[jstownse]

I am attempting to place a branched thiophene onto the 2' hydroxyl of guanosine. I have previously acetylated the amine and tritylated the 5' hydroxyl. I deprotonate the remaining unprotected acidic protons using 3.5 equivalences of NaH in DMSO. This is followed by the addition of 1.1 eq. of 2-chloromethyl-thiophene (neat). See attached scheme . By TLC I have 4 products and very little starting material. HNMR indicates that the major product formed is a bis-addition to what we believe is the 2' and 3'.

Tomorrow I will be attempting the same reaction only this time I will reduce the concentration of the thiophene reagent; the hope being that this will favor mono rather than bis addition. Am I on the right track? What thiophene chloride concentration do you feel is practical for such a reaction? Is there anything else I can do to promote addition onto JUST the 2' position?

Furthermore, any practical advice concerning SN2 reactions such as these would be greatly appreciated. Thanks.

[sjb]

How do you make the modified nucleotide? Would introduction of the thiophene be easier earlier? For instance, I imagine you can tie up the 3 and 4 hydroxyls in a acetal or something, and then form your nucleoside bond, add the thiophene, deprotect 3 and 4 then add @ 4. May just be shifting the problem elsewhere though, and I appreciate that you seem quite advanced down this route.

What's the next step? Can't see much going on with the thophene, and I think you can get some selectivity in forming esters there (can't recall which way is more likely), but then deprotection may add another set of steps and complications

[TheUnassuming]

My phd work has focused on nucleoside chemistry and for hitting the 2' hydroxyl I like to use the 1,1,3,3-tetraisopropyldisiloxane protecting group strategy.  It blocks the 5' and 3' hydroxyls and allows you to get at the 2' selectively without many worries in basic conditions. Otherwise you will certainly get a mix of mono (2' and 3') as well as di alkylated products.

[phth]

Have you also tried protecting 5', 3' with ring strain?   Should give a kinetic and thermo product, and you could just add to the 5' with the undesired pdt. 

[jstownse]

TheUnassuming, thanks for your response. I have previously used di-tert-butyldichloro silane to cover the 5' and 3' positions, however we found that it was extremely labile under basic conditions in the solvent systems we require (ie. DMSO, not THF). Did you ever experience a similar problem with the 1,1,3,3-tetraisopropyldisiloxane? Also, can you remember what sort of solvent system did you typically use for reactions such as these? It seems to be a pretty pricey reagent: $58.50 for a gram !

 One last question...could you PM any of your publication(s)? I would be interested in reviewing your procedure to see if it might be applicable to my work. Thanks so much, I really appreciate it!

[jstownse]

phth, I am not totally sure what you mean. I have not heard of this "protecting with ring strain". Sorry if this is a noobish question.

[TheUnassuming]

Ah, polar systems usually did pose a problem for the TIPDS system.  My compounds were typically soluble in THF, so that wasn't a big problem there though it is a bit touchy no matter what you do.   
To get your compound more non-polar you could consider switching your order a bit and first boc-protect the C2-amino of guanine, do your chemistry at the 2' position, then deprotect and do your desired chemistry at the C2-amino group.  Its more steppy, and would make Phil Baron unhappy, but would make your compound significantly less polar and easier to play with. 
An alternative to the TIPDS system thats been used is to hit the fully deprotected nucleoside with TBSCl (2 equiv).  You will get 5' protection and a mix of 2' and 3' that can be separated.   The TBS protected substrate is more non-polar than the TIPDS system which is handy. 
A completely alternative route that I used for a few analogues was to make the 5'-3' protected arabanoside, then triflate'ing the 2' and displace with my desired nucleophile. 
Currently working on the paper... or avoiding working on the paper as you can tell, so can't point you to the publication yet.  Here are some good ref's for the general chemistry though:

http://pubs.acs.org/doi/abs/10.1021/jo101963z

http://www.sciencedirect.com/science/article/pii/S0960894X02007448

http://pubs.acs.org/doi/abs/10.1021/jo800451m

[phth]

There are two possible diol ring protections and they can be done with different reagents to yield the same ring size therefore a kinetic and thermo pdt will be observed.