Timothy P Ribelin

Bio: Timothy P Ribelin is an academic researcher from University of Kansas. The author has contributed to research in topics: Metathesis & Bicyclic molecule. The author has an hindex of 3, co-authored 5 publications receiving 176 citations.

Highly Stereoselective Ring Expansion Reactions Mediated by Attractive Cation–n Interactions†

Abstract: Most stereoselective reactions are ruled by steric effects. In particular, kinetically controlled asymmetric transformations utilizing chiral reagent, auxiliaries, or catalysts succeed due to energy differences in transition states that most often arise by the minimization of repulsive, non-bonded interactions. Stereoelectronic considerations, which arise when the alignment of particular orbitals are necessary for a successful reaction, can also play a role.[1] An iconic stereoelectronic effect in organic chemistry is the anomeric effect.[2] Reactions controlled by the anomeric effect, such as glycosidations, largely depend on the relative orientation of the non-bonding or n electrons of a nearby alkoxy group. In recent years, alkoxy group control of stereoselective reactions via electrostatic interactions has received renewed scrutiny, led by the Woerpel group.[3] In this communication, we report an alternative and highly effective approach to stereocontrol through the maximization of attractive non-bonded interactions between an alkoxy or alkylthio group and a positively charged leaving group. The Lewis acid-promoted reaction of a symmetrically substituted cyclic ketone with a chiral hydroxyalkyl azide provides a stereoselective route to lactams (Scheme 1).[4] In this reaction, initial formation of a spirocyclic intermediate sets up the selective migration of one of the alkyl groups originally adjacent to the ketone carbonyl. Migration of a C–C bond antiperiplanar to the N2+ leaving group (only possible when the latter is in an axial position as shown) affords an iminium ether that is converted into lactam by workup with aqueous base. For 1- or 3-substituted azidopropanols (not shown), 10:1 selectivities are obtained, corresponding to preferential reaction through the most stable chairlike heterocyclic ring (A or B) resulting from equatorial addition of azide relative to the tert-butyl group. Intermediates A and B can interconvert through conformational reorganization or by reversion to the initially formed oxonium ion followed by reclosure. In this scenario, selectivity is attained by stabilization of A over B due to traditional minimization of 1,3-diaxial interactions by placement of the R1 or R3 into equatorial positions in the former. Scheme 1 Origin of selectivity in asymmetric Schmidt reactions. 2-Substituted 1,3-azidopropanols present a special case that is unusually susceptible to stereoelectronic control due to three factors: (1) the methylene groups near the spiro linkage are locally isoelectronic, so the reaction cannot be controlled by “migratory aptitude”, (2) the presence of either an oxygen ether or an N–N2+ group in a 1,3 relationship to the R group means that 1,3-diaxial steric interactions will be minimized, and (3) the 1,3 relationship between axial R and N2+ groups provides a strong opportunity for attractive electrostatic interactions to occur between these groups in intermediate B. In previous work, it was demonstrated that unusually low selectivities obtained in this system when R = aryl could be ascribed to preferential stabilization of intermediate B by attractive, non-bonded cation–π interactions between the aromatic group and the N2+ leaving group (Table 1).[5] Although such interactions are commonly proposed in biological systems,[6] they are rarely invoked as stereocontrolling features of small-molecule stereoselective reactions.[7] Table 1 Selectivity of reactions of substituted 1,3-hydroxyalkyl azides. A computational study[8] and analogy to the well-known ability of ether groups to bind cations suggested that intermediates like B should be even more enhanced in compounds where R = alkoxy. As shown in Figure 1, isomer B containing a diaxial relationship between methoxy group and leaving group was calculated to be ca. 3.8 kcal/mol more stable than the equatorial isomer for which no interaction between methoxy and N2+ groups are possible. To test this, 1-azido-2-methoxypropanol 3 was prepared and reacted with 4-tert-butylcyclohexanone using BF3•OEt2 as Lewis acid promoter. A striking 24:1 selectivity in favor of the isomer emanating from an axially disposed methoxy group was obtained in high yield (Table 1, entry 3). Figure 1 Calculations for proposed intermediates A and B performed at the MP2/6-311+G**//MP2/6-31G* level of theory.