D. A. Evans Rules for Ring Closure: Introduction Chem 206 Useful Literature Reviews http://www.courses.fasharvardedu/-chem206/ Johnson, C D (1993). " Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules Acc. chem. Res. 26: 476-82 Beak, P (1992). " Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at Chemistry 206 nonstereogenic atoms. Acc. Chem. Res 25: 215 Advanced organic Chemistry The Primary Literature Idwin, Chem. Soc. Chem. Comm. 1976. 734. 736 aldwin J. Chem. Soc. Chem. Comm. 1977 323 Baldwin, J. Org Chem 1977, 42, 3846 Lecture number 3 Baldwin, Tetrahedron 1982. 38 2939 Stereoelectronic Effects-2 Rules for Ring Closure: Baldwin's Rules i Problems of the Day Propose mechanisms for the following reactions Kirby, "Stereoelectronic Effects"Chapters 4, 5 NH2-NH Matthew d shair September 23, 2002
D. A. Evans Chem 206 Useful LIterature Reviews ■ Problems of the Day Chemistry 206 Advanced Organic Chemistry Lecture Number 3 Stereoelectronic Effects-2 Matthew D. Shair Monday, September 23, 2002 http://www.courses.fas.harvard.edu/~chem206/ Rules for Ring Closure: Introduction Johnson, C. D. (1993). “Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules.” Acc. Chem. Res. 26: 476-82. Beak, P. (1992). “Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms.” Acc. Chem. Res. 25: 215. The Primary Literature "Rules for Ring Closure: Baldwin's Rules" Propose mechanisms for the following reactions O O R R HO HO O R R + H + Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734, 736. Baldwin, J. Chem. Soc., Chem. Comm. 1977 323. Baldwin, J. Org. Chem. 1977, 42, 3846. Baldwin, Tetrahedron 1982, 38, 2939. Me OMe O NH2–NH2 HN NH Me O Kirby, "Stereoelectronic Effects" Chapters 4, 5
D. A. Evans.J. Johnson Rules for Ring closure: Introduction Chem 206 Ring Closure and Stereoelectronic Considerations C. Nucleophilic ring closures sub-classified according to hybridization An Examination of baldwin's rules (tetrahedral tet; trigonal trig; digonal dig) "Baldwin,'s Rules"provides a qualitative set of generalizations on the D. Nucleophilic ring closures further subclassified according to size of obability of a given ring closure the fomed ring. For example There are circumstances where the"rules"don't apply a They do not apply to non-first-row elements participating in the 5-exo-t cyclization event. The longer bond lengths and larger atomic radii of 2nd row elements result in relaxed geometrical constraints For example, a change in a heteroatom fromo to S could result in relaxation of a given geometric constraint. X=O VS S u The" rules"do not apply to electrocyclic processes Nomenclature Required trajectories Classes of Ring Closing Processes A. EXo-cyclization modes identified by the breaking bond ing positioned exocyclic to the forming cycle 把“4 B. Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle X=first-row element N. O Baldwin. J. Chem. Soc. Chem. Commun. 1976. 734
D. A. Evans, J. Johnson Rules for Ring Closure: Introduction Chem 206 Ring Closure and Stereoelectronic Connsiderations An Examination of Baldwin's Rules "Baldwin's Rules" provides a qualitative set of generalizations on the probability of a given ring closure. There are circumstances where the "rules" don't apply. ■ They do not apply to non-first-row elements participating in the cyclization event. The longer bond lengths and larger atomic radii of 2nd row elements result in relaxed geometrical constraints. For example, a change in a heteroatom from O to S could result in relaxation of a given geometric constraint. Nomenclature Classes of Ring Closing Processes Y Y – Y Y – exo endo X X X X A. Exo-cyclization modes identified by the breaking bond being positioned exocyclic to the forming cycle. B. Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle. X = first-row element N, O C. Nucleophilic ring closures sub-classified according to hybridization state of electrophilic component: (tetrahedral = tet; trigonal = trig; digonal = dig) D. Nucleophilic ring closures further subclassified according to size of the fomed ring. For example: X – Y X Y – X – Y X Y – X – Y X Y – 5-exo-trig 5-exo-dig 5-exo-tet X Y X Y Y X Y X X Y X Y Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. ■ The "rules" do not apply to electrocyclic processes. Y Y - endo X •• X X = O vs S •• •• Required trajectories: a a a a a a * * a a
D A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon Related Systems Chem 206 Tetrahedral Carbon FURST-PLATTNER RULE In this simple model, the transition-state leading to 1 involves the All exo cyclization modes are allowed: n-exo-tet, n=3-) diaxial orientation of nucleophile and leaving group. This orientation affords the best overlap of the anti-bonding C-Y orbital and the nonbonding electron pairs on the nucleophile O In the formation of the diastereomeric epoxide 2, the proper alignment of orbitals may only be achieved by cyclization through the There are stereoelectronic issues to consider for n-exo-tet cyclizations "allowed", there are large rate differences the the rates of ring closure Formation of 3-Membered Rings (3-exo-tet) While the FURST-PLATTNER RULE deals wilth the microscopic H reverse, in the opening of epoxides by nucleophiles, the XCH2+Y stereoelectronic arguments are the same H2 Stereoelectronic Effects in Epoxide Ring Cleavage Conformational Effects in Epoxide Ring Formation/cleavage t e3C fuence ring formation. at operate in ring cleavage also formation. Consider a rigid cyclohexene oxide system 丰 √ faster 8-d slower < chair The diaxial nucleophilic ring cleavage of epoxides For more information on epoxide cleavage see handout 03A
D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Chem 206 Tetrahedral Carbon All exo cyclization modes are allowed: (n-exo-tet, n = 3 ) Y C C Y – exo X X There are stereoelectronic issues to consider for n-exo-tet cyclizations Formation of 3-Membered Rings (3-exo-tet) X C H2 X CH2 C H2 C Y C H2 C H H X Y + Y– ‡ Conformational Effects in Epoxide Ring Formation/cleavage O H H Y O – Y O – H H H H Those stereoelectronic effects that operate in ring cleavage also influence ring formation. Consider a rigid cyclohexene oxide system: O H H O H Y d – d – ‡ O Y ‡ d – d – faster slower In this simple model, the transition-state leading to 1 involves the diaxial orientation of nucleophile and leaving group. This orientation affords the best overlap of the anti-bonding C–Y orbital and the nonbonding electron pairs on the nucleophile O– . In the formation of the diastereomeric epoxide 2, the proper alignment of orbitals may only be achieved by cyclization through the less-favored boat conformer. Accordingly, while both cyclizations are "allowed", there are large rate differences the the rates of ring closure. While the FÜRST-PLATTNER RULE deals wilth the microscopic reverse, in the opening of epoxides by nucleophiles, the stereoelectronic arguments are the same. 1 chair boat 2 Stereoelectronic Effects in Epoxide Ring Cleavage Me3C H O Nu- Me3C H HO Nu Me3C H O Nu- Me3C H Nu HO "The diaxial nucleophilic ring cleavage of epoxides" For more information on epoxide cleavage see Handout 03A. H H H H O Me H H Me HO Nu NuFÜRST-PLATTNER RULE •• •• H H
