1.Synthesis and conformational analysis of bicyclic extended dipeptide surrogates.
Ranatunga S1, Liyanage W, Del Valle JR. J Org Chem. 2010 Aug 6;75(15):5113-25. doi: 10.1021/jo1008433.
Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel extended dipeptide surrogates. Bicyclic carbamate 9 and fused beta-lactam scaffold 11 were prepared from L-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipeptide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal dipeptide distances indicate that compounds (alpha'S)-14b and 21 approximate the conformation of dipeptides found in beta-sheets, while tripeptide mimic 28 is also highly extended in the solid state.
2.Mechanism and optimisation of the homoboroproline bifunctional catalytic asymmetric aldol reaction: Lewis acid tuning through in situ esterification.
Georgiou I1, Whiting A. Org Biomol Chem. 2012 Mar 28;10(12):2422-30. doi: 10.1039/c2ob06872a. Epub 2012 Feb 10.
The use of homoboroproline as a bifunctional catalyst in the asymmetric aldol reaction has been investigated mechanistically, particularly with respect to tuning the Lewis acidity of boron by in situ esterification with mildly sigma-electron withdrawing diols such as hydrobenzoin and tartrate esters. The stability of simple cyclohexyl and cyclopentyl boronate diol esters shows that the 5-ring boronate esters are more stable, which sheds light on the mode of action of esterified homoboroproline catalyst in the enamine-mediated aldol reaction, which is also studied by NMR. The result is reaction optimisation to provide an efficient aldol reaction and a proposed mechanistic proposal.
3.Synthesis of 4-hydroxy-β3-homoprolines and their insertion in α/β/α-tripeptides.
Cordero FM1, Vurchio C, Lumini M, Brandi A. Amino Acids. 2013 Feb;44(2):769-80. doi: 10.1007/s00726-012-1401-0. Epub 2012 Sep 28.
The stereoselective syntheses of 2-cyclopropyl- and (2S)-2-hydroxymethyl-(3R,4S)-4-hydroxy-β(3)-homoproline are described. The reported amino acids were constructed through 1,3-dipolar cycloaddition of strained alkylidenecyclopropanes with enantiopure pyrroline N-oxides derived from malic acid followed by thermal rearrangement of the adducts in the presence of trifluoroacetic acid. The two-step sequence afforded the homoprolines suitably protected to be directly used as building blocks in peptidomimetic synthesis as proved by the synthesis of the two model mixed α/β/α tripeptides Phe-β(3)-HPro-Val.
4.Diastereodivergent Synthesis of Fluorinated Cyclic β(3)-Amino Acid Derivatives.
Aparici I1, Guerola M1, Dialer C1, Simón-Fuentes A1, Sánchez-Roselló M1,2, del Pozo C1, Fustero S1,2. Org Lett. 2015 Nov 6;17(21):5412-5. doi: 10.1021/acs.orglett.5b02759. Epub 2015 Oct 20.
The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions.