An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K.

To develop expertise, novice chemistry students require deliberate practice with immediate and thoughtful feedback. Whereas opportunities for practice are often abundant, opportunities for feedback tend to be much scarcer. To address this challenge, we collaborated with students to develop a flexible and scalable online platform called “Alchemy.” Students interact with the software through a series of prompts and multiple-choice questions, receiving targeted feedback at each step. Each student can navigate a scenario differently, influenced by their prior knowledge and misconceptions. In design, scenarios are instructor-created graphs that model their expert-level thought process­(es) and teaching experience. This graph format is a distinct and advantageous feature of Alchemy that supports linear, nonlinear, and cyclical progression through a concept or problem. Alchemy-based homework has been assigned in lecture and lab courses, at the sophomore and junior levels, with enrollments ranging from many tens to many hundreds of students. Approximately 80% of students rated Alchemy as very/extremely helpful to their learning, emphasizing the value of the step-by-step process and feedback. Alchemy is discussed in the contexts of other software platforms, its advantages and limitations, lessons learned in its initial deployments, and future directions for its development and usage.

Substoichiometric amounts of tributyltin hydride were utilized in nitrogen-centered radical cyclizations onto silyl enol ethers for the formation of substituted cyclic imines.Aminyl radical cyclizations 1 are powerful synthetic methods for the construction of pyrrolidines and have been utilized in the syntheses of numerous natural products. Of the many methods that have been developed for the generation of nitrogen-centered radicals, 1 the formation of aminyl radicals from azides 2 is synthetically attractive as azides are readily incorporated into molecules and are stable under a variety of reaction conditions. Herein, we report a new methodology for the formation of versatile cyclic imines that utilizes aminyl radicals generated from azides and only a substoichiometric amount of tributyltin hydride.We recently reported a new route to polyhydroxylated pyrrolidines using aminyl radical cyclizations onto silyl enol ethers. 3 These cyclizations required the addition of 1.2 equivalents of tributyltin hydride and 0.1 equivalents of azobisisobutyronitrile (AIBN) to effect clean cyclizations to the desired pyrrolidines. However, a sterically bulky cyclization precursor, azide 1, cyclized to form both the desired pyrrolidine 2 as well as a minor amount of cyclic imine 3 (Scheme 1). Scheme 1 Nitrogen-centered radical cyclization onto a silyl enol etherWe hypothesized that the formation of imine 3 occurs through the mechanism illustrated in Scheme 2. Treatment of azide 1 with tributyltin radical results in the formation of tin-bound aminyl radical 4, which rapidly cyclizes to form pyrrolidine 5. Subsequent radical trapping with hydrogen provides pyrrolidine 6. Protonolysis of the nitrogen-tin bond readily occurs in workup to provide 2. The imine product may be formed through an intermolecular hydrogen transfer 4,5 between pyrrolidines 5 and 6 to form pyrrolidines 6 and 7. Radical fragmentation of pyrrolidine 7 6 results in the formation of the imine 3 and regeneration of tributyltin radical. This mechanism suggests the possibility of cyclizing an azide to the corresponding cyclic imine utilizing only a substoichiometric amout of tributyltin hydride.We began our investigations into the selective formation of cyclic imines using substoichiometric amounts of tributyltin hydride with a simple, unbiased cyclization precursor (8, Scheme 3). Using our optimized conditions developed for pyrrolidine formation, azide 8 cyclized to form exclusively pyrrolidine 10 with no detectable amounts of either cyclic imine 9 or starting material 8. Decreasing the amount of tributyltin hydride to 50 mol% resulted in the formation of pyrrolidine 10, unreacted azide 8, and two imine products (9 and 11). Imine 9 was the expected imine product based upon the mechanism proposed in Scheme 2. Imine 11 is also likely formed through an intermolcular hydrogen transfer at C 2 followed by elimination. Despite the large amount of unreacted azide, the sum of all cyclized products is greater than the percentage of tin added to the reaction.

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Ring closure reactions O 0130Construction of Carbo-and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals. -A new and efficient method to prepare cyclopentanes, pyrrolidines, tetrahydrofurans, and tetrahydropyrans is developed. Slow addition of hydride reagent is necessary to achieve good yields. Under these conditions formation of 8-and 9-membered ring systems is not successful and cyclohexanes can only be obtained in acceptable yields by 6-endo cyclization of geminally substituted alkenes like (XII). -(ZHU, H.; WICKENDEN, J. G.; CAMPBELL, N. E.; LEUNG, J. C. T.; JOHNSON, K. M.; SAMMIS*, G. M.; Org. Lett. 11 (2009) 9, 2019-2022; Dep. Chem., Univ. British Columbia, Vancouver, B. C. V6T 1Z1, Can.; Eng.) -Jannicke 37-034