (X = OH); 33c (X = NH2); reagents: a. NaIO4/RuO2; b. Ac2O; c. NH3; d. CH2N2; e. BH3•SMe2. Figure 5. Trimethylcyclopentane-based 1′-homocarbanucleosides substituted at C1 and C3 36a (X = Cl); 36b (X = OH); 36c (X = NH2); 36d (X = NHcyclopropyl); 37a (X = Cl); 37b (X = OH); 37c (X = NH2); 39a (X = Cl); 39b (X = OH); 39c (X = NH2); 40a (X = H); 40b (X = Br); 40c (X = I).

ACCEPTED MANUSCRIPT Scheme 3. Synthesis of racemic cis-1,3-indandimethanol 42a (R′ = Rʺ = H), its derivatives 42b (R′ = Ac, Rʺ = H), 42c (R′ = Ac, Rʺ = Ms), 42d (R′ = Ac, Rʺ = Ts) and cis-1,3indandimethanol-based 1′-homocarbanucleosides 43a (X = Cl); 43b (X = NH2); 43c (X = NHPr); 43d (X = NHi-Pr); 43e (X = NHcyclopropyl); 43f (X = OH); 43g (X = OMe); 43h (X = OEt); 44a (R = H, X = NH2); 44b (R = H, X = OH); 44c (R = Me, X = OH); 45a (X = H);

RI PT

45b (X = Me); 45c (X = OMe); 45d (X = Cl); reagents: a. Mg, ultrasound; b. O3; c. Me2S; d. LiAlH4; e. Ac2O, pyridine or vinyl acetate, Novozym® 435; f. MsCl, NEt3, DMAP or TsCl, NEt3, DMAP.

SC

Scheme 4. Synthesis of racemic cis-3-hydroxymethylindan-1-ol 48a (R′ = R″ = H), its derivatives 48b (R′ = H, Rʺ = Ac); 48c (R′ = TBDMS, Rʺ = Ac); 48d (R′ = TBDMS, Rʺ = H) and 48e (R′ = TBDMS, Rʺ = Ms) and cis-3-hydroxymethylindan-1-ol-based 1′-

M AN U

homocarbanucleosides 49a (X = Cl); 49b (X = OH); 49c (X = OMe); 49d (X = NH2); 49e (X = NHi-Pr); 50a (X = H); 50b (X = Me); 50c (X = OMe); 50d (X = Cl); 51a (R = H, X = OH); 51b (R = Me, X=OH); 51c (R = Cl, X = OH); 51d (R = Br, X = OH); 51e (R = H, X = NH2); reagents: a. AlCl3; b. MeOH, H+; c. LiBH4; d. vinyl acetate, Novozym® 435; e. TBDMSCl; f.

TE D

MeONa; g. MsCl, NEt3, DMAP.

Scheme 5. Synthesis of racemic cis-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7dimethanol 55a (R′ = Rʺ = H), its derivatives 55b (R′ = Ac, Rʺ = H); 55c (R′ = Ac, Rʺ = Ms) and compounds 56a (X = OMe), 56b (X = NH2) and 56c (X = NHcyclopropyl); reagents: a.

EP

cyclopentadiene; b. OsO4, NMO; c. Me2C(OMe)2, H+; d. KOH; e. PhC(O)C(O)Ph, H+; f. DDQ; g. H2O, H+; h. NaIO4; i. NaBH4; j. Ac2O, pyridine; k. MsCl, NEt3, DMAP.

AC C

Scheme 6. Synthesis of racemic cis-1,4-diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine5,7-dimethanol 58a (R′ = R″ = H), its derivatives 58b (R′ = Ac, Rʺ = H); 58c (R′ = Ac, Rʺ = Ms) and cis-1,4-diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine-5,7-dimethanol-based 1′homocarbanucleosides 59a (X = OH); 59b (X = OMe); 59c (X = NHcyclopropyl); 59d (X = Cl); 59e (X = NHcyclopentyl); 60a (X = Cl); 60b (X = NHcyclopentyl); reagents: a. hydrazine; b. O3; c. NaBH4; d. Ac2O, pyridine; e. MsCl, NEt3, DMAP. Scheme 7. Synthesis of racemic cis-2-benzylcyclopenta[c]pyrazole-4,6-dimethanol 63a (R′ = R″ = H), its derivatives 63b (R′ = TBDPS, Rʺ = H); 63c (R′ = TBDPS, Rʺ = Ms) and cis-2nenzylcyclopenta[c]pyrazole-4,6-dimethanol-based 1′-homocarbanucleosides 64a (R′ = H),

ACCEPTED MANUSCRIPT 64b (R′ = TBDPS), 65a (R′ = H, X = Cl); 65b (R′ = H, X = OH); 65c (R′ = H, X = NHcyclopropyl) and 65d (R′ = TBDPS, X = Cl); reagents: a. hydrazine; b. BnCl, NaH; c. H2O, H+; d. NaIO4; e. NaBH4; f. TBDPSCl, NaH; g. MsCl, NEt3, DMAP. Figure 6. cis-1-Methylcyclopenta[c]pyrazole-4,6-dimethanol-based 1′-homocarbanucleosides

RI PT

66a (R′ = TBDPS, X = Cl); 66b (R′ = H, X = Cl); 66c (R′ = TBDPS, X = Ph); 66d (R′ = H, X = Ph); 66e (R′ = H, X = OH); 67; 68a (R′ = H); 68b (R′ = TBDPS); 69a (R′ = TBDPS, X = H); 69b (R′ = H, X = H); 69c (R′ = H, X = I); 69d (R′ = H, X = Br).

