A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of 18a significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with 18a.
A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and -40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by S2 substitution with sodium azide and aryloxides, respectively.
Many
optically active 2-azaspirocyclic structures have frequently
been found in biologically active natural products. In particular, Nitraria alkaloids, (+)-nitramine, (+)-isonitramine, (−)-isonitramine,
and (−)-sibirine, have stereogenicity on their quaternary carbon
of the 2-azaspiro[5,5]undecane-7-ol structure. To synthesize Nitraria alkaloids, we developed a new enantioselective
synthetic method for chiral α-quaternary lactams via the α-alkylation
of α-tert-butoxycarbonyl lactams. α-Alkylation
of α-tert-butoxycarboxylactams in the circumstances
of phase-transfer catalytic (PTC) system (solid KOH, toluene, and
−40 °C) by virtue of the catalytic action of (S,S)-NAS bromide (5 mol %) furnished the
corresponding α-alkyl-α-tert-butoxycarbonyl
lactams in very high chemical (<99%) and enantioselectivity (<98%
ee). Our catalytic methodology was successfully applied for the enantioselective
total synthesis of Nitraria alkaloids. (+)-Isonitramine
was obtained in 12 steps (98% ee, 43% yield) from δ-valerolactam
through enantioselective phase-transfer catalytic allylation, Dieckmann
condensation, and diastereoselective reduction as the key reactions.
(−)-Sibirine and (+)-nitramine were prepared from (−)-isonitramine
or its intermediate. Switching the phase-transfer catalyst from (S,S)-NAS bromide to (R,R)-NAS bromide afforded (−)-isonitramine
(98% ee, 41% yield). (−)-Sibirine was synthesized by N-ethoxycarbonylation of (−)-isonitramine followed
by reduction (98% ee, 14 steps, 32% yield). Furthermore, the diastereoselective
reduction of (R)-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione
[(R)-15] followed by reductive removal
of the diphenylmethyl group successfully gave (+)-nitramine (98% ee,
11 steps, 40% yield).
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