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Phenyllithium Synthesis Essay

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Introduction of an aromatic core can occur via the attack of organometallic reagents such as a lithium, magnesium, aluminum or titanium reagents to both aldehydes or ketones. Starting from nucleoside and carbohydrate analogues possessing a ketone, and depending of the nature of the glycone part, the reaction can lead to diastereoselectivity.

2.1. Addition of Aromatic Organolithiums to Carbonyl Groups

Two strategies were developed. The first one was the direct addition of an aromatic ring to a carbonyl group starting from nucleoside analogues and the second one was the addition of an aromatic ring to the carbonyl group of carbohydrate as starting material, followed by introduction of a nucleobase.

In 1987, Miyasaka and co-workers reported the synthesis of 3' (S)-C-phenyl-β-d-xylofuranosyluracil (4) in good yield [8]. This family of modified nucleoside analogues has been known to have potent biological activity and to be useful for elucidation of enzyme recognition of substrates. Starting from 2',5'-bis-O-tert-butyldimethylsilyl-3'-ketouridine (2) obtained in two steps from uridine (1) [9], treatment with an excess of phenyllithium in THF for 3 h at below −70 °C furnished the corresponding alcohol 3 in 72% yield. Then, classical deprotection of 3 in presence of TBAF in THF gave the corresponding triol 4 (Scheme 1). The authors did not report the presence of a diastereoisomeric mixture during the addition of the aromatic ring to the carbonyl group. Application of this approach to the synthesis of the corresponding 2'-C- phenyl analogue did not afford the target aromatic derivative, probably due to the known instability of 2'-ketouridine.

Scheme 1. Synthesis of 3'(S)-C-phenyl-β-D-xylofuranosyluracil (4).

Scheme 1. Synthesis of 3'(S)-C-phenyl-β-D-xylofuranosyluracil (4).

Reagents and Conditions: (i) Reference [9]; (ii) PhLi, THF, −70 °C, 3 h, 72%; (iii) TBAF, THF.

A similar sequence was applied to the aldehyde 6 [10] which was obtained in four steps from thymidine (5) via subsequent protection of the 5'-OH group, silylation of the 3'-OH group, removal of the protection of the 5'-OH group and then Moffatt oxidation of the 5'-OH group. This strategy furnished the 5'-C-aryl derivatives 11 and 12 [11] as nucleotide analogues for a study on site-specific DNA cleavage [11,12]. Starting from 1-bromo-2-nitrobenzene in the presence of phenyl lithium, a metal-halide exchange in THF at −105 °C permitted obtaining an epimeric mixture of alcohols 7 and 8 (7 (5'S)/8 (5'R) (4.6:1) in 66% yield. The diastereoisomeric excess (de 64%) was not explained by the authors. Then, conversion of the mixture of isomers 7 and 8 gave, after flash column chromatography, the acetals 9 and 10 in 76% and 16% yields, respectively. A conventional deprotection step followed by transformation of the hydroxyl group in position 3' to a phosphoramidite afforded the intermediates 11 and 12 in 77% and 71% yields (over two steps), respectively (Scheme 2). The phosphoramidites 11 and 12 were incorporated into oligonucleotides by standard automated DNA synthesis.

Scheme 2. Synthesis of 5'(S)- and 5'(R)-C-phenyluridine analogues 11 and 12.

Scheme 2. Synthesis of 5'(S)- and 5'(R)-C-phenyluridine analogues 11 and 12.

Reagents and Conditions: (i) Reference [10]; (ii) 1-bromo-2-nitrobenzene, PhLi, THF, −105 °C, 5 h, 66%; (iii) ethylvinyl ether, PPTS, CH2Cl2, 18 h, 9: 76% and 10: 16%; (iv) (a) TBAF, THF, 2 h; (b) 2-cyanoethyl-N,N-diisopropylphosphorochloroamidite, (iPr)2EtN, CH2Cl2, 2 h, 11: 77%, 12: 71% for the two steps.