D A Evans, J.Johnson Rules for Ring Closure: SP3 Carbon Related Systems Chem 206 Tetrahedral Carbon Case 2: King, J.C.S. Chem. Comm, 1979, 1140 Endo cyclization modes that are disallowed ( n-endo-tet n=3→9) 8-endo-tet disfavored intermolecular endo X 8-endo-tet RXn exclusively The stereoelectronic requirement for a 180% X-C-Y bond angle is only met when the endo cyclization ring size reaches 9 or 10 members 9-endo-tet Case 1: Eschenmoser. Helvetica Chim Acta 1970. 53. 2059 SOzOMe borderline Conclusions 6-endo-tet disfavored Allowed endo cyclization modes will require transition state ring sizes of at least nine members Rxn excl i Intramolecular epoxidation has also been evaluated 8-endo-tet yclization exclusively intermolecular. However the exocyclic analog i disfavored n= 1: rXn exclusively intermolecular 6-exo-tet 0=s=0 Beak states that the conclusions made with carbol substitution also hold for oxygen atom transfer Rxn exclusively Beak, P(1992). Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms ."Acc. chem. Res. 25: 215
D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Chem 206 Tetrahedral Carbon Endo cyclization modes that are disallowed (n-endo-tet, n = 3 9) C Y endo X X Y C(SP3 ) The stereoelectronic requirement for a 180° X–C–Y bond angle is only met when the endo cyclization ring size reaches 9 or 10 members. CX3 O S O O O S O CY3 CX3 O- S O O O S O CY3 Cyclization exclusively intermolecular. However the exocyclic analog is exclusively intramolecular NaH 6-endo-tet disfavored CX2 I O S O O O S O CY3 CX2 O- S O O O S O CY3 NaH 6-exo-tet favored Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059. Case 2: King, J.C.S. Chem. Comm., 1979, 1140. NMe2 Me O S O O NMe3 + O S O O _ 8-endo-tet disfavored Rxn exclusively intermolecular (lecture 2) Rxn exclusively intramolecular Rxn exclusively intermolecular NMe2 SO2OMe NMe3 + SO3 – 8-endo-tet disfavored Rxn exclusively intermolecular NMe2 SO2OMe NMe3 + SO3 – 84% intermolecular, 16% intramolecular 9-endo-tet borderline Conclusions Allowed endo cyclization modes will require transition state ring sizes of at least nine members. Cl O–OH O Cl CO2H O n n Intramolecular epoxidation has also been evaluated Beak, JACS 1991, 113, 6281. n = 1: rxn exclusively intermolecular n = 9: rxn is intramolecular 8-endo-tet disfavored Beak states that the conclusions made with carbon substitution also hold for oxygen atom transfer. •• •• Beak, P. (1992). “Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms.” Acc. Chem. Res. 25: 215
D A Evans,J. Johnson Rules for Ring closure: SP2 Carbon Related Systems Chem 206 Trigonal Carb Endo cyclization modes that are disallowed (3 to 5-endo-trig) n-endo-tng X= first-row element The 5-endo-trig cyclization is a watershed case distance from reacting centers: 2.77A Case 1: Baldwin. J. Chem. Soc. Chem. Commun., 1976. 734 CO,Me base It is possible that a"nonvertical 5-endo-trig trajectory is operational like that suspected in C=o addition however cO, Me base COmE Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin. J. chem. Soc. Chem. Commun. 1976 736 CO,Me MeO2C 5-exo-trig
