An Unexpected Ireland–Claisen Rearrangement Cascade During the Synthesis of the Tricyclic Core of Curcusone C

Subscriber access provided by Caltech Library Article An unexpected Ireland–Claisen rearrangement cascade during the synthesis of the tricyclic core of Curcusone C: Mechanistic elucidation by trial-and- error and automatic artificial force-induced reaction (AFIR) computations Chung Whan Lee, Buck L. H. Taylor, Galina P. Petrova, Ashay Patel, Keiji Morokuma, K. N. Houk, and Brian M. Stoltz J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 Mar 2019 Downloaded from http://pubs.acs.org on March 25, 2019

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1 2 3 4 5 6 7 An unexpected Ireland–Claisen rearrangement cascade dur- 8 ing the synthesis of the tricyclic core of Curcusone C: Mech- 9 10 anistic elucidation by trial-and-error and automatic artificial 11 12 force-induced reaction (AFIR) computations 13 †║§ ‡ § ⊥ ‡# ⊥¶a 14 Chung Whan Lee, Buck L. H. Taylor, ∇ Galina P. Petrova, Ashay Patel, Keiji Morokuma, K. 15 N. Houk,‡* Brian M. Stoltz†* 16 † 17 Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical 18 Engineering, California Institute of Technology, Pasadena, California 91125, United States 19 ‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States 20 ⊥Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan 21 22 a 23 Deceased November 27, 2017 24 KEYWORDS natural products, unexpected rearrangement, curcusone, total synthesis, divinylcyclopropane rearrangement 25 26 27 ABSTRACT: In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered 28 an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. 29 Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the “trial- 30 and-error” testing of various conceivable mechanisms (Houk group) and an “automatic” approach using the Maeda–Morokuma 31 AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade 32 mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrange- 33 ment/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally-allowed pericyclic 34 rearrangements. 35 36 37 1. Introduction likely to occur. Various mechanisms are then explored, guid- 38 ed by chemical intuition and prior results. Intermediates and 39 In the course of multistep total synthesis efforts directed toward a complex molecule, organic chemists sometimes seren- transition states are optimized to obtain energetics for each 40 dipitously discover unexpected structures that arise from un- proposed mechanism, and pathways with activation energies 41 known rearrangement cascades. It is often difficult to deter- too high to be possible are eliminated from consideration. We 42 mine the reaction mechanism. Besides the chemists’ intrinsic refer to this procedure as the “trial-and-error” approach. Gen- 43 curiosity about how the reaction occurs, it is important to in- erally, one mechanism consistent with experimental rates is 44 vestigate an unexpected reaction to understand its potential obtained in this way, but it is always possible that the actual 45 mechanism in order to expand the potential of the reaction. mechanism has not been discovered. 46 Computation has become an important tool to assist in mecha- Because of this lingering concern about overlooking the 1 47 nistic reasoning. As density functional theory (DFT) methods “global minimum mechanism,” or to avoid the use of chemical 48 have become more able to deal with the relatively large (for intuition, chemists have developed new algorithms to predict mechanisms.2,3 One of these, AFIR (artificial force-induced 49 theory) molecules studied by synthetic chemists, it has become an able partner with experiment in exploring mechanism. This reaction), devised by Maeda and Morokuma, involves apply- 50 paper describes a synthetic approach to curcusone C, inter- ing forces to stretch bonded atoms apart or force non-bonded 51 rupted by an unexpected skeletal rearrangemented. Because atoms together, and then a series of calculations to map out 2 52 the mechanism of this rearrangement was not clear, and the low energy mechanisms from reactant to product. This has 53 only likely possibility is forbidden by the Woodward– led to a family of such methods and reasonable success in 54 Hoffmann rules, computations were undertaken to uncover finding known mechanisms and sometimes discovering new 55 other plausible mechanisms. mechanisms. Other methods such as Martinez’s “nanoreactor” 56 The conventional approach to computational mechanism use high temperature molecular dynamics to determine reaction mechanisms, but this method has been applied only to 57 elucidation involves first selecting a method, nowadays one of 3 58 the DFT methods, that will give accurate (± 1 or 2 kcal/mol) small gas-phased processes. MNY methods, such as Chan- dler’s “throwing ropes over rough mountain passes – in the 59 energetics for the atoms involved and the types of mechanisms 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 2 of 12