In parallel, addition of aromatic ring on a carbonyl group was realized on carbohydrate starting materials. In 2001, Sasaki and co-workers reported for the first time the synthesis of W-shape nucleic acid (WNA) designed for selective formation of anti-parallel triplexes formation [13]. WNAs are bicyclic nucleoside analogues bearing an aromatic moiety for stacking and a heterocyclic part as purine base for Hoogesteen hydrogen bonds. The strategy started from D-ribono-1,4-lactone 14 which was prepared in four steps from D-ribose (13) via protection of the 2,3-dihydroxy groups, acetylation of the residual hydroxyl groups, selective deacetylation and then oxidation of the anomeric position. Addition of phenyllithium in THF furnished the two anomers 15 in 53% yield [13] (Scheme 3). In the next steps, this sequence demanded protection of the primary hydroxyl group with a silyl group.

Scheme 3. Synthesis of 1-C-phenyl-D-ribofuranosyl analogues 15.

Scheme 3. Synthesis of 1-C-phenyl-D-ribofuranosyl analogues 15.

Reagents and Conditions: (i) (a) Acetone, H+; (b) Ac2O, pyridine; (c) piperidine, THF, 55% for the three steps; (d) PCC, CH2Cl2; (ii) PhLi, THF, −70 °C, 3 h, 53%.

To complete this work, Sasaki and co-workers reported three years later a similar strategy by changing the protecting group in position 5 (silyl vs. acetyl) (Scheme 4) [13,14]. In this case, the C-C coupling between phenyllithium and the lactone 16 gave the two 1-C-phenyl lactol epimers 17 in 79% yield [14]. Allylation at the 1-position of compounds 17 gave a mixture of two anomers 18 (ratio of α/β 7:6) in 82% yield. An elegant chemical sequence for the bicyclo[3.3.0]octane derivative was reported by Sasaki and co-workers. Subsequent oxidative cleavage of the vinyl group of 18 gave the corresponding aldehyde and deprotection of the diol in position 2,3 spontaneously provided the two corresponding bicyclo[3.3.0]octane derivatives 19 in 28% yield (two steps). After acetylation of the two hydroxyl groups furnishing the two epimers 20 in 90% yield, conventional N-glycosidation with thymine was done to produce the target α- and β-isomers 22 and 21 in 37% and 42% yields, respectively. After flash column chromatography, each nucleoside analogues 21 and 22 were deprotected to give the corresponding diols 23 and 24 in 71% and 47% yields, respectively. After classical protection and activation steps, the corresponding phosphoramidites were incorporated to oligonucleotides by standard automated DNA synthesis.

At this stage, from the mixture of the key glycosyl donors 20, the strategy described provides straightforward access in an efficient fashion to the different nucleoside analogues 2540 in a bicyclo[3.3.0]octane series as presented in Figure 1 [13,14,15]. As usual, N-glycosidation with a guanine derivative afforded a mixture of 7-N and 9-N alkylated isomers and α- and β-isomers 33, 34, 37 and 38. It is noteworthy that introduction of the nucleobase furnished in each case a mixture of two isomers, but the authors did not mention at any time the ratio of the α-isomer. In addition to the above-mentioned syntheses, Sasaki and co-workers reported the preparation of the halogeno- and amino-functionalized bicyclonucleoside analogues 4150 (Figure 2) [16].

During this period, Sasaki and co-workers reported the synthesis of compounds 53 and 54 [17] using the same strategy described above [14]. In this case, acetylation of the hydroxyl group of 17 as pre-treatment for the N-glycosidation did not furnish the corresponding acetate but caused carbohydrate ring opening to yield the corresponding undesired acyclic derivative [18].

Scheme 4. Synthesis of thymidine analogues 23 and 24.

Scheme 4. Synthesis of thymidine analogues 23 and 24.

