Baldwin's Rules for Ring Closure

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Baldwin's Rules: Favored vs. Disfavored Ring-Closure Reactions

1) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. "Activation of 6-Endo Over 5-Exo Hydroxy Epoxide Openings. Synthesis of Tetrahydrofuran and Tetrahydropyran Systems." J. Am. Chem. Soc. 1989,111, 5330-5334. 2) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. "Activation of 7-Endo Over 6-Exo Hydroxy Epoxide Openings. Synthesis of Oxepane and Tetrahydropyran Systems." J. Am. Chem. Soc. 1989, 111, 5335-5340. Goals: Baldwin's rules provide a simplistic model for ring-closure reactions that can be applied to diverse synthetic applications. (1) Baldwin's rules are kinetic rules for relative rates of ring closure and so reflect the D G associated with the transition states of different competing pathways. (2) Lowering the D G of a normally disfavored ring closure can make that pathway competitive.

INTRODUCTION The presence of cyclic structures in the basic framework of many complex and biologically interesting molecules has made their formation a fundamental process in organic synthesis. Therefore, ring-forming processes have garnered the attention of synthetic chemists for many years. A series of guidelines that describe the propensity of various systems to participate in ring forming reactions was put forth by J. E. Baldwin in the 1970's. This set of guidelines, which describe the relative ease of ring formations, has become known as Baldwins rules of ring closure and has proved a useful tool in evaluating the feasibility of ring forming reactions. Baldwin described his rules in terms of three features of the reaction: (1) the ring size being formed (indicated through a numerical prefix), (2) the hybridized state of the carbon atom undergoing the ring closing reaction (sp= digonal, sp2= trigonal, and sp3 = tetrahedral), and (3) the nature of the breaking bond (exo- the breaking bond it is external to the newly formed ring, and endo - the breaking bond is within newly formed ring.)1. Examples of these formalizations are shown for the 6-membered ring closing reactions in Figure 1.

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Figure 1. 6-Membered ring closing reaction types1. Baldwin's rules for ring closure discuss the relative rates of ring closures of these various types. Baldwin summarized the relative nature of ring formation involving 3-7 membered rings as either favorable or unfavorable. These terms are not meant to describe the absolute probability that a reaction will or will not take place but rather are used in a relative sense. A reaction that is disfavored (slow) does not have a rate that is able to compete effectively with an alternative reaction that is favored (fast). However, the disfavored product may be observed, if no alternate reactions are more favored. A summary of Baldwins rules for cycles consisting of 3-7 members is given below.

Table 1. Classification of Ring-Closure Types1

Exocyclic bonds Ring Size sp (dig) sp2 (trig) sp3 (tet) Endocyclic bonds sp (dig) sp2 (trig) sp3 (tet)

3 4 5 6 7

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Since these rules are for rates, they reflect the free energy of activation at the transition state, D G , necessary for ring closure. The physical basis behind the value of D G depends on the number of atoms in the forming ring, and on the geometry in which the electrophile and nucleophile must interact to achieve advantageous orbital overlap and subsequent bonding. In general, if the chain tether allows the two nuclei to align with the required trajectory the reaction is a favorable process. Because stable molecules tend to have bond angles that minimize energy, lower energy transition states will reflect these angles more than higher energy transition states. This means that in favored processes the angle between the interacting nuclei is maintained throughout the transition state and into the final product. In contrast, ring-forming reactions that are generally disfavored have a divergent angle between that found in the transition state and the final product. For example, 5-endo-trig is unfavorable whereas 5-endo-dig is favorable. In the 5-endo-trig case, effective orbital overlap can only be achieved through severe bond angle distortion in the transition state. In contrast, in the case of a 5-endo-dig cyclization, the acetylenic system provides orbitals that allow for a nearly planar mode of approach (Scheme 1)2.

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Scheme 1a. Extreme transition state bond-angle distortion leads to disfavored 5-endo-trig 2.

Scheme 1. Favored transition-state geometry for effective orbital overlap. Nucleophile can approach the acetylenic orbitals in a nearly planar fashion2.

