Multicomponent reactions in nucleoside chemistry

Abstract

This review covers sixty original publications dealing with the application of multicomponent reactions (MCRs) in the synthesis of novel nucleoside analogs. The reported approaches were employed for modifications of the parent nucleoside core or for de novo construction of a nucleoside scaffold from non-nucleoside substrates. The cited references are grouped according to the usually recognized types of the MCRs. Biochemical properties of the novel nucleoside analogs are also presented (if provided by the authors).

Keywords: multicomponent reaction; nucleoside analog; nucleoside antibiotics; nucleoside construction; nucleoside modification.

Figure 1

Selected chemical modifications of natural ribose or 2'-deoxyribose nucleosides leading to the development of medicinally important nucleoside analogs.

Scheme 1

(a) Classical Mannich reaction; (b) general structures of selected hydrogen active components and structures of the resulting Mannich reaction products.

Scheme 2

Reagents and reaction conditions: i. H₂O or H₂O/EtOH, 60–100 °C, 7 h–10 d; ii. H₂, Pd/C or PtO₂; iii. (1) 4-methylbenzenethiol, (2) Ni-Ra; iv. (1) MeI, (2) NaBH₄; v. (1) MeI, (2) nucleophile.

Scheme 3

Reagents and reaction conditions: i. H₂O, 90 °C, overnight.

Scheme 4

Reagents and reaction conditions: i. AcOH, H₂O, 60 °C, 12 h-5 d; ii. AcOH, H₂O, 60 °C, 8 h.

Scheme 5

Reagents and reaction conditions: i. CuBr, THF, reflux, 0.5 h; ii. n-Bu₄NF·3H₂O, THF, rt, 2 h.

Scheme 6

Reagents and reaction conditions: i. [bmim][PF₆], 80 °C, 5–8 h.

Scheme 7

Reagents and reaction conditions: i. EtOH, reflux, 24 h.

Scheme 8

Reagents and reaction conditions: i. NaOAc, H₂O, 95 °C, 1–16 h; ii. NaOAc, H₂O, 95 °C, 1 h.

Scheme 9

Reagents and reaction conditions: i. a. 37% aq HCl, MeOH; b. NaOAc, 1,4-dioxane, H₂O, 100 °C, overnight.

Scheme 10

Reagents and reaction conditions: i. DMAP, DCC, MeOH, rt, 1 h.

Scheme 11

The Kabachnik–Fields reaction.

Scheme 12

Reagents and reaction conditions: i. 60 °C, 3 h; ii. 80 °C, 2 h.

Scheme 13

The four-component Ugi reaction.

Scheme 14

Reagents and reaction conditions: i. MeOH, rt, 2–3 d, yields not given.

Scheme 15

Reagents and reaction conditions: i. MeOH/CH₂Cl₂ (1:1), rt, 24 h, yield not given; ii. 6 N aq HCl, 80 °C, 2 h, 80%.

Scheme 16

Reagents and reaction conditions: i. MeOH/H₂O, rt, 26 h; ii. aq AcOH, reflux, 50%; iii. reversed phase HPLC, then MeOH, Pd black, formic acid, 1 h.

Scheme 17

Reagents and reaction conditions: i. MeOH, rt, 24 h; ii. HCl, MeOH, 0 °C to rt, 6 h, then H₂O, rt, 12 h.

Scheme 18

Reagents and reaction conditions: i. DMF/Py/MeOH (1:1:1), rt, 48 h; ii. 10% HCl/MeOH, rt, 30 min.

Scheme 19

Reagents and reaction conditions (R = CH₃ or H): i. CH₂Cl₂/MeOH (2:1), 35–40 °C, 2 d; ii. HF/pyridine, THF, rt, 2.5 h, then MeOTMS, rt, 3.5 h.

Scheme 20

Reagents and reaction conditions: i. MeOH, 76%; ii. 80% aq TFA, 100%.

Scheme 21

Reagents and reaction conditions: i. EtOH, rt, 72 h; ii. Zn, aq NaH₂PO₄, THF, rt, 1 week; then 80% aq TFA, rt, 8 h; then HPLC separation.

Scheme 22

Reagents and reaction conditions: i. EtOH, rt, 48 h, then silica gel chromatography, 33% for 57 (30% for epi-57).

