We describe a novel and efficient synthesis (62-84% yields) of the eight possible, diastereomerically pure, cis and trans, R and S O6-allyl-protected N2-dGuo phosphoramidite building blocks derived through cis and trans opening of...
moreWe describe a novel and efficient synthesis (62-84% yields) of the eight possible, diastereomerically
pure, cis and trans, R and S O6-allyl-protected N2-dGuo phosphoramidite building blocks derived
through cis and trans opening of (()-3R,4â-dihydroxy-1â,2â-epoxy-1,2,3,4-tetrahydrobenzo[c]-
phenanthrene [BcPh DE-1 (1)] and (()-3R,4â-dihydroxy-1R,2R-epoxy-1,2,3,4-tetrahydrobenzo[c]-
phenanthrene [BcPh DE-2 (2)] by hexafluoropropan-2-ol (HFP)-mediated addition of O6-allyl-3¢,5¢-
di-O-(tert-butyldimethylsilyl)-2¢-deoxyguanosine (3) at C-1 of the epoxides. Simply changing the
relative amount of HFP used in the reaction mixture can achieve a wide ratio of cis/trans addition
products. Thus, the observed cis/trans adduct ratio for the reaction of DE-1 (1) in the presence of
5 equiv of 3 varied from 17/83 to 91/9 over the range of 5-532 equiv of HFP. The corresponding
ratios for DE-2 (2) varied from 2/98 to 61/39 under the same set of conditions. When 1 or 2 was
fused with a 20-fold excess of 3 at 140 °C in the absence of solvent HFP, almost exclusive trans
addition (>95%) was observed for the both DEs. Through the use of varying amounts of HFP in
the reaction mixture as described above, each of the eight possible phosphoramidite oligonucleotide
building blocks (DE-1/DE-2, cis/trans, R/S) of the BcPh DE N2-dGuo adducts can be prepared in an
efficient fashion. To rationalize the varying cis-to-trans ratio, we propose that the addition of 3 to
1 or 2 in the absence of solvent or in the presence of small amounts of HFP proceeds primarily via
an SN2 mechanism to produce mainly trans-opened adducts. In contrast, increasing amounts of
HFP promote increased participation of an SN1 mechanism involving a relatively stable carbocation
with two possible conformations. One of these conformations reacts with 3 to give mostly trans
adduct, while the other conformation reacts with 3 to give mostly cis adduct.