C549 Pericyclic Reactions

Transcription

1 C549 Pericyclic Reactions Introduction Pericyclic reactions are a very special and important class of reactions that do not require the addition of any external chemical reagents These reactions, called pericyclic reactions, only require the addition of energy in the form of heat or light to proceed Chemists long ago recognized that certain molecules, when heated or exposed to light, would undergo chemical change It wasn t until the 1960 s, that a set of principles and mathematical theory to support these principles, were elucidated and published By examining the orbitals that are interacting in the bond-breaking and bond-forming process, it is now possible to predict with a high degree of reliability and accuracy, the outcome of pericyclic reactions The Conservation of rbital Symmetry A theoretical basis for understanding pericyclic reactions was postulated in 1965 by Roald offman of Cornell University and Robert B oodward of arvard University This theory, called the Conservation of rbital Symmetry stated: rbital symmetry controls in an easily discernible manner the feasibility and stereochemical consequences of every concerted reaction This powerful theory relied on the concepts of symmetry, overlap, interaction and the nodal structure of wave functions This theory was later elaborated by Fukui to introduce the concept of frontier molecular orbital theory Basically, pericyclic reactions can be analyzed and rationalized by examining the nodal structure of the wave functions of the highest (energy) occupied (filled) molecular orbital (also abbreviated the M) of one reactant and the lowest (energy) unoccupied molecular orbital (also abbreviated the LUM) of the other reactant The conservation of orbital symmetry theory predicted that the nodal symmetry of the interacting orbitals would be preserved throughout the reaction oodward and offman state in one of their important early papers in 1968: it is possible to transform continuously the molecular orbitals of reactants into those of the product in such a way to preserve the bonding character of all occupied molecular orbitals at all stages of the reaction All three chemists, oodward, offman and Fukui won the obel Prize in Chemistry oodward won the obel prize in 1965 for the art of complex molecule synthesis, work that empirically contributed to developing the oodward-offman rules offman and Fukui shared the obel prize in 1981 for their work on frontier molecular orbital theory which was developed directly from the work on the oodward-offman rules for pericyclic reactions rbital Symmetry-Controlled Reactions have the following characteristics: 1 These reactions require only heat or light (no external reagents) 2 These reactions do T involve ionic intermediates or free radicals 3 Bonds are made and broken simultaneously in a CYCLIC TRASITI STATE 4 These reactions are highly STERESPECIFIC Electrocyclic Reactions: Molecular rbitals of Conjugated ienes Many orbital symmetry-controlled reactions involve the reactions of conjugated polyenes Conjugated polyenes will contain either 4n or 4n2 p-electrons (where n= a whole integer) For butadiene, the simplest conjugated diene, there are 4n p-electrons, where n=1 For ethylene, there are 4n2 p-electrons where n=0 The p-molecular orbitals of these systems are comprised of atomic p-orbitals According to the principle of the linear combination of atomic orbitals (LCA) there must be the same number of p-molecular orbitals as there were atomic p-orbitals from which they (the p-system - a molecular system) were constructed Similarly, for ethylene, there must be two p-molecular orbitals corresponding to the two atomic p-orbitals that were used to construct the p-bond Butadiene has 4n p-electrons (where n=1) The molecular orbitals for butadiene and ethylene are shown below 1

2 UM LUM LUM Antibonding Bonding M LM LM Figure 1 Molecular orbitals of butadiene and ethylene Electrons populate these molecular orbitals in order of increasing energy according to und s rule and the Pauli exclusion principle The wave function coefficients ( or - ) for each p orbital is illustrated with either a shaded grey or white color The asterisk indicates nodes where the probability of finding an electron (in this case, a p-electron) is diminishingly small (ie, there is no bonding interaction or overlap) In order of increasing energy, the molecular orbitals for butadiene consist of two bonding molecular orbitals with two spin-paired electrons in each and two anti-bonding molecular orbitals which are vacant Similarly for ethylene, there is one bonding molecular orbital with two spin-paired electrons and one antibonding molecular orbital which is vacant Example: Consider the thermal interconversion of cis-dimethylcyclobutene to cis,trans-2,4-hexadiene (Figure 2): CIS,TRAS-ISMER LY Figure 2 e can understand this stereospecific transformation by examining the M (ighest ccupied Molecular rbital) (Figure 3): 2