Scheme

8.

Synthesis

of

the

protected

racemic

cis-4-aminomethyl-3,4-

SC

dihydroxycyclopentylmethanol 71; reagents: a. KMnO4; b. Me2C(OMe)2, H+; c. O3; d.

M AN U

NaBH4; e. Ac2O, pyridine; f. TsCl, pyridine; g. NaN3; h. LiAlH4.

Scheme 9. Synthesis of the protected racemic 4-hydroxymethylcyclopentene-based 1′homocarbanucleosides 74, 75a (X = OH), 75b (X = OMe), 76 and 77; reagents: a. 2-amino-6chloropurine, NaH; b. BH3, NMO; c. MCPBA, H2O, H+; d. OsO4, NMO.

TE D

Scheme 10. Synthesis of the enantiomeric 2,3,4-trihydroxycyclopentylmethanol-based 1′homocarbanucleoside 81; reagents: a. Pseudomonas cepacia lipase; b. Ac2O, pyridine; c. OsO4, NMO; d. Me2C(OMe)2, H+; e. KMnO4, KOH; f. NaBH4; g. 6-chloropurine, PPh3,

EP

DIAD; h. MeOH, K2CO3; i. NH3, MeOH; j. H2O, H+. Figure 7. Iridoids-based 1′-homocarbanucleosides 82a (X = OMe), 82b (X = NH2) and 83–

AC C

86.

Scheme

11.

Synthesis

of

[1-(hydroxymethyl)cyclopent-3-enyl]methanol-based

1′-

homocarbanucleoside 87a, 87b (R = H), 87c (R = Me) and 87d; reagents: a. H2C=CHCH2Br, NaH; b. Cl2(Cy3P)2RuCHPh; c. LiAlH4; d. TBDMSCl; e. MsCl, NEt3; f. adenine or uracil or thymine or cytosine, K2CO3; g. TBAF, THF. Scheme 12. Synthesis of racemic 1′-homocarbovir 91a and its congeners 91b (X = NH2) and 91c (X = OH); reagents: a. O3; b. NaBH4; c. Ac2O, pyridine; d. TsCl, pyridine; e. NaN(HCO)2; f. H2O, H+.

ACCEPTED MANUSCRIPT Figure 8. A structural analogue of 1′-homoneplanocin A 92.

Scheme 13. Syntheses of the protected 1-amino-2,5-anhydro-1-deoxy-D-allitols 94a (R = R′ = R″ = H), 94b (R = H, R′,R″ = CMe2), 94c (R = R′ = R″ = Bn), 1-amino-2,5-anhydro-3,4,6-triO-benzyl-1-deoxy-D-altritol 95 from 93a (R = Bn) and 93b (R = Bz) and 1′-homonucleosides

RI PT

96a (X = Cl), 96b (X = OH), 96c (X = NHPh) and 97–99; reagents: a. Hg(CN)2; b. NH3, MeOH; c. Me2C(OMe)2, H+; d. LiAlH4.

Scheme 14. Synthesis of the alcohol 102a (R = H) and its tosylate 102b (R = Ts); reagents: a.

SC

Ph3P=CHCO2Me; b. TBDPSCl; c. DIBAL-H; d. MsCl; e. t-BuOK, f. OsO4, NMO; g. NaIO4; h. NaBH4; i. TsCl.

M AN U

Figure 9. D-arabino-1′-homonucleosides 103, 104a (R = H, X = OH), 104b (R = Me, X = OH), 104c (R = H, X = NH2) and a compound 105.

Scheme 15. Synthesis of 1′-homonucleosides 107a (X = H), 107b (X = Me), 107c (X = H), 107d (X = NH2), 109a (R = NH2, R′ = H), 109b (R = R′ = NH2), 109c (R = H, R′ = NH2),

TE D

109d (R = NHPh, R′ = HN(CH2)3NEt2), 109e (R = NHPh, R′ = NHBn) and 110 by the epoxide ring opening–tetrahydrofuran ring closure sequence; reagents: a. uracil or thymine or adenine, NaH or BSTFA, Mg(ClO4)2 [96] or 2,6-diaminopurine, Cs2CO3 [97]; b. H2, Pd/C; c.

EP

substituted purines, Cs2CO3 [97]; d. H2, Pd/C or HCOONH4, Pd/C [97]. Figure 10. 1′-Homonucleoside-based inhibitors of the MraY enzyme 111a (n = 0, R = OH, R′

AC C

= H) and 111b (n = 1, R = H, R′ = OH).