[8] This result suggests that the methoxy cation–n interaction is considerably stronger than the previously reported cation–π effect, due to the fact that the highest 3:2 ratio observed to date was 57:43 for the electron-rich 3,4,5-trimethoxyphenyl group (not shown).[5] The fact that the small MeO group (A value = 0.6[9]) pays a relatively small steric penalty in the axial orientation is a likely contributor to the high selectivity of this reaction as well. However, the much higher selectivity and opposite direction of stereocontrol obtained for the smaller MeO group as compared to alkyl or aryl substituents (Table 1, entries 1 and 2) is strong evidence for the proposed role of electrostatics in this reaction. We proposed that a similar effect might be observed with a more polarizable heteroatom.[3m] Accordingly, 1d where R = SMe, was prepared and submitted to the asymmetric Schmidt reaction protocol. Remarkably, a >98:2 dr was obtained for this system, favoring 3d. The selectivities obtained with both methoxy and methylthio, which depend mainly on electrostatics and feature axially disposed substituents, are higher than any previously reported, sterically-based, example of this ring-expansion reaction.[4,5] Although the first example of an asymmetric azido-Schmidt reaction reported utilized an azidoethanol reagent, that series has typically provided lower selectivities relative to the three-carbon-containing reagents like 1 and has more recently been shown to occur via predominant steric control, even when a phenyl group is in a position to participate in a cation–π interaction.[5] In sharp contrast to these previous results, the reaction using reagent 4 afforded a high 97:3 ratio of 5 over 6, in which the major product goes through an intermediate in which a syn relationship between the methoxy group and the leaving N2+ substituent is possible (Scheme 2). A computational investigation showed that the cation–n intermediate C is stabilized by 3.9 kcal/mol. Notably, the O–N2+ distances, energy differences, and ratios are similar between systems B and C. Previous work in the reactions of substituted 1,2-azidoethanols has shown the predominant steric feature affecting stereochemistry to exist between the migrating carbon and substituents on the five-membered heterocyclic ring.[4,5b] In cases where the alkyl group is adjacent to oxygen (i.e., across the ring from the migrating methylene group and the N2+ leaving group), steric effects do not play an important role in determining reaction stereochemistry, as clearly demonstrated by the non-selective cyclohexyl case shown in Scheme 2b. Scheme 2 (a) Electrostatically controlled reaction of 1-azidoethanol derivative 4 with 4-tert-butylcyclohexanone (including calculated energies of proposed, minimized intermediates C and D[8]) and (b) a cyclohexyl-containing control.[5b] The model systems used ... The opposite situation occurs when the methoxymethyl group is placed adjacent to the azido group. In this case, there is no substantial difference in distance between the methoxy group and either isomeric intermediate, so electrostatic considerations cannot play a role and the preference for syn E over anti F drops to 0.6 kcal/mol computationally. Instead, the usual steric course of the reaction leads to the same product observed for the analogous example to 14 (Scheme 3). Scheme 3 Sterically controlled reactions of (a) 10 and (b) a previously reported cyclohexanyl example.[5] The model systems used for the calculations are given in the Supporting Information (Figure S1). The most interesting elements of this approach are that: (1) intermediates are subject to non-bonded, attractive interactions that are able to strongly favor one stereoisomeric form over the other, (2) these intermediates lead to the corresponding products in a process entirely controlled by stereoelectronic considerations, and (3) the overall stereoselectivity ultimately depends on the control of leaving group stereoslectivity at an epimerizable nitrogen atom. The high yields of these reactions combined with the utility of the lactam products suggests a high level of utility of the present reaction. Of perhaps greater long-term interest will be the attempted utilization of cation nonbonding electron stabilization in other stereoselective processes.[10]

Concise Construction of Novel Bridged Bicyclic Lactams by Sequenced Ugi/RCM/Heck Reactions.