3 UM LUM 4 Atomic p orbitals ATIBIG BIG M E = node LM Ground State Figure 3 Excited State In the example shown in Figure 2, the cis-dimethylcyclobutene is transformed stereospecifically into cis, trans-2,4-hexadiene Since pericyclic reactions are reversible, orbital symmetry rules govern the stereochemical outcome in both the forward and reverse directions In this case, it proves simpler to examine the orbital symmetry of the reacting orbitals for the reverse (ring-forming) reaction There are four possible rotational motions that the carbon atoms bearing the methyl groups can make: (1) both rotate clockwise; (2) both counterclockwise (which is identical in this particular case to (1)) hen both carbons rotate in the same direction (clockwise or counterclockwise) this is called conrotatory motion Alternatively, (3) one carbon rotates counterclockwise and the other rotates clockwise, or (4) one rotates clockwise and the other rotates counterclockwise (which in this particular case is identical to (3) hen the atoms in question rotate in opposite directions, this is called disrotatory motion In the example shown in Figure 4, we can see that the interacting p-orbitals at the termini will have a favorable, bonding symmetry if the motion is conrotatory (that is, each lobe of the interacting p- orbital has the same quantum mechanical sign coefficient ( or -, or in the diagrams used throughout, shaded or unshaded) Therefore, with conrotatory motion, bonding character is maintained throughout the reaction coordinate and orbital symmetry is preserved By the principle of microscopic reversibility, the ring-forming reaction of the diene to the cyclobutene must also occur in a conrotatory fashion giving only the cis product (observed experimentally) M s (SM) CRTATRY ME F RIG- PEIG TS (The reverse reaction is also concerted) M p (product) Figure 4 3

4 The remarkable stereospecificity of these reactions can also be seen in the example shown in Figure 5 for the interconversion of trans-dimethylcyclobutene and trans,trans-2,4-hexadiene Again, an orbital symmetry analysis (Figure 6) can be used to rationalize (and predict) the stereochemical outcome of this reaction Trans Trans, Trans-isomer only Figure 5 PTCEMICAL -Examine LUM (which is M in the EXCITE STATE) ES M (=GS LUM) cis-isomer only trans-isomer only ISRTATRY MTI Figure 6 Figure 6 In the photochemical reaction, examine the LUM from Figure 3 which corresponds to the M in the photochemically excited state In the examples shown above, a total of four electrons are involved in the ring closure/ring-opening process e can also apply this analysis to higher conjugated polyenes containing, for example, 6 interacting electrons Consider the electrocyclic reaction of hexatriene to cyclohexadiene (Figure 7) Like the interconversions shown above, this process occurs under either thermal or photochemical conditions Before considering the stereochemical aspects of this reaction, examine the molecular orbitals of the parent hexatriene shown in Figure 8 6-electron system or Figure 7 The concerted interconversion of 1,3,5-hexatriene and 1,3-cyclohexadiene ote that there are 6 paired electrons in the three lowest energy (lowest lying) orbitals (the bonding M s) and that the three highest energy orbitals are vacant (anti-bonding M S) Also note the increasing number of nodes (0-5) for each orbital of increasing energy 4

5 # of nodes LUM 2 E M 1 0 Figure 8 Molecular orbitals of 1,3,5-hexatriene Using the same method of analysis used above, let s examine the highest occupied molecular orbital (M) of the hexatriene As shown in Figure 9, we can see that under thermal conditions (ground state of the reactant), a disrotatory motion leads to a net bonding (overlap) interaction of the interacting p-orbitals Conversely, when we excite an electron from the M of the ground state to the next highest energy orbital (the LUM of the ground state) photochemically, the symmetry of that molecular orbital mandates a conrotatory mode of ring closure 5

6 Ground State M (GS) Excited State M (ES) ISRTATRY CRTATRY Stereochemistry Figure 9 Based on both a large number of empirical observations as well as theoretical work, a set of rules governing electrocyclic reactions has been put forth by oodward and offman These rules can be used to predict the mode of ring closure/ring-opening as either conrotatory or disrotatory based on the number of electrons in the conjugated polyene These rules are summarized in Table 1 AR-FFMA RULES # of e - Total Rotation irection Conditions 4n 4n 4n2 4n2 Conrotatory isrotatory isrotatory Conrotatory Table 1 The oodward-offman Rules 6