Figure 11. Inhibitors of tRNA synthetases 112a (n = 1, X = O, R = H, R′ = CH2CH2SMe), 112b (n = 1, X = O, R = Bn, R′ = CH2CH2SMe), 112c (n = 1, X = O, R = H, R′ = CHEtMe), 112d (n = 1, R = H, X = N(OH), R′ = CH2CH2SMe), 112e (n = 1, X = N(OH), R = H, R′ = CH2CH2SMe), 112f (n = 1, X = N(OH), R = H, R′ = CHEtMe), 112g (n = 0, X = O, R = H, R′ = CH2CH2SMe) and 112h (n = 2, X = O, R = H, R′ = CH2CH2SMe). Scheme 16. Synthesis of 1′-homonucleoside analogues 115a (R′ = H, R″ = Me) and 115b (R′ = R″ = Me) and the intermediates 113a (R = SiMeEt2), 113b (R = H), 114a (X = Cl) and 114b (X = 3-iodobenzylamino); reagents: a. CO, HSiMeEt2, Co2(CO)8; b. TBAF; c. 6-chloropurine,

ACCEPTED MANUSCRIPT PPh3, DIAD; d. 3-iodobenzylamine; e. MeONa, MeOH; f. Me2C(OMe)2, H+; g. PDC; h. MeNH2 or Me2NH, EDC, HOBt, DIPEA; i. H2O, H+. Figure 12. Phosphates of 1′-homouridine 116 and 117, 1′-homoadenosine 118a (R = OH) and

RI PT

2′-deoxy-1′-homoadenosine 118b (R = H).

Scheme 17. Synthesis of α- and β-pseudoanomers of 1′-homo-2′-deoxythymidine 120 and 121; reagents: a. p-CH3C6H4COCl; b. HCl/AcOH; c. Et2AlCN; d. separation; e. BH3.

SC

Scheme 18. Synthesis of 1′-homo-2′-deoxy-nucleosides 121a (R = H), 121b (R = Bn), 125a (R = H), 125b (R = Bn), 126a (R = H), 126b (R = Bn), 127 and the intermediates 123a (R = H) and 123b (R = Ms); reagents: a. MeOH, H+; b. BnBr, NaH; c. H2O, H+; d. Ph3P=CH2; e.

M AN U

MCPBA; f. MsCl, NEt3.

Scheme 19. Synthesis of 3,5-di-O-benzoyl-2-deoxy-1-C-(hydroxymethyl)-β-D-ribofuranose 130 via intermediates 129a (R = R = H; R′R′ = CMe2), 129b (R = R = Bz; R′R′ = CMe2) and 129c (R = R = Bz; R′ = R′ = H); reagents: a. H2C=CHMgCl; b. OsO4; c. NaIO4; d. NaBH4; e.

TE D

H2, Pd/C; f. Me2CO, H+; g. BzCl, pyridine; h. H2O, H+; i. (Im)2C=S, Bu3SnH/AIBN. Figure 13. 2′-Deoxy-1′-homonucleosides 131a (R = H, X = O), 131b (R = Bn, X = O), 131c

EP

(R = Bn, X = S), 132, 133, 134a (R = H) and 134b (R = Bn).

Figure 14. 3,4-Dihydroxytetrahydrofuran-based 1′-homonucleosides 135, 136 and 137a (R =

AC C

H), 137b (R = F) and their precursors 138, 139a (X = Cl) and 139b (X = Br).

Scheme 20. Synthesis of 5-(adenine-9-yl)-5-deoxy-1,4-anhydro-D-ribitol 140 and its precursors 142a (R = Tr) and 142b (R = Ts); reagents: a. TrCl, pyridine; b. NaBH4; c. TsCl, pyridine; d. H2O, H+; e. Me2CO, H+; f. adenine, NaH. Scheme 21. Synthesis of ent-140; reagents: a. Me2CO, H+; b. HgCl2; c. LiAlH4; d. TsCl, pyridine; e. NaN3; f. H2, Pd. Scheme 22. Synthesis of 1′-homonucleosides 145 and 146; reagents: a. MsCl, pyridine; b. MeOH, H2O, H+; c. NaH; d. H2O, H+; e NaBH4; f. TsCl, pyridine; g. Ac2O, pyridine; h.

ACCEPTED MANUSCRIPT thymine, NaH; i. H2, Pd-C; j. MeONa, MeOH; k. TIPDSCl2, pyridine; l. MeOOCCOCl, DMAP; m. Bu3SnH; n. TBAF. Scheme 23. Synthesis of cycloadducts 150a and 150b and anti-HCV active compounds 151–

RI PT

158; reagents: a. Me2CHCH2CH2ONO, Cl3CCOOH; b. 60°C; c. NaBH4. Scheme 24. Synthesis of 1′-homostavudine 159; reagents: a. TBDMSCl; b. i-Pr2NH, MeOH; c. TrCl, pyridine; d. PhOC(S)Cl, pyridine; e. Bu3SnH, AIBN; f. TBAF.

SC

Scheme 25. Synthesis of 1′-homonucleosides 162 (X = NH2, Y = H), 163 (X = OH, Y = H) and 164 (X = OH, Y = NH2); reagents: a. NCS; b. LiTMP; c. lithium 1,3-dithiane; d. Boc2O; chloropurine, K2CO3; i. H2O, H+.