Abstract: Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.

Synthesis of enantiomerically enriched (R)-5-tert-butylazepan-2-one using a hydroxyalkyl azide mediated ring-expansion reaction.

Abstract: A procedure for the conversion of a symmetrical ketone to an enantiomerically pure lactam is described. The technique described here involves a ring-expansion reaction of a 4-substituted cyclohexanone accomplished with a chiral 1,3-azidopropanol derivative. The procedure entails first a one-step preparation of (R)-1-phenyl-3-azidopropanol from a commercially available halide precursor, which is then reacted with the ketone using BF(3) x OEt(2) as a Lewis acid promoter. The resulting lactam is subsequently converted into a chiral lactam of high enantiopurity via the two-stage removal of the chiral nitrogen substituent. The present protocol carries out the diastereoselective ring-expansion reaction with higher selectivity than competing processes and is generally useful for the preparation of 5-substituted caprolactams.

Chemistry and Biology Of Multicomponent Reactions

Abstract: Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis. Open in a separate window Figure 1 Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.

Applications of Multicomponent Reactions to the Synthesis of Diverse Heterocyclic Scaffolds

Abstract: The sequencing of multicomponent reactions (MCRs) and subsequent cyclization reactions is a powerful stratagem for the rapid synthesis of diverse heterocyclic scaffolds. The optimal MCR is sufficiently flexible that it can be employed to generate adducts bearing a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products. The growing interest in diversity-oriented synthesis has led to increased attention to this paradigm for library synthesis, which has inspired many advances in the design and implementation of MCRs for the construction of diverse heterocyclic scaffolds.

Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature

Abstract: Direct and rapid heating by microwave irradiation in combination with sealed vessel processing in many cases enables reactions to be carried out in a fraction of the time generally required using conventional conditions. This makes microwave chemistry an ideal tool for rapid reaction scouting and optimization of conditions, allowing very rapid progress through hypotheses–experiment–results iterations. The speed at which multiple variations of reaction conditions can be performed allows a morning discussion of “What should we try?” to become an after-lunch discussion of “What were the results” Not surprisingly, therefore, many scientists both in academia and industry have turned to microwave synthesis as a front-line methodology for their projects. In this review, more than 220 published examples of microwave-assisted synthetic organic transformations from the 2004 to 2008 literature are discussed. An additional ca. 500 reaction schemes are presented in the Electronic Supplementary Material, providing the reader with an overall number of ca. 930 references in this fast-moving and exciting field.

Twisted Amides: From Obscurity to Broadly Useful Transition-Metal Catalyzed Reactions by N-C Amide Bond Activation.

Abstract: The concept of using amide bond distortion to modulate amidic resonance has been known for more than 75 years. Two classic twisted amides (bridged lactams) ingeniously designed and synthesized by Kirby and Stoltz to feature fully perpendicular amide bonds, and as a consequence emanate amino-ketone-like reactivity, are now routinely recognized in all organic chemistry textbooks. However, only recently the use of amide bond twist (distortion) has advanced to the general organic chemistry mainstream enabling a host of highly attractive N−C amide bond cross-coupling reactions of broad synthetic relevance. In this Minireview, we discuss recent progress in this area and present a detailed overview of the prominent role of amide bond destabilization as a driving force in the development of transition-metal-catalyzed cross-coupling reactions by N−C bond activation.

Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds

Abstract: The Ugi-4CR is by far one of the most successful multicomponent reactions leading to high structural diversity and molecular complexity. However, the reaction mostly affords a linear peptide backbone, enabling post-Ugi transformations as the only solution to rigidify the Ugi-adduct into more drug like species. Not surprisingly, the development of these transformations, leading to new structural frameworks, has expanded rapidly over the last few years. As expected, palladium-catalyzed reactions have received the foremost attention, yet other metals, particularly gold complexes, are fast catching up. This tutorial review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects.