Synthesis of 5-fluoro- and 5-hydroxymethanoprolines via lithiation of N-BOC-methanopyrrolidines. Constrained Cγ-exo and Cγ-endo Flp and Hyp conformer mimics.

Proline derivatives with a C(γ)-exo pucker typically display a high amide bond trans/cis (K(T/C)) ratio. This pucker enhances n→π* overlap of the amide oxygen and ester carbonyl carbon, which favors a trans amide bond. If there were no difference in n→π* interaction between the ring puckers, then the correlation between ring pucker and K(T/C) might be broken. To explore this possibility, proline conformations were constrained using a methylene bridge. We synthesized discrete gauche and anti 5-fluoro- and 5-hydroxy-N-acetylmethanoproline methyl esters from 3-syn and 3-anti fluoro- and hydroxymethanopyrrolidines using directed α-metalation to introduce the α-ester group. NBO calculations reveal minimal n→π* orbital interactions, so contributions from other forces might be of greater importance in determining K(T/C) for the methanoprolines. Consistent with this hypothesis, greater trans amide preferences were found in CDCl(3) for anti isomers en-MetFlp and en-MetHyp (72-78% trans) than for the syn stereoisomers ex-MetFlp and ex-MetHyp (54-67% trans). These, and other, K(T/C) results that we report here indicate how substituents on proline analogues can affect amide preferences by pathways other than ring puckering and n→π* overlap and suggest that caution should be exercised in assigning enhanced pyrrolidine C(γ)-exo ring puckering based solely on enhanced trans amide preference.

Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche- and anti-3-fluoro- and 3-hydroxypyrrolidines.

N-acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C(ß)-gauche and C(ß)-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K(T/C) values of N-acetylamide conformers in both CDCl(3) (43-54% trans) and D(2)O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl(3) (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D(2)O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K(T/C) results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

Oligomers of a 5-carboxy-methanopyrrolidine ß-amino acid. A search for order.

CD spectra for homooligomers (n = 4, 6, 8) of (1S,4R,5R)-5-syn-carboxy-2-azabicyclo[2.1.1]hexane (MPCA), a methano-bridged pyrrolidine ß-carboxylic acid, suggest an ordered secondary structure. Even in the absence of internal hydrogen bonding, solution NMR, X-ray, and in silico analyses of the tetramer are indicative of conformations with trans-amides and C(5)-amide-carbonyls oriented toward the C(4) bridgehead. This highly constrained ß-amino acid could prove useful in the ongoing development of well-defined foldamers.

5(6)-anti-Substituted-2-azabicyclo[2.1.1]hexanes: a nucleophilic displacement route.

Nucleophilic displacements of 5(6)-anti-bromo substituents in 2-azabicyclo[2.1.1]hexanes (methanopyrrolidines) have been accomplished. These displacements have produced 5-anti-X-6-anti-Y-difunctionalized-2-azabicyclo[2.1.1]hexanes containing bromo, fluoro, acetoxy, hydroxy, azido, imidazole, thiophenyl, and iodo substituents. Such displacements of anti-bromide ions require an amine nitrogen and are a function of the solvent and the choice of metal salt. Reaction rates were faster and product yields were higher in DMSO when compared to DMF and with CsOAc compared to NaOAc. Sodium or lithium salts gave products, except with NaF, where silver fluoride in nitromethane was best for substitution by fluoride. The presence of electron-withdrawing F, OAc, N(3), Br, or SPh substituents in the 6-anti-position slows bromide displacements at the 5-anti-position.

Neighboring group participation in the additions of iodonium and bromonium ions to N-alkoxycarbonyl-2-azabicyclo[2.2.n]alk-5-enes (n = 1,2).

Additions of iodonium-X reagents to N-alkoxycarbonyl-2-azabicyclo[2.2.1]hept-5-enes and the homologous 2-azabicyclo[2.2.2]oct-5-enes have been found to mirror the outcomes of additions of bromonium-X reagents. Only rearranged products were observed for reactions of either of these halonium ion reagents with the azabicylo[2.2.1]hept-5-enes. For the azabicyclo[2.2.2]oct-5-enes, nitrogen participation in addition of IOH or BrOH was dependent on the N-alkoxycarbonyl group. With larger N-Boc, N-Cbz, or N-Troc protecting groups, unrearranged 5-anti-hydroxy-6-syn-I(or Br)-2-azabicyclo[2.2.2]octanes were formed by nucleophilic attack at C(5) on syn-halonium ions. The structure of N-methyl-8-anti-bromo-4-anti-hydroxy-2-azabicyclo[3.2.1]octane has been reassigned by X-ray analysis.

Selectfluor as a nucleofuge in the reactions of azabicyclo[n.2.1]alkane beta-halocarbamic acid esters (n = 2,3).

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.

The first steps. The attack on the carbonyl carbon of pyridoxal cofactor in pyridoxal-dependent enzymes.

A study of the reaction between gaseous aldehydes and amines has implicated proton transfer from wall-associated water. Carbinolamine formation and subsequent dehydration to imine with assistance by wall associated hydroxyl bearing species has not previously been specifically suggested to obtain in the multitude of enzyme processes using pyridoxal cofactor. However, the data now available make it clear that imine formation in the active site of those systems requires at least one water or hydroxyl bearing amino acid for proton transfer.

On the surface-catalyzed reaction between the gases 2,2-dimethylpropanal and methanamine. formation of active-site imines.

The reaction that occurs when vapors of 2,2-dimethylpropanal and methanamine are allowed to mix in an infrared gas cell has been examined. The disappearance of starting materials and formation of E-imine product, monitored simultaneously, is best fit by a process involving wall-associated water. The same or closely related processes have been successfully modeled; such processes may also be common to pyridoxal-catalyzed transamination and related reactions in biological systems.

Second-chance rearrangement route to novel 5(6)-syn,anti-difunctional 2-azabicyclo[2.1.1]hexanes.

[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 rearrangement route to 2-azabicyclo[2.1.1]hexanes. Solvent and electrophile control of neighboring group participation.

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.

Complex-induced proximity effects. Temperature-dependent regiochemical diversity in lithiation-electrophilic substitution reactions of N-BOC-2-azabicyclo[2.1.1]hexane. 2,4- and 3,5-methanoprolines.

[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 rearrangement route to 3-CH(2)X-2-azabicyclo[2.1.1]hexanes. Substituent control of neighboring group participation.

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]