When applied to experimental systems, Baldwins rules have proved useful to predict the outcome when the possibility to cyclize into two different products arises. An example Baldwin studied is shown in Scheme 2. In this situation, the reactant can go through a 5-exo-trig or 5-endo-trig ring formation, resulting in product 1 or 2 respectively. Under basic conditions, the results of the reaction shown in Scheme 2 were exactly as predicted by Baldwins rules. The 5-exo-trig product formed exclusively over the 5-endo-trig product. With this experiment, Baldwin demonstrates the usefulness of his rules in predicting ring cyclization products when two or more possible products exist3.

Scheme 2. Baldwin's rules applied: Baldwin reports no trace of the 5-endo-trig product3.

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	Although these rules have proved a powerful predictor of the relative facility of ring closures as shown above, manipulation of the reaction conditions and the stereoelectronic nature of the substrates can provide for the formation of ring systems through apparently "disfavored" reaction pathways. Baldwin himself realized that there are ways to allow for the apparently disfavored reaction pathway. Scheme 3 shows a reaction discovered by Baldwin that, according to Baldwins rules, should not be favored due to its 5-endo-trig cyclization pathway 4.

Scheme . Apparent 5-endo-trig cyclization4. Under basic conditions, experimental results showed no ring formation. However, under acid catalyzed conditions, the reaction readily proceeds to the shown disfavored product. It is believed that the reaction does not disregard Baldwins rules, but instead that the reactant in the equation has a significant resonance structure under acidic conditions that rationalizes an altered molecular geometry as shown in Scheme 4.

Scheme 4. Orbital analysis of 5-endo-trig vs. 5-exo-trig The resonance structure shows that a favorable Burgi-Dunitz trajectory can be attained without severe bond angle distortion. For cyclization to take place under basic conditions however, the oxygen must attain a contorted angle to achieve a proper trajectory for cyclization. This is a classic example of Baldwins favored versus disfavored reaction pathways.

Although Baldwins rules have proven to be effective in predicting the outcome of ring formation reactions, recent synthetic literature is filled with "anti-Baldwin" examples or closures that do not follow his rules. In these examples the eletronic stabilities of the electrophile and/or the nucleophile are changed in the transition state so that the electronic demands overwhelm the energy barrier in the bond forming trajectory. One example that has been studied by a number of researchers is the iodocyclization reaction5,6,7,8,9. This reaction has been used successfully to form the normally unfavorable 5-endo-trig product as seen in Scheme 5.

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Scheme 5. Iodocyclization reaction forms 5-endo-trig product (as named from the reactant geometry)5. This reaction forms the anti-Baldwin product for two reasons: (1) Even though the trajectory is still not optimal for bond formation, the electronic attraction between the electrophile and the nucleophile overwhelms this factor to the point where the rate of the reaction becomes reasonable. (2) The molecular set-up was designed to have no alternative kinetically favored pathways, due to the increased strain energy associated with the 4-exo-tet reaction. It was found, however, that the reaction could easily lose its competitive edge if a Baldwin-favored product could be formed. Knight, et al. introduced the possibility of other intramolecular ring closures that would compete through the cyclic iodinium intermediate, resulting in exclusion of the 5-endo-trig product6 (Scheme 6). This attests to the strength of Baldwin's rules.

Scheme 6. Competing reactions of iodocyclization6. Baldwins rules are useful for predicting the ease of ring formation, and have been used in many organic syntheses. Scheme 7 shows examples of natural products that have been synthesized using cyclization reactions, both favored and unfavored by Baldwin's rules.

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Scheme 7. Use of cyclization reactions in synthetic preparations10,11

Not all cyclization reactions necessary for synthesis of useful products fall into the category of a favored reaction. Baldwins rules help to decipher which reactions may readily cyclize and which reactions need assistance, as with the iodocyclization reaction. Being unfavored simply alerts the researcher that a more inventive method of synthesis must be incorporated to make these cyclizations kinetically favored. It does not imply that the reaction is impossible.

RESULTS 	In a series of papers in 1989, Nicolaou et al. asked whether the camphorsulfonic acid (0.1 equivalents) catalyzed cyclization of an hydroxy epoxide in CH2Cl2 at -40-25 oC would proceed through the 5-exo or 6-endo reaction pathway as shown in scheme 8a or similarly through the 6-exo or 7-endo reaction pathway as shown in scheme 8b. 5,6

Scheme 8a. 6-endo-tet vs. 5-exo-tet. 12

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Scheme 8. 7-endo-tet vs. 6-exo-tet 13.

