Development of artificial transition metalloDNAzymes for highly efficient catalytic processes

催化剂每天都变得越来越重要。催化剂改变反应的途径，使得一种产物的形成优于其他产物。因此，反应变得更具选择性，产生的废物更少，也使纯化更容易。另一个优点是催化剂可以加快反应速度，减少能量消耗。一般来说，它们在速度和选择性方面都比人造催化剂更有效，但它们不能进行我们想要的所有反应，如加氢反应。我们的目标是利用寡核苷酸所表现出的分子识别能力，并将其与过渡金属的活性联合收割机结合起来，创造人工金属DNA酶。这些金属DNA酶然后可以用于工业相关的催化反应，其中不存在酶，例如氢化、烯丙基取代和氢化，仅举几例。可以设想两种方法：超分子方法，其中金属与寡核苷酸非共价结合[1];共价方法，其中过渡金属通常通过接头共价连接到DNA链。在第一种情况下，能够与金属配位并与DNA结合的外消旋或非手性配体通过自组装引入DNA链。这种方法具有明显的优点，即可以使用商业上可获得的DNA来优化催化剂，而不是单独合成每条链。不幸的是，目前还不清楚催化中心位于哪里，因为配体有可能与DNA双螺旋中的许多地方结合。共价方法通过将过渡金属直接配位到与DNA结合的接头来克服这个问题。Jschke[2]和我们的研究小组[3]都采用了这种方法，然后将这些DNA寡核苷酸分别与铱和钯配位，并用于烯丙基胺化。虽然对映体选择性适中，但表明该方法确实有效。通过改变碱基序列和增加链长可以提高对映选择性，我们计划将这两种方法联合收割机结合起来。Dervan等人[4]已经开发出与特定DNA序列结合的聚酰胺链，我们将通过将能够与过渡金属配位的配体连接到其上来对其进行修饰。金属配位后，聚酰胺可以选择性地偶联到含有正确序列的DNA双螺旋上。这些新型催化剂将在过渡金属介导的转化中进行测试。使用相同的方法，不同的过渡金属络合物将被固定在二维晶体DNA阵列上，旨在实现级联催化转化。这项由博士生进行的试点研究将由PI和加州理工学院的Dervan教授监督，旨在通过后续联合资助提案实现两个团队之间的长期合作。Dijk，E. W的;费林加，B。L.的; Roelfes，G.，Top Organomet. 2009，25，1.2中所述。Fournier，P.; Fiammengo，R.; Jschke，A.，Angew. Chem.Int.Ed.2009，48，1.3。Ropartz，L.; Meeuwenoord，N. J.道：Marel，G. A. v. d.; Leeuwen，P. W. N. M. v.; Slawin，A. M. Z的;卡梅尔，P. C. J.，Chem. Commun. 2007年，1556.4。Hsu，C. F.地;菲利普斯; Trauger，J. W.; Farkas，M. E.的; Belitsky，J. M.; Heckel，A.;奥列纽克，B。Z的; Puckett，J. W.; Wang，C. C. C.的; Dervan，P. B.，Tetrahedron 2007，63，6146.

Catalysts are becoming more and more important every day. A catalyst changes the pathway of a reaction such that formation of one product is favoured over other products. Consequently, the reaction becomes more selective and less waste is produced, also making purification easier. Another advantage is that catalysts accelerate reaction rates reducing energy consumption.Enzymes are nature's catalysts. They are in general more efficient both in speed and selectivity then man-made catalysts, but they cannot perform all the reaction we would like, such as hydroformylation. Man-made catalysts employing a transition metal are very efficient in these reactions.We aim to utilise the molecular recognition which oligonucleotides exhibit and combine that with the activity of transition metals to create artificial metallo DNAzymes. These metallo DNAzymes can then be used in industrial relevant catalytic reactions for which no enzyme exists such as hydroformylation, allylic substitution and hydrogenation to name a few. Two approaches can be envisioned: the supramolecular approach where the metal is non covalently bound to oligonucleotides[1] and the covalent approach where the transition metal is covalently attach to the DNA strand, often through a linker.In the first case a racemic or nonchiral ligand capable of both coordinating to a metal and binding to DNA is introduced to a DNA strand via self assembly. This approach has the clear advantage that catalyst can be optimised using commercially available DNA instead of synthesising each strand individually. Unfortunately it is unclear where the catalytic centre is located as the ligand has the potential to bind to numerous places in the DNA double helix. The covalent approach overcomes this problem by coordinating the transition metal directly to a linker bound to DNA. The disadvantage of this approach is that it is much more labour intensive, requiring complicated and troublesome synthetic methods.Both Jschke[2] and our group[3] have used this approach after which these DNA oligonucleotides were coordinated to iridium and palladium respectively and used in allylic amination. Although the enantioselectivities were moderate it indicates that this approach does work. By changing the base sequence and increasing the chain length the enantioselectivity might be increased.We plan to combine both approaches. Dervan et al.[4] have developed polyamide chains that bind to specific DNA sequences which we will modify by attaching a ligand capable of coordinating to a transition metal to it. After metal coordination the polyamide can be coupled selectively to a DNA double helix containing the correct sequence. These novel catalysts will then be tested in transition metal mediated conversions.Using the same approach different transition metal complexes will be immobilized on two-dimensional crystalline DNA arrays aiming at cascade catalytic conversions.This pilot study by the PhD student will be supervised by the PI and Prof. Dervan at Caltech and is aiming at long term collaboration between the two groups via follow-up joint grant proposals.1. Dijk, E. W.; Feringa, B. L.; Roelfes, G., Top Organomet. Chem. 2009, 25, 1.2. Fournier, P.; Fiammengo, R.; Jschke, A., Angew. Chem. Int. Ed. 2009, 48, 1.3. Ropartz, L.; Meeuwenoord, N. J.; Marel, G. A. v. d.; Leeuwen, P. W. N. M. v.; Slawin, A. M. Z.; Kamer, P. C. J., Chem. Commun. 2007, 1556.4. Hsu, C. F.; Phillips, J. W.; Trauger, J. W.; Farkas, M. E.; Belitsky, J. M.; Heckel, A.; Olenyuk, B. Z.; Puckett, J. W.; Wang, C. C. C.; Dervan, P. B., Tetrahedron 2007, 63, 6146.