Effects of axial tert-butyl substituents on conformations and geometries of saturated six-membered rings. Crystal and molecular structures of trans-2-methoxy-2-oxo-5-tert-butyl- and cis-2,5-di-tert-butyl-2-thio-1,3,2-dioxaphosphorinane

Abstract

T h e title compounds crystallize in the orthorhombic system, the 2-methoxy compound (I) in the space group Pnma, and the 2-tert-butyl material (11) in space group Pmcn. Lattice parameters are: (I) a = 6.123 (41, b = 10.02 ( l ) , c = 17.65 (1) A, z = 4: (11) a = 10.077 ( 3 ) , b = 10.662 (3), c = 12.703 (3) A, z = 4. Compounds I and I1 both havechair-form ring conformations with the 5-tert-butyl group axial in both. For I the methoxy on phosphorus is axial and the phosphoryl oxygen is equatorial. The 2-tert-butyl is equatorial in I1 with the thiophosphoryl sulfur axial. In comparison to the structures of a large number of other phosphoranes, these rings systems, especially 11, appear to be somewhat flattened about the C(5) end of the molecule. This apparently results from steric interactions involving the axial tert-butyl groups and the ring atoms C(4), O ( l j , and O ( 3 ) and hydrogens bonded thereto. Bond angle deformations within the 5-tert-butyl and a t its point of attachment to the ring also attest t o this fact. T h e phosphorus end of the ring associated with I1 is highly puckered. This property is shown to be a general one for lJ.2-dioxaphosphorinanes with double-bonded 0, S, or Se axial. For I1 the ring pucker is unusually large. Explanations based on nonbonded interactions of the 2-tert-butyl with ring oxygens O(1) and O ( 3 ) or across the ring with the axial <ki-tert-butyl group are suggested.The 2-oxo-and 2-thio-1,3,2-dioxaphosphorinanes are readily substituted in a variety of ways both at phosphorus and on the ring carbons. As they are generally crystalline materials, they provide attractive systems for the determination of structural information on six-membered rings by X-ray crystallographic techniques. The present study presents unambiguous knowledge of the conformations of two such compounds, trans-2-methoxy-2-oxo-5-tert-butyl-1.3,2-dioxaphosphorinane (I) and cis-2,5-di-tert-butyl-2-thio-1,3,2-dioxaphosphorinane (11). A special structural feature of these compounds is the axial orientation of the 5-tert-butyl in both I ant1 I1 in the solid phase, which provides an unusual opportunity to examine the effects on ring geometry of strain effects associated with so sterically bulky an axial substituent. Findings in the rings I and I1 are of wider interest as well, in relation to conformations of the corresponding 1,3-dioxanes (111)' and trimethylene sulfites (IL7).2 11. s = s: Z = / -H u Experimental SectionT h e preparation of the phosphate I was reported earlier,3 mp ( nhexane) 90-91 "C. Compound I1 was prepared from 2-tert-butyl-1,3-butanediol and t-Huf'iS)Cl? in ether solution a t 0-5 "C. T h e isomeric forms were separated by column chromatography on Florisil. Elution solvent WBS initially 3 O h ether in ligroin (60-90 "C). The fraction ether was gradually increased during chromatography.Compound I1 was crystallrzed from ligroin (60-90 "Cj, m p 96-97 "C (uncorrected).Both substances crystallize in an orthorhombic space group with extinctions consistent with either Pn2la or Pnma. The centric s...

Structure of Cyclic Nucleoside Phosphonate Ester Prodrugs: An Inquiry

“…However, trans -2-phenyloxy-2-oxo-5-phenyl-1,3,2-dioxaphosphorinane 30 and trans -2- methoxy-2-oxo-5- tert- butyl-1,3,2-dioxaphosphorinane 31 ( a , a ) conformers have been observed in both the solution and solid states, suggesting that in six-membered cyclic phosphates the anomeric axial preference of the PhO- or CH 3 O-ester groups can compensate for steric repulsions when a 5-phenyl or 5- tert -butyl group is axial.…”

“…1 H, 13 C, 31 P, and 2D NMRs ,, and dipole moment calculations have been previously applied to predict their absolute configurations (AC). The prodrug diastereomers of 5 (Scheme ) were distinguished as axial / equatorial depending on the stipulated position of the exocyclic aryl phosphonate ester group, with the axial isomer assigned to the upfield P NMR peak (Figure ). Conversely, phosphonate ester prodrugs of cyclic 9-( S )-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and cyclic 1-( S )-[3-hydroxy-2-(phosphonomethoxy)-propyl]-5-azacytosine were distinguished as cis / trans , with the cis isomer assigned to the downfield 31 P chemical shift (Figure ).…”

“…A key assumption underlying the axial / equatorial descriptives frequently used ,− to distinguish cyclic ( S )-HPMPC and ( S )-HPMPA diastereomeric diesters is that the nucleobase is invariably equatorial. However, trans -2-phenyloxy-2-oxo-5-phenyl-1,3,2-dioxaphosphorinane and trans -2-methoxy-2-oxo-5- tert- butyl-1,3,2-dioxaphosphorinane ( a , a ) conformers have been observed in both the solution and solid states, suggesting that in six-membered cyclic phosphates the anomeric axial preference of the PhO- or CH 3 O-ester groups can compensate for steric repulsions when a 5-phenyl or 5- tert -butyl group is axial.…”

“…It is clearly important to define the phosphorus configuration and phostonate 26 ring conformations of these prodrugs in order to understand their structure−activity relationships. 1 H, 13 C, 31 P, and 2D NMRs 2,4,6 and dipole moment calculations 3 have been previously applied to predict their absolute configurations (AC). The prodrug diastereomers of 5 (Scheme 1) were distinguished as axial/equatorial 6 depending on the stipulated position of the exocyclic aryl phosphonate ester group, with the axial isomer assigned to the upfield 31 P NMR peak (Figure 2).…”

Bond length and reactivity: structures of five dialkyl aryl phosphates: 2-phenoxy-1,3,2-dioxaphosphorinane 2-oxide, C9H11O4P, (2a); 2-(3-nitrophenoxy)-1,3,2-dioxaphosphorinane 2-oxide, C9H10NO6P, (2b); 2-(2-nitrophenoxy)-1,3,2-dioxaphosphorinane 2-oxide, C9H10NO6P, (2c); 2-(4-chloro-2-nitrophenoxy)-1,3,2-dioxaphosphorinane 2-oxide, C9H9ClNO6P, (2d); and 2-(2,4-dinitrophenoxy)-1,3,2-dioxaphosphorinane 2-oxide, C9H9N2O8P, (2e)

“…1.565 (4) A;Warrent, Caughlan, Hargis, Yee & Bentrude (1978)]. Other compounds containing the 2-aryloxy-or 2-alkyloxy-l,3,2-dioxaphosphorinane 2-oxide unit are unsuitable because of distortions induced by either additional fused rings or electron-withdrawing groups such as chlorine on the phosphorinane ring.…”