K. C. Russell

Stereoselective total synthesis of topographically constrained designer amino acids: 2′, 6′-dimethyl-β-methyltyrosines

Abstract The constrained aromatic α-amino acid 2′, 6′-dimethyl-β-methyl tyrosine (Figure 1) was designed to provide specific local constraints to peptides or peptide mimetics. We report here methods for the total asymmetric synthesis of all four stereoisomers. The precursors used were α,β-unsaturated acid derivatives, (2E) 3-(4′)-methoxy-2′,6′-dimethyl-2-propenoic acid (5) and crotonyl chloride (6). In order to introduce chirality at both the α- and the β-positions of the amino acids, optically pure 4-phenyl-2-oxazolidinones (Xc) were coupled to 5 and 6. The key steps for the synthesis were: (1) a Michael type addition using either methylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex or 4-methoxy-2,6-dimethylphenylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex as nucleophiles; (2) an asymmetric bromination of the α-position of the N-acyloxazolidinones using di(n-butyl)boron triflate/DIEA/NBS as reagents at low temperature. In both cases, the stereoselectivies and yields were excellent; (3) amination was achieved in nearly quantative yield by treating the bromides with azide exchange resin via an SN2 mechanism. (Electrophilic azidation using 2,4,6-triisopropylsulfonyl azide also was achieved). The excellent stereoselectivity (80–98% ee/de) and overall yield (30–60%) made these optically pure amino acids available in amounts practical for peptide synthesis and further conformational and structure-activity relationship studies of various peptide analogues.

Linear free energy relationships in the Bergman cyclization of 4-substituted-1,2-diethynylbenzenes

Abstract A series of 4-substituted-1,2-diethylnylbenzenes were prepared ( 1a – f ) and subjected to Bergman cyclization. Bulk cyclization proceeded to produce the corresponding 2-substituted naphthalenes ( 2a – f ) in good yields (59–78%). Kinetic experiments show a linear free energy relationship between the cyclization rate and the Hammett σ m substituent coefficient and the Swain–Lupton field and resonance parameters.

Asymmetric synthesis of unusual amino acids: An enantioselective synthesis of the four isomers of D- and L-O-Methyl-2′, β-Dimethyltyrosine

Abstract The four individual isomers of D- and L-O-methyl-2′, β-dimethyltyrosines have been synthesized in high optical purity. The evidence for asymmetric induction was cofirmed by the X-ray analysis of one of the key intermediates.

Locally constrained tyrosine analogues with restricted side chain dynamics

Abstract While investigating synthetic locally constrained analogues of amino acids, we have found that a series of tyrosine analogues, such as the 2′,6′-dimethyl-β-methyl-tyrosines, exhibit restricted rotations about their CβCγ bonds which can be detected in the 1H-NMR spectra of these compounds. The dynamic properties of these tyrosine analogues and their synthetic intermediates are described in this paper. The potential use of these tyrosine analogues in the study of the roles of side chain dynamics played in peptide-receptor interactions and protein functions also is discussed.

Self-assembly of a multi-porphyrin supramolecular macrocycle by hydrogen bond molecular recognition

Three triaminotriazine units bearing two appended porphyrins undergo self-assembly through multiple hydrogen-bonding with three complementary dialkylbarbituric acids yielding a supramolecular macrocycle containing six porphyrins.

Synthesis of monocyclic medium ring lactams

Abstract The Claisen rearrangement of the vinyl substituted ketene aminals 4a-c which were generated in situ by selenoxide elimination of the aminal precursors 3a-c in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene gave the monocyclic unsaturated medium ring lactams 5a-c .

Tautomer‐Dependent Bergman Cyclization of Novel Uracil‐Enediyne Chimeras

Uracil-enediyne chimeras 4, 7, and 8 were prepared and examined for their propensity to undergo Bergman cyclization. Kinetic experiments showed lactam tautomers 7 and 8 reacted up to 25 times faster than lactim ether 4. Determination of the activation energy for each cycloaromatization reaction, along with radical trapping agent dependent studies, indicate the rate differences result from different ground state energies of the starting enediynes.

Synthesis and redox properties of novel alkynyl flavins

Abstract The synthesis of C7 and/or C8 alkynyl flavins is described. The yields range from 14–48% over six steps. The reduction potentials of these compounds are in good agreement with the values expected based on the Hammett substituent coefficients.

Synthesis of homochiral unsaturated seven-membered lactams

Abstract The Claisen rearrangement of the vinyl substituted ketene aminals 6 which were generated in situ by selenoxide elimination of the aminal precursors 5 in the presence of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) gave the homochiral unsaturated seven-membered lactams 7.

Formal synthesis of (±)-perhydrohistrionicotoxin

Abstract The syntheses of 1-benzyl-7-butyl-1-azaspirocyclo[5.5]undec-7-ene (14) [a formal precursor of perhydrohistrionicotoxin (2)] and the thermodynamically preferred, exocyclic isomer (13) in six steps from the readily available N -benzyloxycarbonyl-10-amino-Δ 1,9 -octalin (5) are reported.