7 Sigmatropic Reactions Another class of pericyclic reactions involve the formal transposition of a s-bond that is situated in a doubly allylic framework Figure 10 displays the prototypical substrate which undergoes this process when heated [3,3] TE CPE REARRAGEMET 3' 2' 1' Figure 10 The Cope Rearrangement Transition State: CAIR M Figure 11 Transition state for [3,3]-sigmatropic rearrangements ' 1' 2' [3,3] TE CLAISE REARRAGEMET Figure 12 The Claisen rearrangement CRISMATE MUTASE: Pericyclic reactions occur in nature but are relatively rare ne prominent example, is the [3,3] sigmatropic rearrangement catalyzed by the enzyme chorismate mutase (Figure 13) This enzyme, which exists in all plants and microbes catalyses the only known biosynthetic [3,3] sigmatropic rearrangement This reaction is a key step in the biosynthesis of the aromatic amino acids (Phenylalanine, Tryptophan & Tyrosine) C 2 2 C C 2 Chorismate mutase [3,3] C 2 Claisen chorismic acid prephenic acid C 2 2 Phenylalanine TS 2 C C 2 [3,3] Figure 13 The Claisen rearrangement catalyzed by chorismate mutase 7

8 Examples of the Cope Rearrangement: Cope [3,3] 3 C Cope [3,3] C 3 This is a degenerative Cope rearrangement (If the reactant was optically active, the Cope would racemize this compound) Figure 14 egenerative Cope Rearrangements: In situations where the starting material and product are identical (G o = 0), rapid equilibration between identical structures is often observed For example, in bullvalene, all C groups are equivalent by 1 nmr at 120 o C The iels-alder Cycloaddition Reaction Figure 15 The degenerative Cope rearrangement of bullvalene By far, the most important use of conjugated dienes are in condensation reactions with other unsaturated compounds forming six-membered rings This reaction, discovered in 1928 by tto iels and Kurt Alder, established that conjugated dienes react with certain unsaturated compounds (called dienophiles ) with only the application of thermal energy (heat); no other reagents, acids, bases, reducing or oxidizing agents were required The general reaction is shown below and proceeds through a concerted sixmembered ring transition state This reaction forms two C-C s-bonds simultaneously and concomitantly forms a single new C=C p-bond Figure 16 The iels-alder Cycloaddition Reaction The transition state for the iels-alder reaction is highly ordered with a boat-like geometry A molecular orbital picture, shown below (Figure 17), illustrates the interactions The reaction is a concerted, orbital symmetry-controlled process meaning, that there is a smooth and continuous transformation of the interacting orbitals in the starting materials to those in the product There are no discreet charged intermediates and no exogenous reagents are required (other than heat) "IEE" = "IEPILE" Figure 17 Interacting molecular orbitals of the iels-alder Cycloaddition 8

9 Since the iels Alder reaction involves the interaction of 4-p-electrons from the diene and 2-p-electrons from the dienophile, this reaction is also called a [42] cycloaddition reaction iels-alder reactions, like other classes of pericyclic reactions, are stereospecific owing to the one-step, cyclic transition state mechanisms UM LUM LUM Antibonding Bonding M LM LM Figure 18 Molecular orbitals of butadiene and ethylene If we examine the possible M/LUM interactions of butadiene with ethylene, which are the parent substrates upon which we can analyze the iels-alder reaction (Figures 18 and 19), we can see that the symmetry of the orbitals is preserved in the ground state (ie, thermal conditions) SYMMETRY-ALLE M-LUM ITERACTI Approximate transition state geometry: M (diene) LUM (dienophile) View A View B The lengths of the forming C C bonds are Ca 15 times the normal bond distance This factor comes out of various theoretical calculations Figure 19 Transition state for the iels-alder Reaction Structural, Regio- and Stereochemistry of the iels-alder Reaction The iels-alder cycloaddition has become an exceptionally powerful reaction in synthetic organic chemistry for the construction of six-membered rings Let s examine some of the salient structural, regio- and stereochemical issues The diene component must be capable of adopting the s-cis conformation to participate in the iels-alder reaction (Figure 20) The other main conformer, the s-trans conformer, places the termini of the diene component too far apart to interact with the p-orbitals of ethylene In addition, cycloaddition from the s-trans conformer would yield an extremely strained cyclohexene product with a trans-double within the ring that is geometrically impossible 9

