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WIREs Comput Mol Sci
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The Baldwin rules: revised and extended

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The Baldwin rules constitute one of the clearest examples of the success which can be obtained through the application of stereoelectronic concepts to reaction design. With thousands of examples, the predictive power of these rules is inarguable. However, time has revealed a number of exceptions and gray areas within these rules, leading to extensions and revisions. In this review, we will present an overview of how subsequent studies of ring closure have clashed with several of Baldwin's predictions, leading to the revision of some classes of ring closure (alkyne cyclizations, electrophilic closures, etc.). We also discuss for which the original rules were vague (epoxides) or absent (promoted cyclizations), and the evidence revealed since Baldwin's work that has allowed for a better understanding of these ambiguities. With the concise summation of these amendments, this review aims to present an overview of the understanding of cyclization reactions to date. WIREs Comput Mol Sci 2016, 6:487–514. doi: 10.1002/wcms.1261

The Brook rearrangement is a 1,2 shift driven by the increased bond strength of the Si—O bond (110 kcal/mol) compared with the Si—C bond (76 kcal/mol). Note that the possible involvement of hypervalent silicate changes stereoelectronic requirement for the ring formation.
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Stepwise radical mechanisms have been invoked to explain formally 3‐endo‐tet processes.
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Intramolecular substitutions in ‘tetrahedral systems’ are not classified as cyclizations but proceed via cyclic transition states in which an atom/group is transferred. The original Baldwin rules predict most endo‐tet atom transfers as unfavorable.
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Left: 5‐Endo cyclizations are aborted sigmatropic shifts. Additional stabilization to the cyclic structure analogous to the pericyclic TS converts the latter into the global energy minimum. Right: (Top) Favorable symmetry for orbital interactions of the anionic lone pair, in‐plane π bond, and long C2‐C3 σ‐bond allows π* and nonbonding anionic orbital to couple via Through‐Space (TS) and Through‐Bond (TB) interactions simultaneously. (Bottom) Cyclic delocalization and HOMO of the carbanionic 5‐endo‐dig TS.
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The first efficient 5‐endo‐dig radical closure of a carbon‐centered radical.,
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The 4‐exo‐dig cyclizations of the parent system are very efficient for phenyl‐ and silyl‐substituted alkynes.
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The 3‐exo‐dig cyclizations of enolates and propargylic alcohols.
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Stereoelectronic differences between alkenes and alkynes arising from the presence of the in‐plane π‐system in alkynes.
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Three examples used to define the original Baldwin rules for alkynes. (a) With a ‘divergent angle’ of 60°, only the reduced product is obtained. (b) A ‘neutral’ parallel geometry with the angle of 0° results in 5‐endo‐dig closure of the carbanion. (c) A ‘convergent’ geometry exclusively yields the 5‐exo‐dig product.
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The favored trajectories for cyclic closure in tetrahedral, trigonal, and digonal systems.
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The original Baldwin rules: patterns of ring closure for three‐ to six‐membered rings (endo‐tet processes do not formally form cyclic products but are included here because they should proceed through cyclic transition states as well). An updated and corrected version of the rules will be given at the end of the present manuscript. (Reprinted with permission from Ref . Copyright 1976 Royal Society of Chemistry)
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Baldwin's unified classification of cyclization processes based on three factors.
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Comparison of the three classes of intramolecular reactions utilized for cycle formation. Radical cyclizations were used as an example: the scope of cyclizations is, of course, much broader, including nucleophilic, electrophilic, and metal catalyzed processes.
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Baldwin's nomenclature for cyclization reactions and the refined list of favorable and unfavorable modes of nucleophilic and radical cyclization (Rules for Ring Closure). Favorable reactions are boxed with solid lines, the borderline reactions which require additional assistance are boxed with dashed lines. The original Baldwin rules for alkyne cyclizations are changed as suggested by Alabugin and Gilmore.
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Aromatic stabilization of the 6‐endo‐product masks the stereoelectronic preference for the 5‐exo‐dig radical closure.
