Proton NMR analyses, shielding mechanisms, coupling constants, and conformations in steroids bearing halogen, hydroxy, and oxo groups and double bonds
Proton NMR analyses, shielding mechanisms, coupling constants, and conformations in steroids bearing halogen, hydroxy, and oxo groups and double bonds
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质子 NMR 分析、屏蔽机制、耦合常数以及带有卤素、羟基、氧代基团和双键的类固醇的构象
DOI：
10.1021/ja00310a046
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发表时间：
1985
影响因子：
15
通讯作者：
U. Siehl
中科院分区：
文献类型：
--
作者：
H. Schneider;U. Buchheit;N. Becker;G. Schmidt;U. Siehl
~1H-雄烷和一个孕酮类似物的~1H核磁共振分析提供了基本类固醇骨架的位移和偶合常数，以及氧、羟基和卤素基团以及5双键的取代基诱导位移(SIS)。结果表明，即使在最复杂的自旋系统中，只有1ppm的29个强耦合质子，由NOE差谱补充的单个2D实验也能得到完整的指认；通过与一些ID和计算机模拟的谱进行比较，评估了2D技术提供的信息的准确性。在最多六个同时可观察到的耦合的基础上，使用了一种特殊的方法来扫描特别灵活的部件的构象空间。对于含sp2(17-氧代)碳的D环和仅含sp3碳原子的S 10，得到了半椅子和扭曲之间的中间构象，扭转C14-C15-C16-07角为S 20‘，然而，观察到的平面轮廓也允许不同构象的混合，这得到了MM2计算的支持。对于4-3-A环，沙发构型比半椅几何形状更受欢迎。观察到的杂取代物的屏蔽效应与早期的少数观察结果部分不同，这些观察大多是基于多取代化合物。用基于力场最小化结构的SHIFT程序对经典屏蔽机制进行了评估。空间诱导屏蔽在碳氢化合物中占主导地位，导致前场位移随着1，3-二轴相互作用次数的增加而增加。线性电场效应预测了位于C-Hal键附近的赤道质子和轴向质子之间的屏蔽差异，以及观察到的C-Hal/CH键排列的脱层现象。各向异性和电场效应的组合解释了在酮中观察到的除C=0附近的质子以外的所有移位；多元线性回归分析导致Ax！C=0=-36(-27)和2=0=-24(-21)(10™3cm3/分子，括号中的旧阿西蒙值)；然而，已经证明，仅基于核磁共振位移的分析导致了广泛的参数范围。得出了~1H和~(13)C核磁共振位移之间的相似之处，特别是在y和t？C-Hal键的位置。对于现代核磁共振方法的应用，有几个方面使甾体成为一个特别吸引人的挑战：(I)这些可能是最复杂的自旋系统所要克服的技术问题；(Ii)关于化学位移、耦合常数和分子结构之间关系的大量未被发现的丰富信息；(Iii)生物活性随结构变化的变化。强磁场、计算机辅助PFT，特别是2D核磁共振波谱的组合已经被一些工作者用于类固醇的指认，其中官能团和双键的存在导致了光谱的简化。1，2试图用这些技术找到最经济的方法，我们分析了17个类固醇，包括基本骨架雄烷，它由29个不等价和强耦合的质子组成，范围仅为1ppm。光谱技术的惊人进步发现，化学家们还没有为智能消化许多新获得的数据做好准备。在Zürcher、3 Apsimon、4及其同事的经典研究之后，在核磁共振屏蔽参数的定量分析方面进展甚微，他们被迫将自己主要局限于观察类固醇中很少的时间平均甲基信号。一个非常有用的数字
The* H NMR analyses of 16 5<* H-androstanes and one progesterone analogue furnish shifts and coupling constants for thebasic steroid skeleton and substituent-induced shifts (SIS) for oxo, hydroxy, and halogen groups as well as for a 5 double bond. It is shown how a single 2D experiment complemented by a NOE difference spectrum can lead to complete assignments even with themost complicated spin systems comprising, eg, 29 strongly coupled protons within only 1 ppm; the accuracy of information from 2Dtechniques is evaluated by comparison to some ID and computer-simulated spectra. On the basis of up to six simultaneously observable couplings, a special approach is used to scan the conformational space of particularly flexible parts. Intermediate conformations between half-chair and twist are obtained with a torsional C14-C15-C16-07 angle of s 20’for the D ring with a sp2 (17-oxo) carbon and of s 10 with only sp3 carbon atoms; the observed fiat profiles, however, allow also for mixturesof different conformations, which is supported by MM2 calculations. For the 4-3-A ring, a sofa conformation is favored compared to a half-chair geometry. Theobserved shielding effects of heterosubstituents are partially at variance with the few earlier observations, which were mostly based on polysubstituted compounds. Classical shielding mechanisms were evaluated with the program shift, based on force-field-minimized structures. Steric-induced shielding dominates in the hydrocarbon, leading to upfield shifts increasing with the number of 1, 3-diaxial interactions. Linear electric-field effects predict, eg, the shielding difference between equatorial and axial protons vicinal to C-Hal bonds and the deshielding observed for diaxial C-Hal/CH bond arrangements. A combination of anisotropy and electric-field effects explains all shifts observed in the ketones with the exception of protons vicinal to C= 0; a multilinear regression analysis leads to Ax! C= 0=-36 (-27) and 2= 0=-24 (-21)(10™ 3 cm3/molecule, old ApSimon values in parentheses); it is, however, demonstrated, that an analysis on the basis of NMR shifts alone leads to broad ranges of parameters. Parallels between* H and 13C NMR shifts are drawn, particularly at y and t? positions to C-Hal bonds.Several aspects make steroids a particularly attractive challenge for the application of modern NMR methods:(i) the technical problems to be surmounted with these probably most complicated spin systems;(ii) the largely undiscovered wealth of information regarding the relation between chemical shifts, coupling constants, and molecular structure;(iii) the change of biological activity with structural variation. The combination of high magnetic fields, computer-aided PFT, and in particular 2D NMR spectroscopy has already been used by several workers for the assignments of steroids, in which the presence of functionalities and double bonds has led to spectral simplification. 1, 2 Trying to find themost economical approach with these techniques, we analyzed 17 steroids including the basic skeleton androstane, which comprises 29 nonequivalent and strongly coupled protons over a range of only 1 ppm. The spectacular progress of spectral techniques finds the chemists rather unpreparedfor the intelligent digestion of the many newly accessible data. There has been very little progress in the quantitative analysis of NMR shieldingparameters after the classical studies of Zürcher, 3 ApSimon, 4 and co-workers, who were forced to limit themselves largely to the observation of few time-averaged methyl signals in steroids. A very useful number