Scheme 23

Reagents and reaction conditions: i. [bmim]BF₄, 80 °C, 4 h; ii. [bmim]BF₄, 80 °C, 3 h; iii. [bmim]BF₄, 80 °C, 2–4 h; iv. EtOH, 50 °C, overnight.

Scheme 24

Reagents and reaction conditions: i. [bmim]BF₄, 80 °C.

Scheme 25

Reagents and reaction conditions: i. H₃PW₁₂O₄₀ (2 mol %), EtOH, 50 °C, 2–15 h; ii. H₃PW₁₂O₄₀ (2 mol %), EtOH, 50 °C, 8 h.

Scheme 26

General scheme of the Biginelli reaction.

Scheme 27

Reagents and reaction conditions: i. EtOH, reflux.

Scheme 28

Reagents and reaction conditions: i. Bu₄N⁺HSO₄⁻, diethylene glycol, 120 °C, 1.5–3 h.

Scheme 29

Reagents and reaction conditions: i. BF₃·Et₂O, CuCl, AcOH, THF, 65 °C, 24 h; ii. Yb(OTf)₃, THF, reflux, 20 h.

Scheme 30

Reagents and reaction conditions: TCT (10 mol %), rt: i. 100 min; ii. 150 min; iii. 140 min.

Scheme 31

Reagents and reaction conditions: i. EtOH, microwave irradiation (300 W), 10 min; ii. EtOH, 75 °C, 5 h and for 72 h, rt.

Scheme 32

The Hantzsch reaction.

Scheme 33

Reagents and reaction conditions: TCT (10 mol %), rt, 80–150 min.

Scheme 34

Reagents and reaction conditions: i. Yb(OTf)₃, THF, 90 °C, 12 h; ii. 4 Å molecular sieves, EtOH, 90 °C, 48 h.

Scheme 35

Reagents and reaction conditions: i. MeOH, 50 °C, 48 h.

Scheme 36

Reagents and reaction conditions: i. MeOH, 25 °C, 5 d.

Scheme 37

Bu₄N⁺HSO₄⁻, diethylene glycol, 80 °C, 1–2 h.

Scheme 38

The three-component carbopalladation of dienes on the example of buta-1,3-diene.

Scheme 39

Reagents and reaction conditions: i. 5 mol % Pd(dba)₂, Bu₄NCl, ZnCl₂, acetonitrile or DMSO, 80 °C or 100 °C, 1–2 days.

Scheme 40

Reagents and reaction conditions: i. 2.5 mol % Pd₂(dba)₃, tris(2-furyl)phosphine, K₂CO₃, MeCN or DMF, 80 °C, 3–24 h, 77–99%.

Scheme 41

Reagents and reaction conditions: i. 2.5 mol % Pd₂(dba)₃, tris(2-furyl)phosphine, K₂CO₃, MeCN or DMF, 80 °C, 3–24 h, 45–87%.

Scheme 42

The three-component Bucherer–Bergs reaction.

Scheme 43

Reagents and reaction conditions: i. MeOH, H₂O, 70 °C, 4.5 h; ii. (1) H₂, 5% Pd/C, MeOH, 55 °C, 5 h; (2) Dowex 50 W, MeOH, H₂O, rt, 4 h.

Scheme 44

Reagents and reaction conditions: i. pyridine, MgSO₄, 100 °C, 28 h, N₂; ii. DMF, 70–90 °C, 22–30 h, N₂, the cumulative yield of 108/109 from 55% to 96%.

Scheme 45

Reagents and reaction conditions: i. Montmorillonite K-10 clay, microwave irradiation (600 W), 6–10 min (solvent-free conditions).

Scheme 46

Reagents and reaction conditions: i. Montmorillonite K-10 clay, microwave irradiation (560 W), 6–10 min (solvent-free conditions).

Scheme 47

Reagents and reaction conditions: i. CeCl₃·7H₂O (20 mol %), NaI (20 mol %), microwave irradiation (90 °C), 6–8 min; ii. CuSO₄·5H₂O, Al₂O₃, microwave irradiation (90 °C), 3–3.5 min.

Scheme 48

Reagents and reaction conditions: i. PhI(OAc)₂ (3 mol %), microwave irradiation (45 °C), 6–9 min.

Scheme 49

Reagents and reaction conditions: i. 117, ethyl pyruvate, TiCl₄, dichloromethane, −78 °C, 1 h; then 118, −78 °C, 1 h; then 23 °C, 1 h.