Structural studies of organosulfur compounds. 3. Stereochemistry and conformational distortions in trans-hexahydro-1,4-benzoxathiane S-oxides

Nucleoside analogs involving modifications in the carbohydrate ring: nuclear magnetic resonance spectroscopic studies

“…Examination of the spectra of 13 and l a shows that the H-2' signal in the spectrum of l a is shifted downfield by 0.5 ppm relative to the corresponding signal in the spectrum of the sulfide 13. This deshielding has been ascribed to electric-field effects and (or) the acetylene-like anisotropy of the S=O bond, and is consistent with a syn-axial relationship of H-2' to the sulfinyl group (4)(5)(6)(7). This assignment is supported by the observed value for (J2'.3' + J2,,3") which suggests a preponderance of the conformation in which the purine moiety is equatorially oriented.…”

“…The TABLE 1. Carbon-13 chemical-shift data" for saturated-ring carbons in 6-chloropurin-9-yl derivatives of I-oxa-4-thiacyclohexane and I -oxa-4-thiacyclohexane I -oxide oxides relative to those in the corresponding sulfides is associated with an axial disposition of the sulfinyl oxygen in the sulfoxides (2a, 2b, [7][8][9]. The I3C nmr data for 2a are consistent, therefore, with the preponderance of a conformation in which the sulfinyl group is axially disposed, and compound 2a is identified as being cis-6-chloro-9-(l-oxa-4-oxo-4-thiacyclohexan-3-y1)-9H-purine (see Fig.…”

“…The lesser shielding of C-2' and C-6' in 2b as compared to that in 2a (relative to C-2' and C-6' in 14) can be taken as evidence for a lesser proportion of the conformation in which the sulfinyl group is axial in the former case. It should be noted that the equatorial disposition of the sulfinyl group in six-membered, cyclic sulfoxides also results in shielding of the P-carbons relative to those in the parent sulfides, although the magnitude of the shielding is considerably smaller than that observed in the corresponding systems having axially-disposed sulfinyl groups (7)(8)(9). It is not clear whether this is yet another example of shielding as a result of a y-anti substituent effect (10,11).…”

Novel Sulfur-Containing Rapamycin Analogs Prepared by Precursor-Directed Biosynthesis

“…The stereochemistry of the sulfoxide moiety can also be inferred from the NMR data. The large upfield shift for C21 in combination with the observed deshielding of the axial proton H21 (δ 2.31 ppm), relative to H5 axial in 6 (δ 1.52 ppm), support the assignment of the more stable pseudoaxial β-sulfoxide. ,

5 Comparison of idealized chair conformations of the thiazane ring of 6 (left) and 3 (right) illustrating the pseudoaxial sulfoxide configuration based upon the downfield shift of the axial H21 proton chemical shift.

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“…The large upfield shift for C21 in combination with the observed deshielding of the axial proton H21 (δ 2.31 ppm), relative to H5 axial in 6 (δ 1.52 ppm), 24 support the assignment of the more stable pseudoaxial β-sulfoxide. 25,26 The biological activities of rapamycin are dependent upon the binding of rapamycin to FKBP12 and further binding of this complex to the target-of-rapamycin protein, mTOR. 27 It has been shown previously that the pipecolate ring and its flanking region are critical for FKBP12 binding, with important hydrogen bonds involving carbonyls at C15, C16, and C23 of rapamycin.…”