M AN U

e. (CF3COO)2Hg; f. NaBH4; g. MsCl or Tf2O; h. 6-chloropurine or adenine or 2-amino-6-

Scheme 26. Synthesis of 1′-homonucleoside 169; reagents: a. triphosgene; b. BnBr, KI, NaH; c. KOH, H2O; d. CbzCl, TEA; e. TsCl, pyridine; f. 2-amino-6-chloropurine, K2CO3; g.

TE D

HSCH2CH2OH, MeONa; h. BCl3.

Scheme 27. Synthesis of 1′-homonucleosides (2S,3R,4R,5S)-172a (R = H), (2S,3R,4R,5S)172b (R = Me) and (2S,3S,4R,5S)-173; reagents: a. MeOH, Na2CO3; b. TsCl, pyridine; c. adenine, K2CO3; d. Mg, MeOH; e. conc. HCl; f. HCHO, dioxane; g. H2, Pd-C; h. MsCl,

EP

pyridine; i. H2C=C(OMe)Me, H+; j. TfCl, pyridine; k. TFA, CH2Cl2. Scheme 28. Synthesis of 1′-homo-2′-deoxynucleoside 179; reagents: a. H2C=CHCH2B(lcp)2;

AC C

b. TsOH, MeOH; c. TBDMSCl; d. MCPBA; e. AcOH; f. 6-chloropurine, DEAD, PPh3; g. TBAF, THF; h. TFA; i. FmocCl.

Scheme 29. Synthesis of the 1′-homonucleoside 185; reagents: a. TsCl, pyridine; b. CH2N2; c. LiBH4; d. OsO4, NMO; e. adenine, NaH. Scheme 30. Synthesis of the 1′-homonucleoside 186; reagents: a. DHP, H+; b. LiBH4; c. TsCl, pyridine; d. 3-benzoylthymine, K2CO3; e. NaOH, MeOH; f. TFA.

ACCEPTED MANUSCRIPT Scheme 31. Synthesis of the 1′-homonucleoside 188; reagents: a. H2C=CHCOOMe; b. H2, Pd-C, Pd(OH)2. Figure 15. Thiolane-based nucleosides 191 and 192 and 1′-homonucleosides 193a (X = H; Y

RI PT

= F, Cl, Br or I) and 193b (X = Cl; Y = F, Cl, Br or I).

Scheme 32. Synthesis of 1′-homonucleosides 193a (X = H; Y = F, Cl, Br or I) and 193b (X = Cl; Y = F, Cl, Br or I) and precursors 196a (X = H) and 196b (X = Cl); reagents: a. NaBH4; b. MsCl, NEt3; c. Na2S, DMF; d. AcOH; e. Pb(OAc)4; f. POCl3; g. 6-chloropurine or 2,6-

AC C

EP

TE D

M AN U

SC

dichloropurine, NaH; h. H2O, H+; i. 3-halobenzylamine.

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

Figure 1. (–)-Aristeromycin 1, (–)-neplanocin A 2 and (–)-oxetanocin 3.

ACCEPTED MANUSCRIPT NH2 N NH2

HO

R

N

N

O

N

O

R

O

HO

N

5 6a-6d

N

O

O

HO

O

Base

5'

NH N

2'

HO

12 HO

H (OH) 4

NH2

B

HO

HO

O

Me

11a-11b

HO

O

Me

M AN U

N

3'

SC

O

HO

7 OH

O

13

HO

OH

N

O

NH2

N

Me

HN

N

N

O

RI PT

HO

NH2

HO

O

O

OH

S 14a-14b

N

NH

HO

OH

N

O

N

NH N

O

O

N3

8

B

O

NH

N

9a-9b

O

TE D

O

10

O

O

N

EP

N

O

HO

R

AC C

15a-15b

N

NH

N

N

NH2

NH N

NH2

HO OH 16

Figure 2. Selected antiviral nucleoside analogues (5 – vidarabine [7,8], 6a – idoxuridine; IDU (R = I) [9–11], 6b – trifluridine; TFT (R = CF3) [12], 6c – edoxudine (R = Et) [13], 6d – brivudine; BVDU (R = CH=CHBr) [14–16], 7 – telbivudine; L-dT [17–19], 8 – zidovudine; AZT [20–22], 9a – didanosine; ddI (B = hypoxanthin-9-yl) [23–24], 9b – zalcitabine; ddC (B = cytosin-1-yl) [25–26], 10 – stavudine; d4T [27–28], 11a – carbovir (R = guanin-9-yl) [29], 11b – abacavir; ABC (R = 2-amino-6-(cyclopropylamino)purin-9-yl) [30–31], 12 – entecavir; ETV [32], 13 – amdoxovir; DAPD [33–34], 14a – lamivudine; 3TC (R = H) [35–37], 14b – emtricitabine; FTC (R = F) [38–39], 15a – acyclovir; ACV (R = H) [40–41], 15b – ganciclovir; GCV or DHPG (R = CH2OH) [42–44], 16 – penciclovir; PCV [45–47].

SC

TE D

M AN U

Figure 3. Adenosine 17 and 1′-homoadenosine 18.

