When nucleoside chemistry met hypervalent iodine reagents

Abstract

There has been increasing use of hypervalent iodine reagents in the field of nucleoside chemistry. Applications span: (a) synthesis of nucleoside analogues with sulfur and seleno sugar surrogates, (b) synthesis of unusual carbocyclic and ether ring-containing nucleosides, (c) introduction of sulfur and selenium into pyrimidine bases of nucleosides and analogues, (d) synthesis of isoxazole and isoxazoline ring-containing nucleoside analogues, (e) involvement of purine ring nitrogen atoms for remote C-H bond oxidation, and (f) metal-catalyzed and uncatalyzed synthesis of benzimidazolyl purine nucleoside analogues by intramolecular C-N bond formation. This review offers a perspective on developments involving the use of hypervalent iodine reagents in the field of nucleoside chemistry that have appeared in the literature in the 2003-2017 time frame.

Keywords: C-H bond activation; C-N bond formation; hypervalent iodine; nucleoside analogs; nucleosides.

Figure 1

The eight naturally occurring nucleosides

Figure 2

Commonly encountered λ³ and λ⁵ hypervalent iodine reagents

Figure 3

Possible thionium cations that are proposed in the reactions

Figure 4

Examples of isoxazoline-substituted 6-pyrrolidinyl purine derivatives via PIFA oxidation

Figure 5

Oxidation of 6-aryl purine nucleosides with Pd(OAc)₂ and PIDA (PG = t-BuMe₂Si)

Figure 6

Diacetoxylation of 6-aryl purine nucleosides with Pd(OAc)₂ and PIDA (PG = t-BuMe₂Si)

Figure 7

N⁶-biarylyl adenine nucleoside substrates used for the reactions involving Pd(OAc)₂/PIDA (in cases where reaction was observed, red arrows indicate the site of C–N bond formation and the ensuing carbazolyl product yields are shown)

Figure 8

Products obtained in the fluorinated solvents in the absence of any catalyst

Scheme 1

Synthesis of a higher order thymine nucleoside analogue and a plausible mechanism

Scheme 2

Synthesis of a thio analogue of uridine

Scheme 3

Reactions of three purines with a tetrahydrothiophenediol dibenzoate

Scheme 4

Reactions of 6-chloropurine with differentially protected tetrahydothiophene derivatives

Scheme 5

Testing the hypothesis on the role of protecting groups on sites of reactions

Scheme 6

Formation of a tetrahydrothiophene nucleoside analogue from a thietane

Scheme 7

Isomerization of cis–32 and a mechanism for the formation of product 33

Scheme 8

Synthesis of seleno analogues of uridine and cytidine

Scheme 9

Synthesis of the seleno analogue of 6-chloropurine riboside

Scheme 10

Reactions of seleno sugar analogue 40 with 2-amino-6-chloro and 2,6-dichloropurines, and further transformations to a protected seleno guanosine analogue

Scheme 11

Reactions of silyl derivatives of cyclopentene and cyclohexene with uracil

Scheme 12

Synthesis of cyclohexenyl uridine analogues

Scheme 13

Synthesis of four isomeric cytidine nucleoside analogues

Scheme 14

Reactions of dihydropyran and dihydrofuran with bis(trimethylsilyl)uracil

Scheme 15

Various uracil derivatives prepared via the “seleno-glycosylation” approach and a possible mechanism

Scheme 16

Synthesis of dihydropyranyl uracil nucleoside analogues

Scheme 17

Separation of the uracil nucleoside analogues and conversion to the cytosine derivatives

Scheme 18

Sulfenylation and selenation of uracil derivatives and uridine nucleosides, and analogues

Scheme 19

Use of PIFA for the cycloaddition of nitrile oxides with alkynes

Scheme 20

Formation of isoxazolyl 6-pyrrolidinyl purine derivatives by PIFA oxidation

Scheme 21

Acetoxylation of an acetate-protected 6-phenyl purine ribonucleoside

Scheme 22

An isolated and cystallographically characterized cyclopalladated, Pd^II–Pd^II dimer, and its potential conversion to a Pd^III–Pd^III species by PIDA

Scheme 23

PIDA/Cu(OTf)₂-mediated cyclization of N⁶-aryl adenosine triacetate derivatives to benzimidazopurine nucleoside analogues

Scheme 24

A possible catalytic cycle for the Cu(OTf)₂/PIDA-mediated cyclization

Scheme 25

Comparison of the reactivity of disilyl-protected N⁶-phenyl 2′-deoxyadenosine to triacetyl-protected N⁶-phenyl adenosine analogue

Scheme 26

Compounds synthesized using PIDA in HFIP, at room temperature

Scheme 27

A possible mechanistic pathway for the cyclization reaction with PIDA in HFIP

Scheme 28

Two possible cyclization modes with N⁶-biarylyl adenine nucleoside derivatives