D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Chem 206 Trigonal Carbon Endo cyclization modes that are disallowed (3 to 5-endo-trig) n-endo-trig The 5-endo-trig cyclization is a watershed case X = first-row element Case 1: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. OH CO2Me O CO2Me 5-endo-trig Disfavored base X however SH CO2Me S base CO2Me X Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736. NH2 MeO2C CO2Me HN HN MeO2C MeO2C CO2Me O 5-endo-trig 0% 5-exo-trig 100% NH2 MeO2C CO2Me distance from reacting centers: 2.77 Å It is possible that a "nonvertical" trajectory is operational like that suspected in C=O addition Y C Y – C X •• X
D.A. Evans. J. John Rules for Ring Closure: SP2 Carbon Related Systems Chem 206 Case 2: continued Apparent exceptions to disallowed 5-endo-trig cyclization process MeO2C CO, Me 5-endo-trig 0% MeO2C Filer, J. Am. chem. Soc. 1979. 44. 285 100% CO-Me CO2 Me RHC KOBu Control experiment: Intermolecular reaction favors conjugate addtion m人 R= aryl,R2=aryl, alkyl CO Me COmE Grigg, J. Chem. Soc., Chem. Commun. 1980, 648. Case 3: Does the illustrated i ketalization process NH2NH2 necessarily violate"the 65 CH2 OH)2 1)EtO-CCl, pyridine 2)NH2NH disfavored? 5-endo-trig 200C x 5-endo-trig 5-exo-trig Johnson, C D (1993). "Stereoelectronic effects in the formation of 5-and Acc. Chem. Res. 26 476-82
D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Chem 206 X NH2 MeO2C CO2Me HN HN MeO2C MeO2C CO2Me O 5-endo-trig 0% 5-exo-trig 100% CO2Me Me Me CO2Me Me H Ph N O H N Ph Ph OK O Ph OMe O Ph CO2Me HN NH2 HN NH O Ph Ph O NH H2N 100% Control experiment: Intermolecular reaction favors conjugate addtion. 1) EtO2CCl, pyridine 2) NH2NH2 65 5-exo-trig oC 200 oC 5-endo-trig 0% MeI X Apparent exceptions to disallowed 5-endo-trig cyclization process N O N OH N O N R 1HC CO2Me R 2 CO2Me HN CO2Me CO2Me R 1 HN CO2Me R 1 R CO2Me 2 R 2 Filer, J. Am. Chem. Soc. 1979, 44, 285. R 1 = aryl, R2 = aryl, alkyl + KOtBu 3:1 Grigg, J. Chem. Soc., Chem. Commun. 1980, 648. R R O O R R O (CH2OH)2 H + Does the illustrated ketalization process necessarily violate "the rules"? R R O (CH2OH)2 O OH R R HO H+ O OH R R HO + H+ –H2O O OH R R + R R O O 5-exo-tet 5-endo-trig disfavored ? favored ? ( )2 ( )2 ( )2 Case 2: continued... Case 3: Ph OMe O 65 oC HN NH O Ph Johnson, C. D. (1993). “Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules.” Acc. Chem. Res. 26: 476-82. PhCH2NH2 NH2NH2 CH3CO2H NH2NH2
D A Evans, J. Johnson Rules for Ring Closure: SP2 Carbon& Related Systems Chem 206 Trigonal Carbon: EXocyclic Enolate Alkylation distance between reacting exo By definition, an exo-tet cyclization, but stereoelectronically behaves as an endo trig he overlap for C-alkylation is poor due to geometrical constraints of 5-membered ring only observed product distance between reacting The relaxed geometrical constraint KOt-Bu or LDA provided by the added CH2 group >95% by nMr now renders the 6-membered Baldwin. J. chem. Soc. Chem. Commun. 1977. 233 === a Given the failure of the enolate alkylation shown above(eq 1), explain why these two cyclizations are successful base Favorskii Rearrangement (Carey, Pt B, pp 609-610 Your thoughts on the mechani base NH OMs Meo Mec-
D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Chem 206 Trigonal Carbon: Exocyclic Enolate Alkylation Br MO Me Me Me Br Me Me O O Me Me ■ By definition, an exo-tet cyclization, but stereoelectronically behaves as an endo trig. KOt-Bu or LDA > 95% by NMR O Me Me O Me Me X Y C Y - exo C C C C O C –O only observed product However: Baldwin, J. Chem. Soc., Chem. Commun. 1977, 233. N O R R Ar R OMs R O NH Ar base N O Ar base NHAr O Br ■ Given the failure of the enolate alkylation shown above (eq 1), explain why these two cyclizations are successful. (1) Br MO O X The overlap for C-alkylation is poor due to geometrical constraints of 5-membered ring distance between reacting centers: 3.04Å distance between reacting centers: 3.37Å MO Br O The relaxed geometrical constraint provided by the added CH2 group now renders the 6-membered cyclization possible Favorskii Rearrangement (Carey, Pt B, pp 609-610) Your thoughts on the mechanism Cl O MeO– O CO2Me MeO– –HCl