RI PT

ACCEPTED MANUSCRIPT

Scheme 1. Synthetic approaches to 1′-homonucleosides 19 and the target 1′-homonucleosides

AC C

EP

22.

Figure 4. 2-(Aminomethyl)cyclopentylmethanol-based 1′-homocarbanucleosides 25a (X = H); 25b (X = I); 26a (X = Cl); 26b (X = NH2); 26c (X = OH); 27a (X = Cl, n = 1); 27b (X = NH2, n = 1); 27c (X = Cl, n = 0); 27d (X = OH, n = 1).

SC

RI PT

ACCEPTED MANUSCRIPT

M AN U

Scheme 2. Synthesis of racemic cis-3-(aminomethyl)cyclopentylmethanol 28 and cis-3(aminomethyl)cyclopentylmethanol-based 1′-homocarbanucleosides 31a (X = Cl); 31b (X = OH); 31c (X = NH2); 32a (X = H); 32b (X = I); 33a (X = Cl); 33b (X = OH); 33c (X = NH2);

AC C

EP

TE D

reagents: a. NaIO4/RuO2; b. Ac2O; c. NH3; d. CH2N2; e. BH3•SMe2.

Figure 5. Trimethylcyclopentane-based 1′-homocarbanucleosides substituted at C1 and C3 36a (X = Cl); 36b (X = OH); 36c (X = NH2); 36d (X = NHcyclopropyl); 37a (X = Cl); 37b (X = OH); 37c (X = NH2); 39a (X = Cl); 39b (X = OH); 39c (X = NH2); 40a (X = H); 40b (X = Br); 40c (X = I).

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 3. Synthesis of racemic cis-1,3-indandimethanol 42a (R′ = Rʺ = H), its derivatives

TE D

42b (R′ = Ac, Rʺ = H), 42c (R′ = Ac, Rʺ = Ms), 42d (R′ = Ac, Rʺ = Ts) and cis-1,3indandimethanol-based 1′-homocarbanucleosides 43a (X = Cl); 43b (X = NH2); 43c (X = NHPr); 43d (X = NHi-Pr); 43e (X = NHcyclopropyl); 43f (X = OH); 43g (X = OMe); 43h (X = OEt); 44a (R = H, X = NH2); 44b (R = H, X = OH); 44c (R = Me, X = OH); 45a (X = H);

EP

45b (X = Me); 45c (X = OMe); 45d (X = Cl); reagents: a. Mg, ultrasound; b. O3; c. Me2S; d. LiAlH4; e. Ac2O, pyridine or vinyl acetate, Novozym® 435; f. MsCl, NEt3, DMAP or TsCl,

AC C

NEt3, DMAP.

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 4. Synthesis of racemic cis-3-hydroxymethylindan-1-ol 48a (R′ = R″ = H), its derivatives 48b (R′ = H, Rʺ = Ac); 48c (R′ = TBDMS, Rʺ = Ac); 48d (R′ = TBDMS, Rʺ = H) and 48e (R′ = TBDMS, Rʺ = Ms) and cis-3-hydroxymethylindan-1-ol-based 1′-

TE D

homocarbanucleosides 49a (X = Cl); 49b (X = OH); 49c (X = OMe); 49d (X = NH2); 49e (X = NHi-Pr); 50a (X = H); 50b (X = Me); 50c (X = OMe); 50d (X = Cl); 51a (R = H, X = OH); 51b (R = Me, X=OH); 51c (R = Cl, X = OH); 51d (R = Br, X = OH); 51e (R = H, X = NH2);

EP

reagents: a. AlCl3; b. MeOH, H+; c. LiBH4; d. vinyl acetate, Novozym® 435; e. TBDMSCl; f.

AC C

MeONa; g. MsCl, NEt3, DMAP.

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 5. Synthesis of racemic cis-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7dimethanol 55a (R′ = Rʺ = H), its derivatives 55b (R′ = Ac, Rʺ = H); 55c (R′ = Ac, Rʺ = Ms) and compounds 56a (X = OMe), 56b (X = NH2) and 56c (X = NHcyclopropyl); reagents: a.

TE D

cyclopentadiene; b. OsO4, NMO; c. Me2C(OMe)2, H+; d. KOH; e. PhC(O)C(O)Ph, H+; f.

AC C

EP

DDQ; g. H2O, H+; h. NaIO4; i. NaBH4; j. Ac2O, pyridine; k. MsCl, NEt3, DMAP.

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 6. Synthesis of racemic cis-1,4-diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine5,7-dimethanol 58a (R′ = R″ = H), its derivatives 58b (R′ = Ac, Rʺ = H); 58c (R′ = Ac, Rʺ = Ms) and cis-1,4-diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine-5,7-dimethanol-based 1′-

TE D

homocarbanucleosides 59a (X = OH); 59b (X = OMe); 59c (X = NHcyclopropyl); 59d (X = Cl); 59e (X = NHcyclopentyl); 60a (X = Cl); 60b (X = NHcyclopentyl); reagents: a.

AC C

EP

hydrazine; b. O3; c. NaBH4; d. Ac2O, pyridine; e. MsCl, NEt3, DMAP.

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 7. Synthesis of racemic cis-2-benzylcyclopenta[c]pyrazole-4,6-dimethanol 63a (R′ = R″ = H), its derivatives 63b (R′ = TBDPS, Rʺ = H); 63c (R′ = TBDPS, Rʺ = Ms) and cis-2-

TE D

nenzylcyclopenta[c]pyrazole-4,6-dimethanol-based 1′-homocarbanucleosides 64a (R′ = H), 64b (R′ = TBDPS), 65a (R′ = H, X = Cl); 65b (R′ = H, X = OH); 65c (R′ = H, X = NHcyclopropyl) and 65d (R′ = TBDPS, X = Cl); reagents: a. hydrazine; b. BnCl, NaH; c.

AC C

EP

H2O, H+; d. NaIO4; e. NaBH4; f. TBDPSCl, NaH; g. MsCl, NEt3, DMAP.

Figure 6. cis-1-Methylcyclopenta[c]pyrazole-4,6-dimethanol-based 1′-homocarbanucleosides 66a (R′ = TBDPS, X = Cl); 66b (R′ = H, X = Cl); 66c (R′ = TBDPS, X = Ph); 66d (R′ = H, X = Ph); 66e (R′ = H, X = OH); 67; 68a (R′ = H); 68b (R′ = TBDPS); 69a (R′ = TBDPS, X = H); 69b (R′ = H, X = H); 69c (R′ = H, X = I); 69d (R′ = H, X = Br).

Scheme

8.

Synthesis

of

the

protected

RI PT

ACCEPTED MANUSCRIPT

racemic

cis-4-aminomethyl-3,4-

SC

dihydroxycyclopentylmethanol 71; reagents: a. KMnO4; b. Me2C(OMe)2, H+; c. O3; d.

AC C

EP

TE D

M AN U

NaBH4; e. Ac2O, pyridine; f. TsCl, pyridine; g. NaN3; h. LiAlH4.

Scheme 9. Synthesis of the protected racemic 4-hydroxymethylcyclopentene-based 1′homocarbanucleosides 74, 75a (X = OH), 75b (X = OMe), 76 and 77; reagents: a. 2-amino-6chloropurine, NaH; b. BH3, NMO; c. MCPBA, H2O, H+; d. OsO4, NMO.

SC

RI PT

ACCEPTED MANUSCRIPT

Scheme 10. Synthesis of the enantiomeric 2,3,4-trihydroxycyclopentylmethanol-based 1′-

M AN U

homocarbanucleoside 81; reagents: a. Pseudomonas cepacia lipase; b. Ac2O, pyridine; c. OsO4, NMO; d. Me2C(OMe)2, H+; e. KMnO4, KOH; f. NaBH4; g. 6-chloropurine, PPh3,

TE D

DIAD; h. MeOH, K2CO3; i. NH3, MeOH; j. H2O, H+.

EP

Figure 7. Iridoids-based 1′-homocarbanucleosides 82a (X = OMe), 82b (X = NH2) and 83–

AC C

86.

Scheme

11.

Synthesis

of

[1-(hydroxymethyl)cyclopent-3-enyl]methanol-based

1′-

homocarbanucleoside 87a, 87b (R = H), 87c (R = Me) and 87d; reagents: a. H2C=CHCH2Br,

ACCEPTED MANUSCRIPT NaH; b. Cl2(Cy3P)2RuCHPh; c. LiAlH4; d. TBDMSCl; e. MsCl, NEt3; f. adenine or uracil or

RI PT

thymine or cytosine, K2CO3; g. TBAF, THF.

Scheme 12. Synthesis of racemic 1′-homocarbovir 91a and its congeners 91b (X = NH2) and 91c (X = OH); reagents: a. O3; b. NaBH4; c. Ac2O, pyridine; d. TsCl, pyridine; e.

M AN U

SC

NaN(HCO)2; f. H2O, H+.

AC C

EP

TE D

Figure 8. A structural analogue of 1′-homoneplanocin A 92.

Scheme 13. Syntheses of the protected 1-amino-2,5-anhydro-1-deoxy-D-allitols 94a (R = R′ = R″ = H), 94b (R = H, R′,R″ = CMe2), 94c (R = R′ = R″ = Bn), 1-amino-2,5-anhydro-3,4,6-triO-benzyl-1-deoxy-D-altritol 95 from 93a (R = Bn) and 93b (R = Bz) and 1′-homonucleosides

ACCEPTED MANUSCRIPT 96a (X = Cl), 96b (X = OH), 96c (X = NHPh) and 97–99; reagents: a. Hg(CN)2; b. NH3, MeOH; c. Me2C(OMe)2, H+; d. LiAlH4.

OH

TBDPSO O

O

O

OH a. - c. O

O

100

OR

TBDPSO

O

d. - h.

O

101

RI PT

HO

O

i.

O

102a 102b

SC

Scheme 14. Synthesis of the alcohol 102a (R = H) and its tosylate 102b (R = Ts); reagents: a. Ph3P=CHCO2Me; b. TBDPSCl; c. DIBAL-H; d. MsCl; e. t-BuOK, f. OsO4, NMO; g. NaIO4;

TE D

M AN U

h. NaBH4; i. TsCl.