10 the end p-orbitals are too far apart in the s-trans conformation s-cis s-trans reactive geometry unreactive geometry C 3 C3 cis,cis-cyclic 1,3-dienes are locked in the correct geometry for the iels-alder C 2 C 3 C 2 C 3 dienophile IELS ALER PRUCT this 1,3-diene is locked in the unreactive s-trans geometry and does not undergo the iels-alder cycloaddition Figure 20 The iels-alder reaction mandates an s-cis diene geometry Some additional examples of the iels-alder cycloaddition illustrate that the reaction is highly stereospecific C 2 C 3 C 2 C 3 C 2 C 3 C 2 C 3 cis cis-only C 2 C 3 C 2 C 3 3 C 2 C C 2 C 3 trans trans-only Figure 21 C 3 acyclic diene cyclic diene C3 C 3 C 3 C 3 C 3 C 2 C 3 C 2 C 3 C 3 C 3 Figure 22 Electronic rate acceleration Consideration of the FM s of diene and dienophile components in the iels- Alder cycloaddition dictates that the addition of electron-withdrawing substituents on the dienophile should lower the energy of the LUM of the dienophile resulting in a lower E and a commensurate rate acceleration This has been borne out repeatedly experimentally This is illustrated in Figure 23 10

11 Ethylene & Butadiene vs Butadiene & Acrolein LUM 2 LUM 1 E LUM 3 M 2 M 1 M 3 E (LUM 3 -M 1 ) < E (LUM 2 -M 1 ) Rate Acceleration Figure 23 Lewis acid catalysis A consideration of the M/LUM interactions in the iels-alder reaction leads to the prediction that Lewis acid catalysis should lower the M of the dienophile in normal electron-demand iels-alder reactions leading to amore favorable FM interaction as illustrated below (Figure 24): Ethylene & Butadiene vs Butadiene & Acrolein LUM 2 LUM 1 E LUM 3 M 2 M 1 M 3 E (LUM 3 -M 1 ) < E (LUM 2 -M 1 ) Rate Acceleration Figure 24 The E Rule Based on a large body of experimental evidence, the iels-alder reaction favors a transition state with the maximum of secondary orbital overlap Thus, these cycloadditions are governed generally by the E RULE, which can be stated as follows: hen the dienophile has a p-system comprising its electronwithdrawing group this p-system will overlap with the 2,3-p-orbitals of the diene favoring formation of the E product This type of interaction has been popularly called secondary orbital overlap and involves weak bonding interactions between the respective p-systems Recent theoretical work however, has revealed that there is no quantum chemical basis for secondary orbital overlap and that dipolar and solvent medium effects are most likely responsible for the physical basis of the endo rule For pertinent references, see: (1) Substituent Effects and Transition State Structures for iels-alder reactions with Butadiene and Cyclopentadiene with Cycloalkanes ouk, K; Loncharich, RJ; Blake, JF; Jorgensen, L, J Am Chem Soc, 1989, 111, 9172~9176 (2) Influence of Reactant Polarity on the Course of (42) Cycloadditions Sustmann, R; Sicking,, J Am Chem Soc, 1996, 118, 12562~

12 (3) Solvent Effects on Endo/Exo Selectivities in (42) cycloadditions of Cyanoethylenes Karcher, T; Sicking, ; Sauer, J; Sustmann, Tetrahedron Lett, 1992, 33, 8027~8030 The endo rule is depicted with examples in Figures disfavored favored "Exo product" "Endo product" Secondary bservation: The endo iels-alder adduct is formed faster even though the exo orbital overlap product is more stable There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state Exo TS Endo TS Endo TS Energy 2 f the two possible transition states, the one having the "greatest accumulation of interacting double bonds will be preferred" (the Alder Endo Rule) Secondary orbital overlap is noted below Exo TS Figure 25 E (major) EX (minor) Secondary overlap E TRASITI STATE EX TRASITI STATE Figure 26 The E Rule 12

13 E d,l EX d,l Figure 27 C 3 C 3 trans,trans C 3 C 3 C 3 C3 C 3 C 3 cis,cis C 3 C3 C 3 C 3 C 3 C 3 cis,trans C 3 C 3 C 3 C3 Figure 28 Substituent Effects ormal iels-alder reactions contain an electron-donating group () on the diene and an electronwithdrawing group () on the dienophile Two different regio-isomers are possible, but the reaction is highly regio-selective (Figure 29) For example, with a diene containing an electron-donating group (eg, C 3 ) at C-2 of the diene, only the 1,4-product is observed and the alternative 1,3-product is not obtained 1,4-product (observed) 1,3-product (not observed) Figure 29 The regiochemical outcome in the examples shown in Figures 29 and 30, can be rationalized based on the polarity of the diene and dienophile components The relevant resonance structures (Figure 31) clearly 13