Nicolaou's results from Schemes 8a and 8b are shown below and indicate that either product could be formed depending on the R group that was adjacent to the epoxide ring unit. As the p-donating ability of the R-group on the trans-hydroxy epoxide increased, the percentage of the normally disfavored product increased (Table 2). Table 2. Competing Cyclizations of Hydroxy Epoxides 12,13. Cyclization of Trans -Hydroxy Epoxides for 6-Endo or 5-Exo Reactions Substrate R= CH2CH2CO2Me R= (E)-CH=CHCO2Me R= CH=CH2 R= CH=CBr2 Ratio of products (endo::exo) O::100 6O::4O 1OO::O 1OO::O

Cyclization of Cis -Hydroxy Epoxides for 6-Endo or 5-Exo Reactions Substrate R= (E)-CH=CHCO2Me R= CH=CH2 R= (E)-CH=CHCl R= (Z)-CH=CHCl R= C=CBr Ratio of products (endo::exo) O::100 44::56 76::24 33::67 0::100 Cyclization of Trans-Hydroxy Epoxides for 7-Endo or 6-Exo Reactions Substrate R= CH2CH2CO2Me Ratio of products (endo::exo) O:100

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R= (E)-CH=CHCO2Me R= (E)-CH=CHCl R= (Z)-CH=CHCl

22::78 92::8 60::40 Cyclization of Cis -Hydroxy Epoxides for 7-Endo or 6-Exo Reactions

Substrate R= (E)-CH=CHCO2Me R= CH=CH2 R= (E)-CH=CHCl R= (Z)-CH=CHCl

Ratio of products (endo::exo) 0::100 50::50 68::32 33::67

DISCUSSION Baldwin's rules compare strictly the relative free energies that different pathways need to achieve a transition-state molecular arrangement. Therefore, if it were possible to lower the free energy associated with the transition state that leads to a product disfavored by Baldwin's rules, this pathway's rate could become competitive. The essence of Nicolaou's papers is that he achieves this lowering of energy through p -donating-substituent stabilization at the transition state. Scheme 9 shows that p -donation stabilizes the developing positive charge in the transition state that leads to the 6-endo product, but not the transition state that leads to the 5-exo product. Scheme 9 also represents a competition, a race, between what is still a sterically favored 5-exo Baldwin pathway versus a now p -stabilized 6-endo pathway. Depending on the degree of p -stabilization the exo and endo products finish the race in different amounts, as is shown in Nicolaou's papers (Table 2).

Scheme 9. Nicolaou's reagents provide p -stabilization for the 6-endo case that overrides the steric preference

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for the 5-exo case12.	 One such example of this competition is the case in which (E)-CH=CHCl is used as the R group for the competitive 6-exo or 7-endo cyclization of the trans-hydroxy epoxide. Steric preference would predict that the 6-exo product would be favored. p -stabilization, however, accounts for the observed 92:8 ratio of endo:exo. In an interesting testament to the strength of Baldwin's rules, the change from E to Z olefin geometry reduces Nicolaou's yield of the anti-Baldwin product. In the case of the (Z)-CH=CHCl, steric interactions between the hydroxy group and the chlorine substituent lower the extent of (p -stabilization at the transition state by disrupting the planar arrangement of the (p -donating substituent and the partial positive charge. This yields only a 60:40 endo:exo product ratio, unlike the 92:8 ratio for the E isomer as discussed above. An analogous argument can be made for the decrease in observed disfavored product when the cis-hydroxy epoxide was used. The reason that the endo-product is not as favored in these reactions is speculated to be because the cis structures exhibit steric hindrances which prevent the planar arrangement of the donating (p -orbitals. This causes a decrease in the stabilization of the transition state and consequently does not lower the energy of the kinetic pathway to the extent of its trans counterpart. Because Nicolaou had to modify reagents in order to override Baldwin's rules, his papers validate their general prevalence. CONCLUSION With any scientific model, there is a tradeoff between simplicity and universality. Baldwin's rules appear to maximize both qualities to an appreciable extent. On one hand, they are an extraordinarily simple model for predicting cyclization reaction products, and the physical reasoning for these rules is easily comprehendible. On the other hand, the rules are so broadly applicable that Nicolaou had to create special circumstances to override them. 	 REFERENCES 1) Baldwin, J. E. "Rules for Ring Closure." J. C. S. Chem. Comm.. 1976, 18, 734-736 2) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part A: Structures and Mechanisms, 3rd ed.; Plenum Press: New York, 1990; pp. 165-167. 3) Baldwin, J. E. "5-Endo-Trigonal Reactions: A Disfavored Ring Closure." J. C. S. Chem. Comm. 1976, 18, 736-738. 4) Baldwin, J. E. "Rules for Ring Closure: Ring Formation by Conjugate Addition of Oxygen Nucleophiles." J. Org. Chem. 1977,42, 3846-3852. 5) Bedford, S. B.; Bell, K. E.; Bennett, F.; Hayes, C. J.; Knight, D. W.; Shaw, D. E. "Model Studies of the Overall 5-endo-trig Iodocyclization of Homoallylic Alcohols." J. Chem. Soc. Perkin Trans. I 1999, 15, 2143-2148. 6) David, W. K.; Redfern, A. L.; Gilmore, J. "A Method for Effectively Favouring 5-Endo over 5-ExoCyclisations" Tetrahedron Lett. 1998, 39, 8909-8910. 7) Macritchie, J. A.; Peakman, T. M.; Silcock, A.; Willis, C. L. "Iodocyclisation Studies on Unsaturated a-Hydroxy Esters." Tetrahedron Lett. 1998,39, 7415-7418.

