150407-67-3Relevant academic research and scientific papers
Efficient Synthesis of an Indinavir Precursor from Biomass-Derived (-)-Levoglucosenone
Ledingham, Edward T.,Stockton, Kieran P.,Greatrex, Ben W.
, p. 1146 - 1150 (2017)
Lignocellulosic biomass pyrolysis with acid catalysis selectively produces the useful chiral synthon 6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one ((-)-levoglucosenone, LGO). In this report, LGO was used to prepare (3R,5S)-3-benzyl-5-(hydroxymethyl)-4,5-dihydrofuran-2(3H)-one, which is an intermediate used in the construction of antivirals including the protease inhibitor indinavir. To achieve the synthesis, the hydrogenated derivative of LGO was functionalised using aldol chemistry and various aromatic aldehydes were used to show the scope of the reaction. Choice of base affected reaction times and the best yields were obtained using 1,1,3,3-tetramethylguanidine. Hydrogenation of the α-benzylidene-substituted bicyclic system afforded a 4:3 equatorial/axial mixture of isomers, which was equilibrated to a 97:3 mixture under basic conditions. Subsequent Baeyer-Villiger reaction afforded the target lactone in 57% overall yield for four steps, a route that avoids the protection and strong base required in the traditional approach. The aldol route is contrasted with the α-alkylation and a Baylis-Hillman approach that also both start with LGO.
RETROVIRAL PROTEASE INHIBITING PIPERAZINE COMPOUNDS
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, (2008/06/13)
Retroviral protease inhibiting compounds of the formula: STR1 are disclosed.
Amino acids, XV: Synthesis of enantiopure DAVA-derivatives (5-amino-4-hydroxypentanoic acids) from (S)-glutamic acid
Herdeis,Lutsch,Waibel
, p. 41 - 47 (2007/10/02)
Starting from (S)-glutamic acid the readily available hydroxymethyl lactone 1 is protected as the TBDPS ether 2. Alkylation of the lithium enolate of 2 provides the lactones 3a,b with high diastereomeric excess. On the other hand 1,4 addition of Gilman cuprates to 10 furnishes the alcohols 12a,b after deprotection. Transformation of 4,12 via the mesylates 5,13 and the azides 6,14 affords the Boc protected amines 7,15 after catalytic hydrogenation in the presence of Boc2O. After treatment of 7,15 with methanolic HCl the rings of the crystalline hydrochlorides 8,16 are opened to the DAVA-derivatives (δ-aminovaleric acid derivatives) 9,17.
L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor
Dorsey,Levin,McDaniel,Vacca,Guare,Darke,Zugay,Emini,Schleif,Quintero,Lin,Chen -,Holloway,Fitzgerald,Axel,Ostovic,Anderson,Huff
, p. 3443 - 3451 (2007/10/02)
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with K(i) values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1(IIIb)-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.
