Enantioselective Synthesis of (R)-Sitagliptin via Phase-Transfer Catalytic aza-Michael Addition.

The highly enantioselective synthesis of (R)-sitagliptin has been achieved through a series of key steps, including the aza-Michael addition and Baeyer-Villiger oxidation. The enantioselective aza-Michael addition involved the reaction of tert-butyl ß-naphthylmethoxycarbamate with (E)-1-(4-methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one, utilizing a quinine-derived C(9)-urea ammonium catalyst under phase-transfer catalytic conditions. The aza-Michael addition successfully introduced chirality to the amine in (R)-sitagliptin with 96% ee. The subsequent Baeyer-Villiger oxidation of the aza-Michael adduct led to the formation of 4-methoxyphenyl ester. Hydrolysis and amide coupling were then employed to construct the amide moiety. Further deprotections were performed to complete the synthesis of (R)-sitagliptin (7 steps, 41%, 96% ee).

Synthesis of chiral malonates by α-alkylation of 2,2-diphenylethyl tert-butyl malonates via enantioselective phase-transfer catalysis.

An efficient synthetic approach for chiral malonates was established via enantioselective phase transfer catalysis. The α-alkylation of 2,2-diphenylethyl tert-butyl α-methylmalonates with (S,S)-3,4,5-trifluorophenyl-NAS bromide as a phase-transfer catalyst under phase-transfer catalytic conditions successfully produced corresponding α-methyl-α-alkylmalonates; these compounds are versatile chiral building blocks containing a quaternary carbon center in high chemical yields (up to 99%) with excellent enantioselectivities (up to 98% ee). α,α-Dialkylmalonates were selectively hydrolyzed to the corresponding chiral malonic monoacids under basic (KOH/MeOH) and acidic conditions (TFA/CH2Cl2), showing the practicality of the method.

Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols.

The highly enantioselective aza-Michael reaction of tert-butyl ß-naphthylmethoxycarbamate to cyclic enones has been accomplished by using a new cinchona alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions with up to 98% ee at 0 °C. The resulting aza-Michael adducts can be converted to versatile intermediates by selective deprotection and the cyclic 1,3-aminoalcohols by diastereoselective reduction with up to 32:1, which have been widely used as important pharmacophores in pharmaceutical development.

Enantioselective Total Synthesis of Nitraria Alkaloids: (+)-Nitramine, (+)-Isonitramine, (-)-Isonitramine, and (-)-Sibirine via Asymmetric Phase-Transfer Catalytic α-Allylations of α-Carboxylactams.

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).

Enantioselective Synthesis of (+)-Coerulescine by a Phase-Transfer Catalytic Allylation of Diphenylmethyl tert-Butyl α-(2-Nitrophenyl)Malonate.

A 7-step enantioselective synthetic method for preparing (S)(+)-coerulescine is reported through the use of diphenylmethyl tert-butyl α-(2-nitrophenyl)malonate (16% overall yield, >99% ee). Allylation is the key step under phase-transfer catalytic conditions (86% ee). This synthetic method can be used as a practical route for the synthesis of various derivatives of (S)(+)-coerulescine for analyzing its structure-activity relationships against its biological activities.

Discovery of BR102375, a new class of non-TZD PPARγ full agonist for the treatment of type 2 diabetes.

As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead, closely resembled to those of TZD full agonists.

Identification of BR101549 as a lead candidate of non-TZD PPARγ agonist for the treatment of type 2 diabetes: Proof-of-concept evaluation and SAR.

The new class of PPARgamma non-TZD agonist originally derived from the backbone of anti-hypertensive Fimasartan, BR101549, was identified as a potential lead for anti-diabetic drug development. The X-ray crystallography of BR101549 with PPARgamma ligand binding domain (LBD) revealed unique binding characteristics versus traditional TZD full agonists. The lead candidate, BR101549, has been found activating PPARgamma to the level of Pioglitazone in vitro and indeed has demonstrated its effects on blood glucose control in mouse proof-of-concept evaluation. The attempts to improve its metabolic stability profile through follow-up SAR including deuterium incorporation have been also described.

Discovery of the bifunctional modulator of angiotensin II type 1 receptor (AT1R) and PPARγ derived from the AT1R antagonist, Fimasartan.

Inspired by the well-known PPARγ partial agonism of angiotensin II type 1 receptor (AT1R) antagonists exemplified by an antihypertensive drug, Telmisartan, efforts to identify compounds with the dual activities have been pursued in order to control the two major metabolic disorders, hypertension and hyperglycemia simultaneously. Lead compound 18 derived from the AT1R antagonist, Fimasartan, has successfully presented the possibility to control the medical conditions by a single molecule.

Enantioselective Synthesis of Chiral α-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed α-Alkylation of α-Acylthiomalonates.

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 °C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding α-acylthio-α-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee).

Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors.

Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor.

Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis.

Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 µM).