Search

The diastereoselectivities and rates of epoxidation (upon treatment with Cl3CCO2H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn2), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

2-Azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. Compound 12 crystallizes in the monoclinic space group P2 1 /n with cell parameters of a = 13.7059(2) A, b = 10.8861(2) A, c = 13.8675(3) A, β = 117.2365(10)°, V = 1839.67(6) A3 and Z = 4. Compound 14 crystallizes in the orthorhombic space group Pcab with cell parameters of a = 9.9508(1) A, b = 10.9839(2) A, c = 24.7035(4) A, V = 2700.06(7) A3 and Z = 8. Compound 16 crystallizes in the triclinic space group $$\text{P}\bar{\it{1}}$$ with cell parameters of a = 10.9511(3) A, b = 11.3148(3) A, c = 15.9545(5) A, α = 86.3487(11)°, β = 87.4723(11)°, γ = 89.3398(10)°, V = 1970.91(10) A3 and Z = 4. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed their conformations, which gave valuable information into the regioselectivity of epoxide ring-opening during their formation. Three 2-azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed valuable conformational data which was used to rationalise the regioselectivity of epoxide ring-opening during their formation.

Diastereoselective syntheses of dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 have been achieved from N-protected 4-aminocyclohex-2-en-1-ols via two complementary procedures for epoxidation as the key step. Treatment of either trans- or cis-4-N-benzylaminocyclohex-2-en-1-ol with Cl3CCO2H and then m-chloroperoxybenzoic acid (m-CPBA) resulted in initial formation of the corresponding ammonium species, followed by epoxidation on the face syn to the ammonium moiety exclusively; chemoselective N-benzylation then provided either (1RS,2SR,3RS,4RS)- or (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. Treatment of either trans- or cis-4-N,N-dibenzylaminocyclohex-2-en-1-ol with m-CPBA resulted in initial formation of the corresponding N-oxide, followed by epoxidation on the face syn to the hydroxyl group exclusively; reduction then provided either (1RS,2RS,3SR,4RS)- or an alternative route to (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. In all cases, S(N)2-type ring opening of these epoxides upon treatment with aqueous H2SO4 proceeded by nucleophilic attack with inversion at C(2) preferentially, distal to the in situ formed ammonium moiety. Hydrogenolytic N-deprotection then gave the corresponding dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.

The ammonium-directed olefinic epoxidations of a range of differentially N-substituted cyclic allylic and homoallylic amines (derived from cyclopentene, cyclohexene, and cycloheptene) have been investigated, and the reaction kinetics have been analyzed. The results of these studies suggest that both the ring size and the identity of the substituents on nitrogen are important in determining both the overall rate and the stereochemical outcome of the epoxidation reaction. In general, secondary amines or tertiary amines with nonsterically demanding substituents on nitrogen are superior to tertiary amines with sterically demanding substituents on nitrogen in their ability to promote the oxidation reaction. Furthermore, in all cases examined, the ability of the (in situ formed) ammonium substituent to direct the stereochemical course of the epoxidation reaction is either comparable or superior to that of the analogous hydroxyl substituent. Much slower rates of ring-opening of the intermediate epoxides are observed in cyclopentene-derived and cycloheptene-derived allylic amines as compared with their cyclohexene-derived allylic and homoallylic amine counterparts, allowing for isolation of these intermediates in both of the former cases.

N-Substituted trans-4-aminocyclohex-2-en-1-ols undergo epoxidation upon treatment with Cl3CCO2H followed by meta-chloroperbenzoic acid (m-CPBA) via competitive pathways resulting from hydrogen-bonding delivery by both the hydroxy group and the in situ formed ammonium ion. The absence of epoxide ring-opening in these reactions renders these substrates a unique platform for analysing the effect of the two competing directing groups on the rate of the epoxidation reaction: the diastereoisomeric ratio of the epoxide products is also the ratio of the rate constants describing the competing epoxidation processes (the group with the higher directing ability dominating the stereochemical course of the reaction). Analysis of the diastereoisomeric epoxide mixtures obtained from these reactions allowed the following order of directing group ability to be defined: NHBn >> NMeBn > OH > NBn2. The large difference in rate between the secondary and tertiary amino groups is consistent with superior directing ability of the former due to the presence of two hydrogen-bond donor sites on the secondary ammonium ion and/or an increased conformational flexibility to adopt an optimum geometry. The rate of an ammonium-directed epoxidation proceeds ~10 times slower in the presence of an allylic hydroxy group than in its absence, consistent with the presence of the additional, inductively electron-withdrawing heteroatom abating the nucleophilicity of the olefin. The relative rate of the hydroxy-directed epoxidation process in the presence of a more sterically demanding ammonium substituent is greater than that in the presence of a less sterically demanding one: this effect is attributed to an increased bias for the half-chair conformer in which the bulky ammonium substituent and, hence, the hydroxy group occupy pseudo-equatorial sites, thus allowing the latter to direct the reaction more efficiently.