EP

Figure 9. D-arabino-1′-homonucleosides 103, 104a (R = H, X = OH), 104b (R = Me, X =

AC C

OH), 104c (R = H, X = NH2) and a compound 105.

SC

RI PT

ACCEPTED MANUSCRIPT

M AN U

Scheme 15. Synthesis of 1′-homonucleosides 107a (X = H), 107b (X = Me), 107c (X = H), 107d (X = NH2), 109a (R = NH2, R′ = H), 109b (R = R′ = NH2), 109c (R = H, R′ = NH2), 109d (R = NHPh, R′ = HN(CH2)3NEt2), 109e (R = NHPh, R′ = NHBn) and 110 by the epoxide ring opening–tetrahydrofuran ring closure sequence; reagents: a. uracil or thymine or adenine, NaH or BSTFA, Mg(ClO4)2 [96] or 2,6-diaminopurine, Cs2CO3 [97]; b. H2, Pd/C; c.

AC C

EP

TE D

substituted purines, Cs2CO3 [97]; d. H2, Pd/C or HCOONH4, Pd/C [97].

Figure 10. 1′-Homonucleoside-based inhibitors of the MraY enzyme 111a (n = 0, R = OH, R′ = H) and 111b (n = 1, R = H, R′ = OH).

RI PT

ACCEPTED MANUSCRIPT

Figure 11. Inhibitors of tRNA synthetases 112a (n = 1, X = O, R = H, R′ = CH2CH2SMe), 112b (n = 1, X = O, R = Bn, R′ = CH2CH2SMe), 112c (n = 1, X = O, R = H, R′ = CHEtMe), 112d (n = 1, R = H, X = N(OH), R′ = CH2CH2SMe), 112e (n = 1, X = N(OH), R = H, R′ =

SC

CH2CH2SMe), 112f (n = 1, X = N(OH), R = H, R′ = CHEtMe), 112g (n = 0, X = O, R = H, R′

EP

TE D

M AN U

= CH2CH2SMe) and 112h (n = 2, X = O, R = H, R′ = CH2CH2SMe).

Scheme 16. Synthesis of 1′-homonucleoside analogues 115a (R′ = H, R″ = Me) and 115b (R′

AC C

= R″ = Me) and the intermediates 113a (R = SiMeEt2), 113b (R = H), 114a (X = Cl) and 114b (X = 3-iodobenzylamino); reagents: a. CO, HSiMeEt2, Co2(CO)8; b. TBAF; c. 6-chloropurine, PPh3, DIAD; d. 3-iodobenzylamine; e. MeONa, MeOH; f. Me2C(OMe)2, H+; g. PDC; h. MeNH2 or Me2NH, EDC, HOBt, DIPEA; i. H2O, H+.

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

2′-deoxy-1′-homoadenosine 118b (R = H).

SC

Figure 12. Phosphates of 1′-homouridine 116 and 117, 1′-homoadenosine 118a (R = OH) and

Scheme 17. Synthesis of α- and β-pseudoanomers of 1′-homo-2′-deoxythymidine 120 and 121; reagents: a. p-CH3C6H4COCl; b. HCl/AcOH; c. Et2AlCN; d. separation; e. BH3.

RI PT

ACCEPTED MANUSCRIPT

SC

Scheme 18. Synthesis of 1′-homo-2′-deoxy-nucleosides 121a (R = H), 121b (R = Bn), 125a (R = H), 125b (R = Bn), 126a (R = H), 126b (R = Bn), 127 and the intermediates 123a (R =

MCPBA; f. MsCl, NEt3.

BnO

BnO Cl a. - d.

O

BnO

OBn

OH

O

BnO

OBn

BzO

OR'

RO

O

e. - f.

RO

TE D

128

M AN U

H) and 123b (R = Ms); reagents: a. MeOH, H+; b. BnBr, NaH; c. H2O, H+; d. Ph3P=CH2; e.

g. h.

OH O

i.

OR'

129a 129b 129c

121a

BzO 130

Scheme 19. Synthesis of 3,5-di-O-benzoyl-2-deoxy-1-C-(hydroxymethyl)-β-D-ribofuranose 130 via intermediates 129a (R = R = H; R′R′ = CMe2), 129b (R = R = Bz; R′R′ = CMe2) and

EP

129c (R = R = Bz; R′ = R′ = H); reagents: a. H2C=CHMgCl; b. OsO4; c. NaIO4; d. NaBH4; e.

AC C

H2, Pd/C; f. Me2CO, H+; g. BzCl, pyridine; h. H2O, H+; i. (Im)2C=S, Bu3SnH/AIBN.

Figure 13. 2′-Deoxy-1′-homonucleosides 131a (R = H, X = O), 131b (R = Bn, X = O), 131c (R = Bn, X = S), 132, 133, 134a (R = H) and 134b (R = Bn).

RI PT

ACCEPTED MANUSCRIPT

SC

Figure 14. 3,4-Dihydroxytetrahydrofuran-based 1′-homonucleosides 135, 136 and 137a (R =

TE D

M AN U

H), 137b (R = F) and their precursors 138, 139a (X = Cl) and 139b (X = Br).