D.A. Evans, J. Johnson Rules for Ring Closure: SP2& SP Carbon Related Systems Chem 206 Trigonal Carbon: Intramolecular Aldol Condensations Digonal Carbon: Cyclizations on to Acetylenes Baldwin. Tetrahedron 1982. 38. 2939 DIGONAL: Angle of approach for attack on triple bonds molenda)-EXo- aldwin 120 3 and 4-EXo-dig are disfavored Favored: 6-7-enolendo) -exo-trig Disfavored: 3-5-enolendo)-exo-trig 5 to 7-Exo-dig are favored 3 to 7-Endo-dig are favored (Enolexo) -exo-trig Ab initio scf 4-31G calculations for the interaction of hydride with acetylene Favored: 3-7-enolexo)-exo-trig H、 4-31G basis set 0 5(Enolendo)-Exo-trig 6-(Enolendol-Exo-trig 712 Houk. J.AcS1979,101,1340 H STo-3G minimal basis 110°120 Crystal Structures do not support Baldwin stical Distribution, (+ Ii)/=2: 1 erimental distribution (KOH, MeOH, r t, 5 min, 77%y) Caution: Baldwins conclusions assume that the RDs is ring closure however, it is well known(by some! that the rate determining step is dehydration in a base-catalyzed aldol condensation J Dunitz and j. wallis J. C. S. Chem. Comm. 1984. 671
D. A. Evans, J. Johnson Rules for Ring Closure: SP2 & SP Carbon & Related Systems Chem 206 Trigonal Carbon: Intramolecular Aldol Condensations R MO X Y R O X YM R MO X Y X YM R O O Me Me O Me O Me O Me O Me Me O O Me O Me O (Enolendo)-Exo-trig (Enolexo)-exo-trig Favored: 3-7-(enolexo)-exo-trig Favored: 6-7-(enolendo)-exo-trig Disfavored: 3-5-(enolendo)-exo-trig 5-(Enolendo)-Exo-trig 6-(Enolendo)-Exo-trig Statistical Distribution, (I + II)/III = 2:1 Experimental Distribution, = 0:100 (KOH, MeOH, r.t., 5 min, 77% y.) Baldwin, Tetrahedron 1982, 38, 2939 favored Caution: Baldwin's conclusions assume that the RDS is ring closure; however, it is well known (by some!) that the rate determining step is dehydration in a base-catalyzed aldol condensation. Digonal Carbon: Cyclizations on to Acetylenes DIGONAL: Angle of approach for attack on triple bonds - 3 and 4-Exo-dig are disfavored - 5 to 7-Exo-dig are favored - 3 to 7-Endo-dig are favored Baldwin: Ab initio SCF 4-31G calculations for the interaction of hydride with acetylene: J. Dunitz and J. Wallis J. C. S. Chem. Comm. 1984, 671. N N N + O- + Crystal Structures do not support Baldwin H H C C H H H C C H H H _ 127 o 156o 148o 2.13 4-31G basis set Houk, J.ACS.1979, 101, 1340. 1.22 110o -120o 1.5-2.0 STO-3G minimal basis set Dunitz, Helv Chim. Acta 1978, 61, 2538. N O N N 104o 93o 2.44 2.92 86o 120° 120° E + NuI II III H
D A Evans, J. Johnson Rules for Ring closure: SP Carbon Related Systems Chem 206 Endo Digonal versus Endo Trigonal Cyclizations Indole synthesis CHaR 5-endo-trig R=Me, Bu, CO, Me LiTMP Out-of-plane approach nucleophile lone pair is nucleophile lone pair can't Saegusa, J. Am. Chem. Soc. 1977, 99, 3532 rthogonal to t achieve Burgi-Dunitz angle 5-endo-dig I Spiro dihydrofuranones Allowed due to in-plane pi orbitals KOBu For an opposing viewpoint to Baldwin's view of nucleophile trajectories, see Developing negative charge on the central allenic carbon is Menger's article on directionality in solution organic chemist in the same plane as the oMe group Tetrahedron 1983. 39. 1013 Magnus, J Am. Chem. Soc. 1978, 100, 7746 MeOH 5-endo-dig NaOMe 5-endo-trig however, the acid catalyzed version does cyclize 4-endo-dig win. J. Chem. Soc. Chem. Commun. 1976. 736 4928:909236