dark,”4 or Zimmerman’s “Growing String Method”5 are more O O O H HH H 1 or less automatic ways of finding transition states for conver- 1 2 1 H H H R 10 8 10 8 sion of one molecule to another but require intensive calcula- 4 2 R1 2 4 3 tions to locate the lowest energy pathway. All of these meth- HO MeO ods are designed to find the best pathway across a potential O O O 4 Curcusone R1 R2 surface to convert reactants into products, but are less appro- Curcusone E (5) Curcusone F (6) 5 A (1) Me H 6 priate for multi-step mechanisms that often occur in organic B (2) H Me chemistry. C (3) Me OH 7 D (4) OH Me 8 In the course of synthetic studies by the Stoltz group toward O O O H 9 the natural product curcusone C, an unexpected reaction prod- H H H uct was encountered from a synthetic intermediate. Chal- H H H 10 OH R O O lenged to use computations to determine the mechanism of the OH 11 MeO MeO reaction, the Houk and Morokuma groups agreed to test the O O O 12 conventional “trial-and-error” and the automatic Maeda– Curcusone G (7) Curcusone H (8) R = β-Me : Curcusone I (9) R = α-Me : Curcusone J (10) 13 Morokuma AFIR methods. The calculations were performed originally reported structures 14 by the Houk and Morokuma groups, respectively. We wished 15 to see which method worked best and the relative time needed H 16 to determine an unknown mechanism for a real organic prob- H lem. In the event, Morokuma’s group using AFIR, and O 17 O Houk’s group, using the “trial-and-error” methods, converged 18 Spirocurcasone (11) 19 on the same mechanism for which experimental analogy was then found in the chemical literature. Both took about one 20 Figure 1. Curcusones A−J (1–10) and Spirocurcasone (11). year of part-time human effort and significant computer time. 21 This paper describes a general mechanism for the unusual Curcusones (1–10) possess novel tricyclic skeletons featur- 22 reaction discovered and provides an assessment of the apti- ing a 2,3,7,8-tetrahydroazulene-1,4-dione moiety with four 23 tudes of currently available methods to solve such problems. stereogenic carbon centers. Since the initial isolation in 1986, 24 2. Background a completed total synthesis has not been reported, although 25 Dai recently completed elegant syntheses of the proposed 26 Native to Central America, Jatropha curcas is a species of structures of curcusones I and J (9 and 10), but unfortunately flowering plant belonging to the Euphorbiaceae family that the data for the synthetic material did not match the isolation 27 can be found in many parts of the world. J. curcas has been 28 spectra, calling the original structural assignments into ques- used as a source of soap and lamp oil for hundreds of years, tion.7e Additionally, one methodological study for the con- 29 and recently J. curcas has attracted attention due to its possi- 6 struction of the 7-membered ring of curcusones A–D was re- 30 8 ble use in biodiesel production. ported in 2001. These interesting biological properties and 31 J. curcas has intrigued natural product chemists as a source structural features make the curcusones attractive targets, in- 32 of versatile diterpenoids. Diterpenes curcusones A–D (1–4), spiring us to undertake the total synthesis of curcusone C (3). 33 which possess novel tricyclic skeletons, were isolated by 34 Naengchomnong and co-workers in 1986.7a The structures of 35 curcusones B (2) and C (3) were confirmed by X-ray diffrac- 3. Results and Discussion 36 tion analysis. Primary NMR data indicated that curcusones A 3.1. Retrosynthetic analysis; Divinylcyclopropane 37 (1) and B (2) were epimeric at C(2), as were curcusones C (3) rearrangement strategy to curcusone C. and D (4). Recently, J. curcas has been further investigated 38 Our retrosynthetic analysis of curcusone C 3 is outlined in and yielded more natural products. In 2011, Taglialatela- 39 Scheme 1. We envisioned that natural product 3 could be Scafati and co-workers reported curcusone E (5) and spirocur- synthesized by oxidative cleavage, and olefin migration fol- 40 casone (11) as other secondary metabolites isolated from the 7b lowed by alpha carbon functionalization of tricyclic core 12. 41 plant and again found curcusones A–E. Furthermore, cur- The tricyclic core 12 could be prepared by divinylcyclopro- 42 cusones F–J (6-10) and 4-epi-curcusone E were discovered in pane rearrangement of cyclopropane 13 in a stereospecific 43 2013 (Figure 1), although the originally proposed structures of fashion by an endo-boat transition state. Construction of cy- 44 curcusones I and J have been called into question.7c,e Among clopropane 13 could be achieved via intramolecular cyclopro- curcusones A–E and spirocurcasone, curcusone C has the 45 panation followed by lactone opening of diazo ester 14. Cy- 46 greatest antiproliferative activity on L5178 cell lines (mouse -1 7b clopropanation precursor 14 could be disconnected by trans- lymphoma, IC in 0.08 µg mL ). Furthermore, curcusone C 47 50 esterification followed by diazo transfer of allylic alcohol, exhibited considerable potency toward HL-60 (human pro- 48 7c which itself would be assembled by cross-coupling of vinyl myelocytic leukemia, IC50 in 1.36 µM), SMMC-7221 (hu- 49 7c boronic ester 15 and vinyl triflate 16. Vinyl boronic ester 15 man heptoma, IC50 in 2.17 µM), A-549 (adenocarcinomic 50 7c would be prepared from cyclopentenone 17 according to lit- human alveolar basal epithelial, IC50 in 3.88 µM), MCF-7 9 51 7c erature precedent, and vinyl triflate 16 would be prepared (human breast cancer, IC50 in 1.61 µM), SW480 (human 10 52 7c from triflation of a known ketone derived from (+)-limonene colon adenocarcinoma, IC50 in 1.99 µM), and SK-OV3 (hu- 7d oxide (18). 53 man ovarian cancer, IC50 in 0.160 µM) cell lines. 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 12 Journal of the American Chemical Society

