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Keywords:
Appel reaction; azidolysis; cholesterol; crystal structure; Walden inversion
Abstract
Cholesterol reacts under Appel conditions (CBr4/PPh3) to give 3,5-cholestadiene (elimination) and 3β-bromocholest-5-ene (substitution with retention of configuration). Thus, the bromination of cholesterol deviates from the stereochemistry of the standard Appel mechanism due to participation of the Δ 5 π-electrons. In contrast, the subsequent azidolysis (NaN3 /DMF) of 3β-bromo-cholest-5-ene proceeds predominantly by Walden inversion (SN2) affording 3α-azidocholest-5-ene. The structures of all relevant products were revealed by X-ray single crystal structure analyses, and the NMR data are in agreement to the reported ones. In light of these findings, we herein correct the previous stereochemical assignments reported by one of us in the Beilstein J. Org. Chem. 2015, 11, 1922-1932 and the Monatsh. Chem. 2018, 149, 505-517.
Introduction
3ß-Hydroxycholest-5-ene (cholesterol) is a structural and physiologic amphipathic steroid in human and animals as well. Cholesterol is an essential component of the plasma membrane, where it acts as fluidity buffer, permeability switch, and consequently in cell signaling pathways. Physiologically, cholesterol is the substrate for the biosynthesis of steroidal hormones, vitamin D and bile acids [1.2].
Although cholesterol can adopt 256 stereoisomeric structures, biological significances were only reported for the natural com- pound (/Mí-cholesterol. 1) and its enantiomer (¿'///-cholesterol. ent-1} (Figure 1) [3]. While 1 and ent-1 are characterized by hydroxy groups in ß-position at C3. epicholesterol (epi-1} has an a-OH at C3.
Diets of animal sources like red meat, liver, milk, and butter provide the body with its daily needs of cholesterol. In addition, hepatocyctes synthesize cholesterol through the mevalonate pathway. Dietary cholesterol is absorbed into the blood stream through a specific membrane bound protein named NiemannPick Cl-Like 1 (NPC1L1) on the gastrointestinal tract epithelial cells as well as in hepatocytes. As hydrophobic molecule, it circulates in the blood stream engulfed in carrier lipoproteins of two types, high density lipoproteins (HDD or good proteins and low-density lipoproteins (LDL) or bad proteins [4.5].
People with a total blood cholesterol over 125-200 mg/dL are considered hypercholesterimic. They are under high risk of cholelithiasis (formation of gallstones), atherosclerosis, heart attack, stroke, peripheral artery disease, and cancer [4.5]. Synergistic cholesterol lowering medications are inhibitors of cholesterol absorption (ezetimibe) and cholesterol biosynthesis (statins ). However, the side effects of these drugs are controversial. Therefore,...