D. A. Evans, J. Johnson Rules for Ring Closure: SP Carbon & Related Systems Chem 206 Endo Digonal versus Endo Trigonal Cyclizations 5-endo-trig In-plane approach; nucleophile lone pair is Out-of-plane approach; nucleophile lone pair can't achieve Bürgi-Dunitz angle X: Y orthogonal to p* Y :X Allowed due to in-plane pi orbitals For an opposing viewpoint to Baldwin's view of nucleophile trajectories, see Menger's article on directionality in solution organic chemistry: Tetrahedron 1983, 39, 1013. 5-endo-dig OH O R O O R 5-endo-trig R = H, OMe 5-endo-dig HO O Ph Me Me O Me Me Ph O NaOMe MeOH however, the acid catalyzed version does cyclize Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736. Johnson, Can. J. Chem. 1990, 68, 1780 J. Am. Chem. Soc. 1983, 105, 5090 J. Chem. Soc., Chem. Commun. 1982, 36. CH3 N + C - CH2R N + C - N R 2 equiv. LDA 2 equiv. RX -78 oC R = Me, Bu, CO2Me LiTMP O _ HO OMe O OMe Saegusa, J. Am. Chem. Soc. 1977, 99, 3532. ■ Indole synthesis: ■ Spiro dihydrofuranones: n n Li MeO n KOtBu Developing negative charge on the central allenic carbon is in the same plane as the OMe group Magnus, J. Am. Chem. Soc. 1978, 100, 7746. n = 1,2 4-endo-dig 5-exo-dig Li Ph Ph Li Li Ph Li Ph X X X NaOMe Li+
D. A Evans, J. Johnson Rules for Ring Closure: SP Carbon Related Systems Chem 206 Digonal Cyclizations: Interesting EXamples EtN, Toluene, reflux Trost. J. Am. Chem. Soc. 1979 101. 1284 12h,65-70%1 Proposes E-olefin geometry, EZ>95: 5 5-exo-dig CO,Me 30-40 kcal'mol and caveats a Baldwin's Rules are an effective first line of analysis in evaluating the stereoelectronics of a given ring closure otbs 1)RCOCl a Baldwin's Rules have provided an important foundation for the 71% study of reaction mechanism studies between different modes of cyclization only R ve impemtatios on about relative rates and are not an absolute indicator of whether a process is"or disfavored Works for varying ring sizes and R groups acylnitriliur ion can also work as an electophile in a Friedel-Crafts a Structural modifications can dramatically affect the cyclization type of reaction mode; beware of imines and epoxides Livinghouse, Tetrahedron 1992, 48, 2209 Tet Trig Di Tet Trig Dig v√√
D. A. Evans, J. Johnson Rules for Ring Closure: SP Carbon & Related Systems Chem 206 O CN MeO2C O CO2Me CN R R' O OH HO2C H H O Me OTBS Me N + C - OTBS Digonal Cyclizations: Interesting Examples N + C 5-exo-dig Et3N, Toluene, reflux 12 h, 65-70% y. O R ■ Trost, J. Am. Chem. Soc., 1979, 101, 1284. Proposes E-olefin geometry, E/Z > 95:5 : N O O R H Me 30-40 kcal/mol ? Hirsutic Acid C LiCH2NC; TBS-Cl 71% 1) RCOCl 2) AgBF4 86% ■ Livinghouse, Tetrahedron 1992, 48, 2209. 5-endo-dig Works for varying ring sizes and R groups; acylnitrilium ion can also work as an electophile in a Friedel-Crafts type of reaction R R' : Conclusions and Caveats ■ Baldwin's Rules are an effective first line of analysis in evaluating the stereoelectronics of a given ring closure ■ Baldwin's Rules have provided an important foundation for the study of reaction mechanism ■ Competition studies between different modes of cyclization only give information about relative rates, and are not an absolute indicator of whether a process is "favored" or "disfavored" ■ Structural modifications can dramatically affect the cyclization mode; beware of imines and epoxides EXO Tet Trig Dig ENDO 3 4 5 6 7 Tet Trig Dig X X X X X X X X