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The unusual 5‐endo‐trig cyclization is photochemically facilitated via access of an excited twisted alkene.
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Experimental Arrhenius activation energies, E (kcal/mol) for 5‐exo‐trig cyclizations of selected O, C, N radicals.
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Effect of π*‐orbital polarization on the magnitude of stabilizing orbital interaction in a 5‐exo‐trig nucleophilic attack at a π‐bond.
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Direct 5‐endo‐trig onto the oxygen center of a carbonyl group.
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Left: Stereoelectronic restriction on the 5‐exo‐dig→6‐endo‐dig homoallylic ring expansion. Right: ‘Recycling’ of 5‐exo‐trig products into 6‐endo‐trig products via homoallylic ring expansion.
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The observed 6‐endo‐trig selectivity in radical enyne cyclizations originates from 5‐exo‐trig cyclization followed by homoallylic ring expansion.
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Rearrangement routes subsequent to 3‐exo‐trig radical cyclization. The rate constants are from Ref .
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Top: A highly enantio‐ and diastereoselective route to indanes via a 5‐endo‐trig cyclization catalyzed by a chiral ammonium salt. Bottom: Baldwin's original observation of only 5‐exo‐trig cyclization product.
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Intramolecular interception of cationic center in Au‐catalyzed C1‐C5 cyclization of enediynes.
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Au(I)‐catalyzed isomerization/cyclization cascade of skipped enediynes and extension via subsequent cyclization.
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The formal ‘all‐endo’ metal‐assisted EPNC cascade is initiated by EPN‐5‐endo‐dig closure followed by multiple EPN‐6‐endo‐dig closures.
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External nucleophilies can also promote endo‐digonal closures to form larger cycles.
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The competition between 3‐exo‐dig and 4‐endo‐dig in NPE closures is controlled by substituents.
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Stereoelectronics for NPE and EPN cyclizations.
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Comparison of orbital interactions and the expected regioselectivities for nucleophilic (left) and electrophilic (right) cyclizations of alkynes. Dominant stabilizing interactions are shown with straight arrows; secondary (stabilizing or destabilizing) interactions are shown with dashed lines.
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Intramolecular 4‐exo‐tet/4‐exo‐trig epoxide opening outcompetes the alternative 5‐exo‐tet/5‐endo‐trig cyclization to form oxazetidine.
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This selective epoxide‐opening cascade is promoted by water in step‐wise fashion in which the rate increases with each consecutive closure.
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Nomenclature defining the two modes of cyclizations onto epoxides. See Ref for stereoelectronic analysis.
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Comparison of exo‐tet, endo‐trig, and epoxide cyclizations.
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Extended classification of possible ring closure patterns separated into structural motifs. Top: isolated reactive center (‘X*’ can either be a cation, anion, or radical). Center: the reactive center is orthogonal to the second π‐system. Bottom: the reactive center is included in a larger π‐system which can be positioned either outside or inside the formed ring.
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(Left) Distinction between C‐enolexo and C‐enolendo patterns for exo‐tet cyclizations. (Right) Cyclizations of enolates can occur at either the carbon or oxygen. The stereoelectronic restrictions are less stringent for oxygen.
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A Norrish 1 process is followed by self‐terminating 1,4‐HAT to form a closed shell intermediate in the synthesis of 1,22‐dihydroxynitianes and fuscicoccane A‐B ring systems.
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1,5‐HAT following initial generation of a vinyl radical.
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1,5‐HAT constitutes a crucial step in the radical cascade closure of ortho‐alkynes.
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The formation of tetrahydrofurans via a sequence of PhS. addition, 1,5‐HAT, and 5‐exo‐trig cyclization.
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Favorable endo cyclization modes required transition state ring sizes of at least nine atoms.
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Top: Since the 180° bond angle between the nucleophile and leaving group cannot be achieved, the formation of the product occurs via an intermolecular process. Bottom: In contrast, exocyclic substitution is feasible intramolecularly.
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