14 illustrate the complementary polarity of the two reacting components leading to the (observed) 1,4- and 1,2- substitution products 1,2-product (observed) 1,3-product (not observed) Figure 30 Figure 31 Resonance helps predict the regiochemistry of the iels-alder cycloaddition The iels-alder reaction has proven to be one of the most powerful methods for constructing sixmembered rings and has been exploited extensively in the synthesis of natural products Both intermolecular and intramolecular versions of this reaction have been used very successfully Example of syntheses of the natural products lancanthocarpone and marasmic acid are shown below that utilize the intramolecular iels-alder reaction as the key ring-forming reaction [ox] Ac C 2 2 C Ac lancanthocarpone C Marasmic acid Figure 32 Examples of the intramolecular iels-alder reaction in synthesis of natural products In many applications, the dienophile can be generated from a precursor molecule and then induced to participate in the [42] cycloaddition Try to write a mechanism for the condensation reaction shown below in Figure 33 3 C 3 C C C 3 C 3 3 C 3 C C C 3 C 3 Figure 33 14

15 [22] Photocycloadditions: Cyclobutane Synthesis The iels-alder reaction was an example of a [4n2] p-electron cycloaddition reaction (where n=1; with a total of 6-p-electrons interacting) that was symmetry allowed thermally ther types of p-systems with 4n2 p-electrons also undergo symmetry-allowed cycloaddition reactions Experimentally, it has been known for a long time that, ethylene derivatives do not undergo cycloadditions thermally but do undergo cycloadditions photochemically This is known as a photochemical [22] cycloaddition reaction and provides a very useful method to make cyclobutane derivatives (Figure 34) C 2 C 2 C 2 C 2 Figure 34 The photo [22] cycloaddition e can rationalize why the [22] cycloaddition reaction is forbidden thermally by applying orbital symmetry rules The p-molecular orbitals for ethylene in the ground state are shown in Figure 35 Using the analysis we used above for the [42] cycloaddition reaction, the highest occupied molecular orbital (M) of one ethylene will interact with the lowest unoccupied molecular orbital (LUM) of another ethylene molecule In order to maintain a bonding character of all the orbitals throughout the reaction (ie, conserve orbital symmetry), there should be no nodes between interacting orbitals As you can see from the figure below, the M-LUM interaction of ground state ethylene is symmetry forbidden due to the appearance of a node between two of the interacting p-orbitals LUM Antibonding Bonding M Ground State Figure 35 p-molecular orbitals of ethylene e can the symmetry-forbidden interaction in the ground state-ground state interactions in Figure 36 Antibonding interaction (node) LUM (GS) M (GS) Symmetry FRBIE Figure 36 e can promote an electron from the lowest energy p-molecular orbital of ethylene to the next highestenergy orbital photochemically generating the excited state of ethylene As shown in Figure 37, the M of ethylene in the excited state corresponds to the LUM of ethylene in the ground state 15

16 LUM M Antibonding Bonding M LM Ground State Excited State Figure 37 ow, if we examine the interaction of the M of one ethylene that is in the photochemically excited state with the LUM of another ethylene that is in the ground state, we can see that orbital symmetry will be preserved for the photocycloaddition reaction (Figure 38) LUM (GS) M (ES) Symmetry Allowed! Figure 38 The photochemical [22] cycloaddition reaction has become a very potent tool for constructing fourmembered rings An example given below in Figure 39, illustrates the use of the [22] cycloaddition in the synthesis of grandisol, the boll weevil pheromone 3 C C 2 C 2 3 C 3 C several steps C 2 C 3 Grandisol (boll weevil pheromone) Figure 39 Study problem: Propose a mechanism for the following transformation: C 2 R R C 2 Thymine imer Formation in A An important biochemical example of a photo [22] cycloaddition reaction is the UV light-induced dimerization of adjacent thymine base pairs in A The product, the TYMIE IMER (Figure 40) is a lesion in A that must be repaired; the production of this lesion has been strongly implicated in skin cancer 16

