Lessons in Strain and Stability: Enantioselective Synthesis of (+)‐[5]‐Ladderanoic Acid

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)‐[5]‐ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.     

Total synthesis of haouamine A: the indeno-tetrahydropyridine core

A full account of synthetic efforts toward the indeno-tetrahydropyridine core of haouamine A is presented. Initial failed strategies led to the unexpected discovery of a mild abnormal Chichibabin pyridine synthesis and provided knowledge and inspiration for the development of a cascade annulation that has enabled rapid and scalable access to the core in either racemic or enantiopure form.     

Unexpected Direct Synthesis of N-Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.     

Unexpected Direct Synthesis of N‐Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

The unexpected synthesis of industrially important N ‐vinyl amides directly from aldehydes and α,β‐unsaturated N ‐vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom‐efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.     

Structure and Reactivity of Late Transition Metal η3‐Benzyl Complexes

The coordination of transition metals to organic fragments can yield complexes with fascinating and unexpected binding patterns. The study of metal‐benzyl complexes has demonstrated the feasibility of η³‐coordination, which results in a dearomatized ring. These complexes also offer insight into reaction mechanisms as proposed intermediates in catalytic cycles. In this Review we discuss the synthesis and characterization of these complexes with late transition metals and the subsequent development of catalytic benzylic functionalization methods, including asymmetric variants.     

Phosphenium cations/iminophosphane reactions. Synthesis of a spiranic azadiphosphiranium cation

The unexpected synthesis of the first spiranic azadiphosphiranium cation is reported, as well as a new entry to diazadiphosphetidine systems.     

Serendipitous synthesis of a cyclic formamidine. Application to the synthesis of polyazamacrocycles

An unexpected synthesis of 4,5,6,7,8,9-hexahydro-1,3-diazonine, using hexamethylenediamine and dimethylformamide, is presented. The cyclization process was explained as a two-step process involving formylation and subsequent intramolecular condensation. The scope of this process was demonstrated through the synthesis of two other nitrogen-containing macroheterocycles.     

An enantioselective total synthesis of (+)-aigialospirol

A concise and enantioselective total synthesis of (+)-aigialospirol is described here, featuring the first complex natural product synthesis that employs a cyclic ketal-tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxyl group. The 15-step synthetic sequence illustrates the proof-of-concept that such an approach can be competitive with the classical spiroketal formation in the natural product synthesis.     

Two remarkable epimerizations imperative for the success of an asymmetric total synthesis of (+)-aigialospirol

Two remarkable epimerization processes were uncovered during our pursuit of an enantioselective synthesis of(+)-aigialospirol featuring a cyclic acetal tethered ring-closing metathesis.Through modeling,we were able to turn these two unexpected epimerizations to our advantage via modeling to ensure a successful and concise total synthesis,thereby firmly establishing cyclic acetal tethered RCM as a powerful strategy in natural product synthesis.Most importantly,calculations allowed us to fully understand the ...     

Synthesis of fused indazole ring systems and application to nigeglanine hydrobromide

The single-step synthesis of fused tricyclic pyridazino[1,2-a]indazolium ring systems is described. Structural details revealed by crystallography explain the unexpected reactivity. The method is applied to the gram scale synthesis of nigeglanine hydrobromide.     

Unexpected 5,6,7,8,9,10-hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines from Skraup-Doebner-Von Miller quinoline synthesis and their implications for the mechanism of that reaction

The real mechanism of the Skraup-Doebner-Von Miller quinoline synthesis remains controversial and not well understood despite several mechanistic studies reported on the matter. A series of unexpected and unusual 5,6,7,8,9,10-hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines have been obtained through the Skraup-Doebner-Von Miller quinoline synthesis. On the basis of these unexpected results and in agreement with some of the previously reported quinoline syntheses, an alternative mechanistic pathway is proposed for this variant of the reaction. It involves the formation of a Schiff base through a reaction between the ketone and the aniline derivative in the first step, followed by a cycloalkenylation at the ortho-position to the amine functional group of the aniline derivative, and an annulation in the final step to close the quinoline ring, leading to a dihydroquinoline derivative. To the best of our knowledge, this is the first report of such a mechanistic pathway being proposed for any variant of the Skraup-Doebner-Von Miller quinoline synthesis.     

Development of a new dimeric cyclophane ligand: application to enhanced diastereo- and enantioselectivity in the catalytic synthesis of beta-lactams

We detail the synthesis of a new C(2)-symmetric bis(cyclophane) ligand system that can be thought of as electronically analogous to binol, but which possesses the added "third dimension" of cyclophane chirality. The ligand synthesis involves a spontaneous (but unexpected) atropisomerization to the desired product. We have employed this ligand to form a metal complex that is an effective cocatalyst for the highly enantio- and diastereoselective catalytic asymmetric synthesis of a beta-lactam.     

Studies toward the synthesis of oximidines I and II

The synthesis of compound 1, a precursor for the synthesis of the oximidine II core structure 2, is described. An undesired C8-C9 isomerization occurred during the intramolecular Castro-Stephens reaction leading to macrocyle 3. The thermodynamic driving force for this unexpected isomerization was established by DFT and MP2 calculations. [reaction: see text]     

Synthesis of the glucuronide metabolite of ABT-751

A linear synthesis of the glucuronide metabolite of ABT-751 was replaced with a convergent synthesis that features direct glycosidic coupling between the aglycone and a trichloroacetimidate glucuronyl donor. Structural elucidation of a unique and unexpected difluoroboron complex of the desired glycosidic coupling product along with optimization of the synthetic steps is described.     

Synthesis of polyhydroxylated α-nitrocyclohexane carboxylic acids derived from d-glucose: a striking case of racemization

The first total synthesis of polyhydroxylated α-nitrocyclohexane carboxylic acids from sugars is reported. A salient aspect of the synthesis is an unexpected Henry-mediated racemization of this new class of highly functionalized cyclohexanes.     

Unexpected Reaction of Oximinoacetoacetate with Amines: A Novel Synthesis of Carbamates

The synthesis of alkyl carbamates by a solvent-free reaction of oximinoacetoacetate and amine at 130°C is reported. A preliminary mechanism to this unexpected reaction is also given.     

Ring opening of 1,3,2-oxazaphospholidine-2-thiones with alkyl lithiums; synthesis of chiral phosphinothioic acids

Chiral phosphinothioic acids are prepared by a novel synthesis involving an unexpected P  O bond cleavage with retention of configuration at phosphorus.     

Studies on the stability of the cyclobutane β-aminoacid skeleton: a cautionary tale

The 2-amino-1-cyclobutanecarboxylic acid skeleton undergoes facile retro-Mannich type ring opening in solution, which may lead to unexpected by-products during its synthesis or manipulation.     

An unexpected palladium-catalyzed reaction of 2-alkynylhalobenzene with 2-alkynylaniline: a novel and efficient route to 11H-indeno[1,2-c]quinolin-11-ols

An unexpected palladium-catalyzed cascade reaction of 2-alkynylhalobenzene with 2-alkynylaniline is reported, which provides a novel and efficient pathway for the synthesis of 11H-indeno[1,2-c]quinolin-11-ols.     

Unexpected observations during the total synthesis of calothrixin B–sodium methoxide as a source of hydride

During the total synthesis of calothrixin B, various novel and unexpected results were noticed such as cleavage of C–N bond in imine using sodium cyanoborohydride, sodium methoxide as a hydride source for reduction, deformylation in the presence of bromine, and deacylation using ceric ammonium nitrate (CAN). A detailed mechanism has been proposed for the unexpected results and a few of them are generalized. Temperature dependent NMR studies have been carried out for confirmation of the structure of one of the intermediates in the synthetic sequence.