This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: Through stepwise changes in the size of the nitrogen bearing ring.Through the oxidation state of the carbon centered point of diversification.Through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic.Through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp3 carbon content which is essential for the three dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e. the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to “split the difference” between the two diastereomers by preparation of their corresponding unsaturated version.

This communication extends the scope of the rhodium(I)-catalyzed allenic Alder-ene carbocyclization reaction to the preparation of δ-and ε-lactams from amides. A variety of allenic propiolamides were cycloisomerized to give a number of unsaturated δ-lactams. In addition, allenic propargylamides give good yields of the corresponding ε-lactams. Formation of lactams possessing these ring sizes has rarely been accomplished via transition-metal catalyzed carboncarbon bond forming strategies. Thus, this approach provides an alternative strategy for synthesizing these substructures.Discovery of new and biologically significant compounds from nature provides a remarkable collection of structurally complex targets. Thus, there is a continual need for the development of new, more robust strategies for stitching atoms together. Expanding the synthetic toolbox to include under-utilized functional groups can serve as a springboard for these investigations. Our group is involved in examining transition metal catalyzed reactions of allenes, and these investigations have led to useful arrays of functionality via novel cyclocarbonylation and carbocyclization reactions. For example, we have previously demonstrated that the Rh(I)-catalyzed Alder-ene carbocyclization process affords crossconjugated trienes in high yields and is tolerant of a wide array of functionality. 1 Moreover, the resulting trienes can be used in a variety of ways, including tandem transition metal catalyzed carbon-carbon bond forming reactions 2 and DOS strategies. 3 It was upon consideration of these triene products that inspired us to explore the formal Alder-ene reaction of alkynyl allenes possessing amide tethers as a method for preparing highly unsaturated lactams. 4 Lactams are most commonly obtained via cyclodehydration reactions of amino acids, from ketones using either the Schmidt or Beckmann rearrangement reactions or cyclization of the amide nitrogen onto an alkene, alkyne or allene. 5 It is much less common to access amides via carbon-carbon bond forming reactions. 6 There are a handful of reports demonstrating the feasibility of an amide tether in carbocyclization reactions but these protocols have been limited to the preparation of γ-lactams. 7 Moreover, the reaction conditions are not generally tolerant of an unprotected amide, which is typically attributed to a disfavored rotamer population of the amide bond. 8 We would now like to report on our kbrummon@pitt.edu. Supporting Information Available. Characterization data and full experimental procedures are provided for all compounds in Tables 1 and 2 and Schemes 1, 2 and 3. This material is available free of charge via the internet at http://pubs.acs.org. progress towards extending the scope of the allenic Alder-ene carbocyclization reaction to amides for the formation of δ-and ε-lactams. 9 NIH Public AccessAllenic amino ester 1a was prepared as a single diasteromer using a Claisen rearrangment protocol developed in the Kazmaier laboratories. 10 Allenic amino esters 1b and 1c were obta...

A two-stage synthesis of lactams in flow is described. Thus, a keto alkyl halide is displaced in a microwave-assisted, continuous flow organic synthesis format (MACOS) to generate a reactive alkyl azide. Without isolation, a flowed solution containing this azide is then combined with TFA to afford a lactam.

A Rh(I)-catalyzed carbocyclization reaction of alleneynones affords functionalized 2-alkylidene-3-vinylcyclohexenones and 2-alkylidene-3-vinylcyclopentenones. The scope, limitations, and utility of this triene-forming protocol have been examined and the results reported within.Selective and concise entry into molecular complexity via carbocyclization reactions of unsaturated carbon-carbon bonds is an important area in organometallic chemistry. 1 Recently, it was demonstrated that Rh(I)-catalyzed cycloisomerization reactions of allenes lead to trienyl-containing carbocycles, 2 heterocycles, 2 d-and e-lactams, 3 and d-lactones. 4 Combining these functional motifs with a cross-conjugated trienyl moiety provides functionally dense substructures and if chemical reactivity can be controlled, a means of gaining rapid access to molecular complexity.Using cross-conjugated trienes in complexity generating reactions requires novel approaches to controlling doublebond selectivity. 5 It was this control element that led us to consider the carbocyclization reactions of alkynones 6 because the resulting trienones would possess double bonds that are sterically biased and electronically differentiated by the carbonyl group. In this Letter we report on the assembly of the allene-ynones and their participation in Rh(I)-catalyzed carbocylization reactions to produce trienones. Selective reactions of the double bonds of the trienones were briefly investigated and also reported on.Allene-ynones 3a-j 7 were conveniently prepared by addition of the corresponding lithium acetylides 2a-j to amide 1 (Scheme 1). Compound 3k, possessing a terminal alkynone, was obtained by removal of the TMS group from 3e. 7c Subjecting allene-ynone 3e to the standard reaction protocol developed in our group for the Rh(I)-catalyzed cycloisomerization reaction {10 mol% [Rh(CO) 2 Cl] 2 , r.t.} afforded a 10% yield of 4e. Reasoning that alkynone 3e was either more reactive and/or trienone 4e less stable, the reaction was performed at 0°C using only 3 mol% of catalyst. 8 To our delight, trienone 4e was obtained in 95% yield after only five minutes at 0°C (entry 5, Table 1). Scheme 1 Formation of allenyl alkynones 3a-kNext, the scope and limitations of this reaction were examined by varying the substituents on the alkyne. These variations had a significant impact on the rate and yields of these cycloisomerization reactions. For example, if R 1 = Me (3a) or a TBS-protected propanol 3b, conversion to 4a or 4b required 90 minutes (entries 1 and 2, Table 1). Interestingly, shortening the tether between the protected alcohol and the alkyne from three to two methylene units dramatically reduces the reaction time to ca. 20 minutes (entries 3 and 4, Table 1). 9 Alternatively, placing an aromatic ring on the alkyne terminus slows the reaction, requiring that substrate 3g be heated to 50°C and 8 mol% of Rh(I) catalyst to effect the formation of trienone 4g. An electron-withdrawing or electron-donating group on the para-position of the aryl ring had a negligible effect on...

A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-β-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-β-carboline followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as a template for the construction of a virtual library of 11,748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.