17 3 C Rib 3 C Rib Rib Rib 3 C 3 C The Thymine imer Figure 40 Photo [22] formation of the thymine dimer results in damage to A UV irradiation has been known for a long time as a potent means of damaging cellular A and other vital compounds The mechanism for UV-induced A damage is fairly well understood A absorbs light in the ultraviolet portion of the electromagnetic spectrum Thymine bases situated directly adjacent on a strand of A are p-stacked in the double helix (see Figure 41) and align the p-systems of the heterocyclic thymidine rings proximally Upon absorption of ultraviolet irradiation, the thymine p-system is excited to a higher energy excited state and undergoes a subsequent symmetry-allowed [22] photocycloaddition reaction resulting in the cyclobutane photoadduct (shown) The thymine dimer can cause lesions in A (strand breaks or replication mismatches) unless repaired There are two main mechanisms for repairing such lesions in A An EXIUCLEASE enzyme can detect the presence of the thymine dimer and cut out a twelve base residue including the thymine dimer The gapped A is then refilled with A PLYMERASE and ligated back together with A LIGASE Another repair mechanism involves A PTLYASE This enzyme effects the photosensitized symmetry-allowed [22] cycloreversion of the thymine dimer back to the original T-T sequence Extensive UV light irradiation can, however, damage the genes responsible for directing the synthesis of these repair enzymes UV-induced A damage (ie, thymine dimer formation) is one of the primary mechanisms responsible for skin cancer - - P 3 C - - P - 3 C - Photochemical [22] cycloaddition - P 3 C P - 3 C P - - P P - - P P - P- Figure 41 Photochemical formation of the thymine dimer in duplex A 17

18 C549 Electrocyclic Reactions: Examples RM illiams conrot [1,7] 7-dehydrocholesterol previtamin 3 (precalciferol) viamin o C Cl 90% conrot Cl disrot [red] xylopinine Kametani, T; gasawara, K; Takahashi, T, Tetrahedron, 1973, 29, 73 xyanion-accelerated Cope Rearrangements: a, TF 88% [3,3] C 2 coronafacic acid EE Jung, ME; udspeth, JP; JAmChemSoc, 1980, 102, 2463 K K TMSCl; 18-Cr-6 m-cpba EE EE periplanone B Still, C, JAmChemSoc, 1979, 101, 2493 Ireland-Claisen Rearrangement: 2 C (i-pr) 3 SiTf [3,3] 2 C Ph,, Et 3 2 C Si(i-Pr) 3 2 C Si(i-Pr) 3 2 C Funk, RL; lmstead, TA; Parvez, M, JAmChemSoc, 1988, 110, 3298 ingenol 18

19 iels-alder Cycloadditions: C 3 C 3 C 3 C 3 3 C 3 C C 3 C 3 C C 3 C 3 C conrotatory electrocyclic ring-opening C C 3 C 3 iels-alder [42] Bn C 2 Bn, 55% C / Pd-C, 2 BrC 2 C 2 Br, MF a 2 C 3 20% minovine C 2 MM Ziegler, FE; Spitzner, EB, JAmChemSoc, 1970, 92, 3492 LA Li MM Bn [42] or double Michael? 62% MM Bn steps MM Bn Br, 2 aac Br MM Bn Zn o MM Bn steps pleuromutilin Gibbons, EG, JAmChemSoc, 1982, 104, 1767 Kt-Bu MS PdCl 2, aac 46% Chapman, L; Engel, MR; Springer, JP; Clardy, JC, JAmChemSoc, 1971, 93, 6696 carpanone 19

20 C 2 Ph, C 2 1 ab 4 2 PhC 3 C 2 Ac 2 aac Al(i-Pr) 3 i-pr Br a BS, 2 2 S 4 Cr 3 Ac Br Zn o, 1 C Ac 2, py 2 C Ac 1 s 4, 2 2 acl 4 2 C Ac 1 ai 4 2 C C 2 C C Ac 2 1 Ph 2 ab 4 2 C Ac 1 PCl 3 2 ab 4 2 C Ac 1 a 2 gallic acid chloride 2 C reserpine oodward, RB; Bader, FE; Bickel, ; Frey, AJ; Kierstead, R, JAmChemSoc, 1956, 78, 2023; Tetrahedron, 1958, 2, 1 deoxybrevianamide E 3 BF % Q 24-60% K, 2, 0 o CÆ rt 1 mcpba, TF 2 a, 3 Cl, (46%) 68% SY 2 : 1 (65%) d,l-breviaamie B ATI illiams, RM; Sanz-Cervera, JF; alligan, K; Sancenon, F JAmChemSoc JAmChemSoc 1998, 120,

21 n the Importance of Secondary rbital verlap in the iels-alder Reaction: igh level theory has failed to provide evidence for secondary orbital overlap as being responsible for the observed proclivity of the iels-alder cycloaddition reaction to favor the endo product; see: Sustmann, R, et al, Tetrahedron Lett, 1992, 33, 8027~8030 Sustmann, R, et al, JAmChemSoc, 1996, 118, 12562~12571 ouk, K; et al, JAmChemSoc 1989, 111, 9172~9176 FM: Cope rearrangement c b b' c' a a' M abc / LUM a'b'c' s / p two "allyl radicals" 21