Nucleic Acids in Chemistry and Biology

3.2 CHEMISTRY OF ESTERS AND ANHYDRIDES OF PHOSPHORUS OXYACIDS

3.2.1 Phosphate Esters

The predominant forms of phosphorus in biology are orthophosphoric acid (HO) 3 P^ O, its esters, anhydrides
and some amides. Orthophosphates are tetra-substituted at phosphorus, which is in the P(V) oxidation state
and has tetrahedral geometry. The bonding can be described by using sp^3 hybrid orbitals at phosphorus for
the ‘single’ P O bonds, which are
1.6 Å long. In triesters the P O ‘double’ bond is shorter,
1.46 Å, and
involves additional -bonding from d–poverlap between the phosphorus and oxygen (Figure 3.40).
Phosphorus can participate in such bonding simultaneously to more than one oxygen ligand and so any neg-
ative charge is delocalized across all unsubstituted oxygen atoms (Figure 3.41). The corresponding -bonding
to neutral nitrogen ligands in phosphoramidates is rather weak, so the nitrogen remains moderately basic.

3.2.1.1 Phosphate Triesters. Triesters have all three hydrogen atoms of phosphoric acid replaced by

alkyl or aryl groups. They are non-ionic, soluble in many organic solvents, and sufficiently stable to be
purified by chromatography. The P^ O bond is effectively transparent in the UV region and has an IR
absorption at 1280 cm^1. When all three ester groups are different, the phosphorus atom is a stereogenic
centre, as in SPmethyl ethyl phenyl phosphate (Figure 3.42a), and so optically active triesters can be made.

3.2.1.2 Phosphate Diesters. Diesters have two hydrogen atoms replaced by alkyl or aryl groups.

The remaining OH group is strongly acidic (pKa
1.5). Consequently, phosphate diesters exist as monoan-
ions at pH 2, and are usually water-soluble. The negative charge is shared equally between the two
unsubstituted oxygen atoms (Figure 3.42b). When the two ester groups are different, the two unsubstituted

100 Chapter 3

HO O

HO OMe

N

NH

N

N

O

NH 2

HO O

HO OH

N

N

N

N

Cl

NH 2

O

HO N

HO OMe

N

N

N NH 2

HO O

HO OMe

N

N

NH 2

O O

AcO

AcO OMe

N

N

NHAc

O

HO O

HO OMe

N

N

N

N

Cl

NH 2

(i) (ii),(iii)

65% (+ 15% 2',3' bis-methylated)

(iv) (v)

Figure 3.38 Syntheses of 2-OMe modified purine nucleosides. Reagents: (i) Ac 2 O, DMF, pyridine; (ii) N^6 -
benzoyladenine, bistrimethylsilyl acetamide, TMSOTf, CH 3 CN, heat; (iii) NH 3 / MeOH; (iv) MeI, NaH,
DMF, 20°C; and (v) 1,4-diazabicyclo[2.2.2]octane (DABCO)/water, heat

HO O

HO OH

B

RO O

AcO

Br

B

RO O

Br

OAc

B

O

Me O Me

Me

O

HO O

B

HO O

B

(i)

B = Ade, Cyt, Gua, Ura, purine & 7-deazapurine

analogues R =

and/ or acyl groups

derived from α-acetoxyisobutyryl bromide

(ii), (iii) (iv)

2',3'-didehydro-

2',3'-dideoxyribonucleosides

+

2',3'-dideoxyribo-

nucleosides

Figure 3.39 Syntheses of 2,3-didehydro-2,3-dideoxyribonucleosides and 2,3-dideoxyribonucleosides. Reagents:
(i) Me 2 C(OAc)COBr in CH 3 CN/H 2 O; (ii) Zn-Cu/DMF or Zn/HOAc/DMF; (iii) NH 3 / MeOH; and (iv) H 2 ,
Pd-C in EtOH

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