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8) Jorda-Gregori, J. M.; Gonzalez-Rosende, E. M.; Sepulveda-Arques, J.; Galeazzi, R.; Orena, M. "Highly Regio- and Stereoselective Iodocyclization of Chiral 3-alkoxycarbonyl-4-propenyl-2,2-dimethyl1,3-oxazolidines: A Computational Investigation." Teterahedron Asym. 1999, 10, 1135-1143. 9) Andrey, O; Ducry, L.; Landais, Y.; Planchenault, D.; Weber, V. "Electrophilic 5-endo-trig cyclisations of 2-silyl-3-alkenols. A Stereoselective Route to Polysubstituted Tetrahydrofurans." Tetrahedron 1997, 12, 4339-4352. 10) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. "Total Synthesis of Mucocin." J. Am.. Chem.. Soc. 1998, 120, 11279-11284. 11) Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. "5-endo-trig Cyclisations in Heterocycle Synthesis: Enantiospecific Synthesis of (+)-Monomorine I." Chem. Commun. 1997, 2141-2142. 12) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. "Activation of 6-Endo Over 5-Exo Hydroxy Epoxide Openings. Synthesis of Tetrahydrofuran and Tetrahydropyran Systems." J. Am.. Chem.. Soc. 1989,111, 5330-5334. 13) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. "Activation of 7-Endo Over 6-Exo Hydroxy Epoxide Openings. Synthesis of Oxepane and Tetrahydropyran Systems." J. Am. Chem. Soc. 1989, 111, 5335-5340.

POTENTIAL EXAM QUESTIONS Question 1: Gliotoxin is made biosynthetically from a precursor in the presence of an enzyme with cysteine in the active site. It has been suggested that an enzyme achieves optimal catalytic efficiency when its mechanism conforms closely to plausible mechanisms in solution chemistry. Propose a mechanism for the conversion. Neglect stereochemical implications.

Answer 1:

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The direct addition shown above is a chemically disfavored 5-endo-trig reaction, which is expected to be disfavored biochemically as well. A better mechanism is shown below:

In this case, the cysteine mercaptan group does the initial attack, which is followed by a favored 5-exo-tet reaction to complete the cyclization. Piccirilli, J. A. "Do Enzymes Obey Baldwins Rules? A Mechanistic Imperative in Enzymatic Cyclization Reactions." Chem. Biol. 1999, 6, R59-R64.

Question 2: Predict the outcome of this reaction, using knowledge of Baldwins rules and cyclization kinetics.

Answer 2: First, lithium-halide exchange occurs to give:

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This can cyclize in 4 ways: 6-exo-trig (A), 6-endo-trig (B), 5-exo-trig (C), and 7-endo-trig (D).

All are favored to an extent by Baldwins rules but due to the fact that 5-membered rings will form more quickly than 6- or 7-membered rings the following product should dominate:

This will react further to give another 5-membered ring (by a 5-exo-trig pathway)

Thebtaranonth, C.; Thebtaranonth, Y. "Developments in Cyclization Reactions." Tetrahedron1990, 96,

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1385-1489.

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