Biomedical subjects
Publications and source records attributed to Guoliang Lin.
Novel 5-X-substituted-2-azabicyclo[2.1.1]hexanes (X = 5-syn-Cl, -Br, -I, -Ph, -NHCOOR (R = Me, Bn, t-Bu), -CH2CH2COOMe and X = 5-anti-Br, -I, -Ph) were synthesized from the X = 5-syn-carboxy derivative. New 5-anti-X-2-azabicyclo[2.1.1]hexanes, X = NHCOOR (R = Me, Bn), were prepared stereoselectively from the X = 5-anti-carboxy substrate.
Improved stereocontrolled syntheses of 5-anti-hydroxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]hexanes have been effected from pyridine. The key step in the electrophilic addition-rearrangement of 2-azabicyclo[2.2.0]hex-5-ene precursors incorporates either a 3-endo-phenyl group, as an acid precursor, or a 3-endo-phenyldimethylsilylmethyl group, as a potential hydroxymethyl and acid precursor.
Among the proteinogenic amino acids, only proline is a secondary amine and only proline has a saturated ring. Electronegative substituents on C-4 (that is, C(gamma)) have a substantial effect on the trans/cis ratio of the prolyl peptide bond and the pucker of the pyrrolidine ring. 2-Azabicyclo[2.1.1]hexane is, in essence, a proline analogue with two C(gamma) atoms, one in each of the two prevalent ring puckers of proline. Here, 2-azabicyclo[2.1.1]hexane analogues of 2S-proline, (2S,4S)-4-hydroxyproline, and (2S,4S)-4-fluoroproline residues were synthesized, and their trans/cis ratios were shown to be invariant in a particular solvent. Thus, the substitution of a proline residue on C-4 affects the trans/cis ratio by altering the pucker of its pyrrolidine ring. This finding has implications for the conformation of collagen, which has an abundance of 2S-proline and (2S,4R)-4-hydroxyproline residues, and can be stabilized by (2S,4R)-4-fluoroproline and (2S,4S)-4-fluoroproline residues.
Stereoselective syntheses of novel 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing 5-anti-fluoro or hydroxyl in one methano bridge and a variety of syn- or anti-chloro, fluoro, hydroxy, methyl, or phenyl substituents in the other methano bridge have been effected. Rearrangements of iodides to alcohols were initiated using Selectfluor. Rearrangement of alcohols to fluorides was initiated using Deoxo-Fluor. Ring opening of 2-azabicyclo[2.2.0]hex-5-ene exo-epoxide with organocopper reagents is regioselective at C(5).
An efficient four-step synthesis of N-BOC-5-syn- and 5-anti-carboxymethanopyrrolidines (12 and 13) and the conversion of 12 to N-BOC-methanopyrrolidine (2) are described.
[reaction: see text] The first syntheses of 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing syn-hydroxy and syn-fluoro substituents have been effected in a stereocontrolled manner. The key reactions are regioselective additions to the aziridinium ions formed from 6-exo-iodo(bromo)-5-endo-X-2-azabicyclo[2.2.0]hexanes (X = F, OH) upon silver or mercury salt enhancement of iodide nucleofugacity.
The reactions of N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 5 with halonium ion electrophiles were studied in polar and nonpolar aprotic solvents and also in protic media with the aim of controlling nitrogen neighboring group participation. Specifically, for bromonium ions nitrogen participation is facilitated by the polar aprotic solvent nitromethane and by the poorly nucleophilic protic solvent acetic acid. Alkene 5b and bromine/nitromethane afford only the rearranged anti,anti-5,6-dibromo-2-azabicyclo[2.1.1]hexane 6b, and NBS/acetic acid gives an 8:1 mixture favoring rearranged 5-bromo-6-acetate 6f. Conversely, pyridinium bromide perbromide/CH(2)Cl(2) is selective for only unrearranged 5,6-dibromide 7. Iodonium and phenylselenonium ions react with alkenes 5 to give only unrearranged 1,2-addition products 9 and 10, regardless of solvent. Chloronium and fluoronium ions react with alkenes 5 to give 4-aminomethyl-3-hydroxycyclobutene 11, derived by ring cleavage.
Addition of the uniparticulate electrophile chlorosulfonyl isocyanate to the nitrogen atom of N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 1 is followed by ring cleavage and recombination. The parent 4-methyl, 5-methyl, 5-bromo, and 5-phenyl azabicycles 1a-f afforded novel 2,4-diaza-3-oxo-bicyclo[4.2.0]oct-7-enes 10a-f. The 3-endo-phenyl azabicycle 1g rearranged to a 6-styryl-1,3-diaza-2-oxo-cyclohex-4-ene 12.
[reaction: see text] Azabicycle 4 and sec-butyllithium/TMEDA afford the C(1) bridgehead alpha-lithio anion at 0 degrees C. Anion quenching with carbon dioxide, methyl chloroformate, or DMF provide the bridgehead acid 8a (N-BOC-2,4-methanoproline), ester 8b, or aldehyde 8c, respectively. By contrast, at -78 degrees C these same reagents give a mixture of regioisomeric methylene and bridgehead anions whose quenching leads to mixtures of regioisomeric methylene and bridgehead acids 6a/8a, esters 6b/8b, or aldehydes 6c/8c, respectively. The previously unknown 3,5-methanoproline was prepared as its N-BOC methyl ester 6b.
The stereocontrolled synthesis of a functionalized 3-hydroxymethyl-2-azabicyclo[2.1.1]hexane synthon for a variety of methano-bridged pyrrolidines has been effected. The key step in an electrophilic addition-rearrangement route uses a 3-nosyloxymethyl group in the 2-azabicyclo[2.2.0]hex-5-ene precursor in order to suppress unwanted competitive oxygen neighboring group participation. [reaction: see text]