Scheme 20. Synthesis of 5-(adenine-9-yl)-5-deoxy-1,4-anhydro-D-ribitol 140 and its precursors 142a (R = Tr) and 142b (R = Ts); reagents: a. TrCl, pyridine; b. NaBH4; c. TsCl,

AC C

EP

pyridine; d. H2O, H+; e. Me2CO, H+; f. adenine, NaH.

Scheme 21. Synthesis of ent-140; reagents: a. Me2CO, H+; b. HgCl2; c. LiAlH4; d. TsCl, pyridine; e. NaN3; f. H2, Pd.

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Scheme 22. Synthesis of 1′-homonucleosides 145 and 146; reagents: a. MsCl, pyridine; b. MeOH, H2O, H+; c. NaH; d. H2O, H+; e NaBH4; f. TsCl, pyridine; g. Ac2O, pyridine; h. thymine, NaH; i. H2, Pd-C; j. MeONa, MeOH; k. TIPDSCl2, pyridine; l. MeOOCCOCl,

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DMAP; m. Bu3SnH; n. TBAF.

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Scheme 23. Synthesis of cycloadducts 150a and 150b and anti-HCV active compounds 151–

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158; reagents: a. Me2CHCH2CH2ONO, Cl3CCOOH; b. 60°C; c. NaBH4.

Scheme 24. Synthesis of 1′-homostavudine 159; reagents: a. TBDMSCl; b. i-Pr2NH, MeOH; c. TrCl, pyridine; d. PhOC(S)Cl, pyridine; e. Bu3SnH, AIBN; f. TBAF.

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Scheme 25. Synthesis of 1′-homonucleosides 162 (X = NH2, Y = H), 163 (X = OH, Y = H) and 164 (X = OH, Y = NH2); reagents: a. NCS; b. LiTMP; c. lithium 1,3-dithiane; d. Boc2O; e. (CF3COO)2Hg; f. NaBH4; g. MsCl or Tf2O; h. 6-chloropurine or adenine or 2-amino-6-

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chloropurine, K2CO3; i. H2O, H+.

Scheme 26. Synthesis of 1′-homonucleoside 169; reagents: a. triphosgene; b. BnBr, KI, NaH; c. KOH, H2O; d. CbzCl, TEA; e. TsCl, pyridine; f. 2-amino-6-chloropurine, K2CO3; g.

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HSCH2CH2OH, MeONa; h. BCl3.

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Scheme 27. Synthesis of 1′-homonucleosides (2S,3R,4R,5S)-172a (R = H), (2S,3R,4R,5S)172b (R = Me) and (2S,3S,4R,5S)-173; reagents: a. MeOH, Na2CO3; b. TsCl, pyridine; c. adenine, K2CO3; d. Mg, MeOH; e. conc. HCl; f. HCHO, dioxane; g. H2, Pd-C; h. MsCl,

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pyridine; i. H2C=C(OMe)Me, H+; j. TfCl, pyridine; k. TFA, CH2Cl2.

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Scheme 28. Synthesis of 1′-homo-2′-deoxynucleoside 179; reagents: a. H2C=CHCH2B(lcp)2;

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TBAF, THF; h. TFA; i. FmocCl.

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b. TsOH, MeOH; c. TBDMSCl; d. MCPBA; e. AcOH; f. 6-chloropurine, DEAD, PPh3; g.

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Scheme 29. Synthesis of the 1′-homonucleoside 185; reagents: a. TsCl, pyridine; b. CH2N2; c.

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LiBH4; d. OsO4, NMO; e. adenine, NaH.

Scheme 30. Synthesis of the 1′-homonucleoside 186; reagents: a. DHP, H+; b. LiBH4; c. TsCl, pyridine; d. 3-benzoylthymine, K2CO3; e. NaOH, MeOH; f. TFA.

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Scheme 31. Synthesis of the 1′-homonucleoside 188; reagents: a. H2C=CHCOOMe; b. H2,

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Pd-C, Pd(OH)2.

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Figure 15. Thiolane-based nucleosides 191 and 192 and 1′-homonucleosides 193a (X = H; Y

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= F, Cl, Br or I) and 193b (X = Cl; Y = F, Cl, Br or I).

Scheme 32. Synthesis of 1′-homonucleosides 193a (X = H; Y = F, Cl, Br or I) and 193b (X = Cl; Y = F, Cl, Br or I) and precursors 196a (X = H) and 196b (X = Cl); reagents: a. NaBH4; b. MsCl, NEt3; c. Na2S, DMF; d. AcOH; e. Pb(OAc)4; f. POCl3; g. 6-chloropurine or 2,6dichloropurine, NaH; h. H2O, H+; i. 3-halobenzylamine.

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Research Highlights

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(1) 1′-Homonucleosides were comprehensively reviewed for the first time.

(2) Analogues containing cyclopentane, pyrrolidine and thiolane frameworks were also covered.

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(3) Syntheses of relevant five-membered rings as sugar replacers were outlined.

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(4) Biological activities (e.g. antiviral, cytotoxicity) were presented.

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