Bidirectional synthesis

DNA synthesis occurs in both directions at each of the rep-licating forks. Once a DNA strand has been primed, synthesis toward the replicating fork can be visualized as continuous. Growth of the opposite, 

DNA ligase is not only important in DNA replication it is also used to seal deoxyri-bonucleotide segments in the crossover events during gene recombination. The enzyme also functions to close breaks in segments of DNA undergoing repair and is required to join theends of mitochondrial DNA to form their characteristic circular structure. 

Armed with this information, the unwinding problem mentioned ear-lier can be reconsidered. By the alternating action of endonucleolytic and ligase activities, the unwinding of DNA could be reduced to an untwisting of only a small part of the double helix at any given time. Both activities are part of the enzyme called topo-isomerase 1. 

---

With the bulky metallo-organic Pd(II) catalyst 98, on the other hand, selective formation of 99 was possible here functional groups are tolerated that would react with an Ag(I) catalyst (for example, terminal alkynes, alkyl chlorides, alkyl bromides and alkyl iodides) [59]. With l,n-diallenyl diketones (100), easily accessible by a bidirectional synthesis, up to 52-membered macrocycles (101) could be prepared in an end-group differentiating intramolecular reaction (Scheme 15.26) [60], For ring sizes lager than 12 only the E-diastereomer is formed overall yields of the macrocydes varied between 17 and 38%. Only with tethers shorter than 11 carbon atoms could the Z-diastereomer of the products be observed, a stereoisomer unknown from the intermolecular dimerization reactions of 96. 

Diol (165) is an intermediate in the synthesis of the symmetrical triterpene, squalene (167). Succin-dialdehyde serves as the central four carbons followed by bidirectional synthesis through diol (164). The transformation of diol (164) into its higher homolog (165) requires several operations (i) orthoacetate rearrangement s to a diester (ii) reduction to a diol (iii) oxidation to a dialdehyde and (iv) addition of iso-propenyllithium. A more convergent approach employs 3,3-dimethoxy-2-methylbut-l-ene in conjunction with diol (164), a sequence that only requires reduction of the resultant isopropenyl ketone after rearrangement to realize diol (165). ... 

Scheme 1 Glycosyl acceptor (Case 1) and donor (Case 2) bound to the solid support, and bidirectional synthesis (Case 3) S, solid support P, unique protecting group X, activating group asterisk, uniquely differentiated hydroxyl group.

When DNA replication was first observed experimentally (using electron microscopy and autoradiography), investigators were confronted with a paradox. The bidirectional synthesis of DNA as it appeared in their research seemed to indicate that continuous synthesis occurs in the 5 —> 3 direction on one strand and in the 3 —> 5 direction on the other strand. (Recall that DNA double helix has an antiparallel configuration.) However, all the enzymes that catalyze DNA synthesis do so in the 5 —> 3 direction only. It was later determined that only one strand, referred to as the leading strand, is continuously synthesized in the 5 —> 3 direction. The other strand, referred to as the lagging strand, is also synthesized in the 5 — 3 direction but in small pieces (Figure 18.6). (Reiji... 

The bidirectional synthesis of DNA implies that one strand is synthesized in the 5 —> 3 direction and the other in the 3 —> 5 direction. However, all known enzymes that synthesize DNA do so in the 5 —> 3 direction. How did Reiji Okazaki explain this paradox ... 

SCHEME 7.8 The solid phase approach to bidirectional synthesis of oligo 1,4-phenylene ethynylenes. 

Fig. 11. The peptide cyclization in polymer phase after bidirectional synthesis of the linear precursor...

Fig. 12. The 2,4-dinitrophenylene bridge links histidine to the modified support for bidirectional synthesis...

SCHEME 25.65. A double carbonyl-alkene cyclization in the bidirectional synthesis of trans-fused polycyclic ethers. 

---