Reagents and Conditions: (i) (a) Acetone, H+; (b) TBDPSCl, TEA, DMAP, CH2Cl2; (c) PCC, CH2Cl2, 77% for the three steps; (ii) PhLi, THF, −78 °C, 2 h, 79%; (iii) CH2=CHCH2TMS, ZnBr2, CH3NO2, 0 °C then rt, 2 h, 82%; (iv) (a) aq. OsO4, NaIO4, pyridine, rt, 30 h; (b) H2SO4 (5%), THF, 60 °C, 6 h, 28% for the two steps; (v) Ac2O, pyridine, 0 °C, 39 h, 90%; (vi) HDMS, TMSCl, SnCl4, thymine, CH3CN, 50 °C, 4 h, 21: 42%; 22: 37%; (vii) (a) TBAF, THF, rt, 2 h; (b) NaOH, THF, MeOH, 0 °C, 1 h, 23: 71%; 24: 47% for the two steps.

Due to this reactivity, the authors developed the direct N-glycosidation of the two epimeric alcohols 17. Thymine was mixed in presence of the silylating agent BSA and Lewis acid TMSOTf with the epimeric mixture of 17 at 0 °C to produce the β-nucleoside 51 (α-phenyl) in 31% yield. The same reaction at 50 °C furnished a mixture of two isomers (α-nucleoside/β-nucleoside, 52/51, 6:31) showing that the β-nucleoside 51 was formed by thermodynamic process. Then, classical deprotection of the primary hydroxyl group of 51 and 52 afforded the nucleoside analogues 53 and 54 in 49% and 63% yields, respectively (Scheme 5).

Figure 1. Bicyclo[3.3.0]octane nucleoside analogues 2540 having a phenyl group [13,14,15].

Figure 1. Bicyclo[3.3.0]octane nucleoside analogues 2540 having a phenyl group [13,14,15].

Figure 2. Bicyclo[3.3.0]octane nucleoside analogues 4150 having a substituted aromatic ring.

Figure 2. Bicyclo[3.3.0]octane nucleoside analogues 4150 having a substituted aromatic ring.

Scheme 5. Synthesis of 1'(R)- and 1'(S)-C-phenyl-D-ribofuranosylthymine analogues 53 and 54.

Scheme 5. Synthesis of 1'(R)- and 1'(S)-C-phenyl-D-ribofuranosylthymine analogues 53 and 54.

Reagents and Conditions: (i) PhLi, THF, −78 °C then rt, 4 h, 71%; (ii) thymine, BSA, TMSOTf, 50 °C, 4.5 h, 51: 31%, 52: 6%; (iii) TBAF, THF, rt, 2 h, 53: 49%, 54: 63%.

Introduction of all four nucleobases were realized using similar strategy giving compounds 5560 and two of them were selectively deprotected to obtain the β-isomers 61 and 62 (Figure 3). In 1982, Vasella and co-workers reported the synthesis of 4'-C-aryl-D-ribonucleosides as synthons for the synthesis of antibiotics [19]. Starting from the 1,4-lactone derivative 64 obtained from the ribonolactone 63 in two steps, addition of an excess of 2-methoxymethoxyphenyllithium at 10 °C afforded two isomeric lactones 65 and 66 in 65% yield with an excess of the L-lyxo 66 (54%). In order to have more D-ribose derivative, the authors described the conversion of the L-lyxo form 66 to the target D-ribo form 65 in 89% yield by treatment with piperidine and the addition of methanesulfonyl chloride and TEA. Reduction of the isolated lactone 65 with DiBAL-H afforded the two lactols 67 in 95% yield and then subsequent deprotection of the diol and acetylation of the free hydroxyl group gave the glycone derivatives 68 in 90% yield, respectively.

Figure 3. 1'(R)- and 1'(S)-C-phenyl-D-ribofuranosylnucleoside analogues 5562.

Figure 3. 1'(R)- and 1'(S)-C-phenyl-D-ribofuranosylnucleoside analogues 5562.

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