A new class of enantiomerically pure lactols is presented that react with rac -alkylarylcarbinols in high diastereoselectivity and can be used for the extractive racemate resolution of alkylarylcarbinols. Graphical abstract

Experiments will be presented and reviewed to support the hypothesis that the intrinsic reactivity of formaldehyde may lead to the formation of a rather comprehensive set of defined biomolecules, including D-glucose, thus fostering concepts of evolution considering the existence of a premetabolic system as a primordial step in the generation of life.

In this article, we present the synthesis of a series of oligo(oxymethylenes) capped with 1-phenylethanol and MeOH. The anionic condition affords enantiomerically pure oligo(oxymethylene) oligomers, while the cationic oligomerization leads to a racemic mixture of the oligo(oxymethylene) chain.

The design of substituted lactols is described, which in their reaction with racemic alkyl aryl carbinols react preferentially with one of the enantiomers exhibiting selectivities up to 14:1.

A first series of enantiomerically pure helical oligo (formaldehyde)s (=oligo(oxymethylen)s) 16-20 was synthesized. To induce the chiral uniformity of the helices, we used (IS)-2,2-dimethyl-l-phenylpropan-1-ol (14) to generate the end groups at the alpha and omega terminus (Scheme 6). Propanol 14 was accessible from its racemate by acetal formation with lactol 12 and separation of the diastereoisomers (Scheme 5). The helicity of the oligomers was investigated by temperature-dependent CD, NMR, and optical-rotation studies. In addition to qualitative considerations concerning the helicity of oligo(formaldehyde)s, we performed calculations of the dimer 17 and the pentamer 20 as well as X-ray structure analyses of the dimer 17 and the tetramer 19 to establish the handedness of the helices and to correlate their sense with the absolute configuration of the inducing stereogenic center. The results may be of relevance with respect to induction and propagation of chirality in prebiotic chemistry.

A linear and a convergent synthesis of uridine-derived backbone-base-dedifferentiated (backbone including) oligonucleotide analogues were compared. ne Sonogashira cross-coupling of the alkyne 1 and the iodide 2 gave the dimer 4 that was C-desilylated and again coupled with 2 to give the trimer 6 (Scheme 7). Repeating this linear sequence led to the pentamer 10. Coupling yields were satisfactory up to formation of the trimer 6, but decreased for the coupling to higher oligomers. Similarly, coupling of the alkynes 5, 7, and 9 with the iodouridine 3 gave, in decreasing yields, the trimer 12, tetramer 13, and pentamer 14, respectively. The dimeric iodouracil 20 was synthesized by coupling the alkyne 17 with the iodide 16 to the dimer 18, followed by iodination at C(6/I) to 19 and O-silylation (Scheme 2). The iodinated dimer 23 was prepared by iodinating and O-silylating the known dimer 21. Coupling of 20 and 23 with the dimer 5, trimer 7, and tetramer 9 gave the tetramers 8 and 13, the pentamers 10 and 14, and the hexamer 15, respectively (Scheme 3). The oligomers up to the pentamer 14 were deprotected to provide the trimer 24, tetramer 25, and pentamer 26 (Scheme 4). There was no evidence for the heteropairing of the pentamer 26 and rA(7), nor for the pairing of rU(5) and rA(7), while a UV melting experiment showed the beginning of a sigmoid curve for the interaction of rU(7) with rA(7). Therefore, the pentamer 26 does not pair more strongly with rA(7) than rU(5).

In contradistinction to the corresponding Grignard reagent, bis[(trimethylsilyl)ethynyl]zinc reacted with the 5'-oxoadenosine 3 diastercoselectively to the beta-D-allo-hept-6-ynofuranosyladenine 5. Lithiation/iodination of the monomeric propargyl alcohol 5 and of the dimeric propargyl alcohol 22 provided the 8-iodoadenosines 7 and 18, respectively, considerably shortening the synthesis of the dimeric O-silylated 8-iodoadenosine 25. The mixed uridine- and adenosine-derived tetramers 21 and 32 were synthesised. The tetramer 21 was prepared by a linear sequence. Sonogashira coupling of 9 and 13 yielded the trimer 16 that was C-desilylated to 17 A second Sonogashira coupling of 17 and 19 yielded the tetramer 21. Tetramer 32 was prepared in higher yields by a convergent route, coupling the acetylene 29 and the iodide 30. The uridine-derived iodides proved more reactive than the adenosine-derived analogues, and the N-6-unprotected adenosine-derived alkynes were more reactive than their N-6-benzoylated analogues.

The D-allo- and L-talo-hept-6-ynofuranosyluracil-derived phosphoramidites 11A and 11T were prepared in 9-10% yield over eight steps from the previously described propargylic alcohols 1A and IT, respectively. The corresponding nucleotides were incorporated into rU(14) by standard solid-phase synthesis. While the duplex consisting of rU(14) with one L-talo-hept-6-ynofuranosyluracil in the middle of the strand and rA(14) (I (.) V) had the same melting point as the reference duplex rU(14) - rAA (I - H), the duplex with one D-allo-hept-6-ynofuranosyluracil in the middle of rU(14) and rA(14) (I (.) In) Melted 1.5degrees lower than the reference duplex. The duplex I - VI consisting of rU(14), with Six L-talo-hept-6-ynofuranosyluracils distributed over the entire strand and rA(14) showed a melting point that is 11degrees lower than the reference duplex. The corresponding duplex I (.) IV of rU(14) possessing six D-allo-hept-6-ynofuranosyluracils and rA(14) showed a melting point which is more than 20degrees below the one of the reference duplex. These results are in qualitative agreement with the predictions based on the conformational analysis of the nucleosides and the interference of the ethynyl moiety with the hydration of the oligonucleotides.

A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a nucleobase-including backbone to form homo- and/or heteroduplexes (cf: Fig. 2). It is characterised by ethynyl-linkages between C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine-derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine-5'-carbaldehyde (2) with triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1:2, 80%;Scheme 1). Their configuration at C(5') was determined on the basis of NOE experiments and X-ray crystal-structure analysis. Iodination at C(6) of the (R)-configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%),which was silylated at O- C(5') to yield 18 (89%;Scheme 2). C-Desilylation of 7 with NaOH in MeOH/H2O led to the alkyne 10 (98%); O-silylation of 10 at O- C(5') gave 16 (84%). Cross-coupling of 18 and 16 yielded 63% of the dimer 19, which was C-desilylated to 20 in 63% yield. Cross-coupling of 10 and the 6-iodouridine 13 (70%), followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H2O, gave the deprotected dimer 15 (73%).