Scheme 1. Retrosynthetic analysis Scheme 2. Preparation of the Cyclopropane 25 1

2 O O H O 3 H H B HO O OTBS i-PrO O OTBS 4 Me O oxidative divinycyclopropane n-BuLi, THF, -78 ºC Me cleavage R Br B O rearrangement 5 O 3 steps (89% yield) O 12 OH 6 3 17 19 rac-15 7 transesterification OTf 8 O O O 9 O O OH O 10 OH O N2 20 O 22 11 Pd(OAc)2, PPh3 H cyclopropanation 12 and K3PO4, H2O, cat. DMAP, HO R lactone opening Dioxane, 60 ºC Et2O, 0 ºC O then TBAF 21 23 13 13 14 (91% yield) 14 cross-coupling (63% yield) 15 16 OTBS O O t-Bu O cat. N O- 17 2 Cu + O O BPin O- 18 O N N2 t-Bu 19 15 17 p-ABSA, Et3N O MeCN, 23 ºC 20 O toluene, 110 ºC TfO 21 (99% yield) 24 (65% yield) 25 22 23 24 16 (+)-limonene oxide (18) NHTs 25 O N 26 3.2. Model system approach and an unexpected TsNHNH2 27 O rearrangement MeOH 28 Due to the complex structure of diazo ester 14, we sought to (99% yield) 29 26 (X-ray) first examine the cyclopropanation and divinylcyclopropane 26 30 rearrangement sequence using model substrate 24. Studies on 31 this substrate could later be applied to limonene oxide (18) to With cyclopropane 25 in hand, we directed our attention to 32 accomplish the total synthesis. the divinylcyclopropane rearrangement in order to construct 33 Investigation started with preparing model cyclopropanation the tricyclic system. We first investigated silyl enol ethers as 34 precursor 24. Diazo ester 24 was synthesized from allylic the rearrangement precursor and divinylcyclopropanes 26 and 35 alcohol 21 via esterification with diketene (22) and a diazo 27 were prepared by silylation of ketone 25. Divinylcyclopro- 36 transfer reaction. Allylic alcohol 21 was derived by Suzuki panes 26 and 27 possessed a lactone moiety and would form two bridgehead olefins in 29 as a result of the divinylcyclo- 37 coupling of vinyl boronate rac-15 and cyclohexanone triflate propane rearrangement. Thus, silyl enol ethers 25 and 26 were 38 20 followed by deprotection. Vinyl boronate rac-15 was synthesized from known vinyl bromide 19,10 which was assem- expected to have low reactivity. Several nucleophiles (KOH, 39 bled by bromination, followed by Luche reduction and TBS NaOMe, Morpholine-DIBAL, Weinreb amine) were applied to 40 protection from pentenone 17. Subsequent cyclopropanation release the lactone in order to initiate the rearrangement reac- 41 tion; however all of our attempts were unsuccessful (Scheme was affected by Cu(TBS)2, and the desired cyclopropane 25 42 was observed in good yield. Cyclopropane 25 was easily con- 3). 43 verted to hydrazone 26, of which we were able to confirm the Scheme 3. Lactone opening screen 44 structure from crystal X-ray diffraction (Scheme 2). O 45 O O OR 46 O ROTf O

47 i-Pr2NEt, DCM 25 48 R = TES (95% yield) 26: R = TES 49 R = TBS (75% yield) 27: R = TBS 50 O OR 51 O Nucleophile Nu 52 HO O KOH 29 53 NaOMe OR Morpholine-DiBAL 54 NHMe(OMe) 28 (Not observed) anti-Bredt olefins 55 56 57 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 4 of 12

Although divinylcyclopropane 27 was expected to show low Scheme 5. Synthesis of tricyclic core 36 1 reactivity due to its lactone moiety and formation of two po- 2 tentially strained olefins (i.e., 33), surprisingly it transformed O O O 3 to another silyl enol ether (i.e., 30) under mild heating. De- O RhCl(PPh3)3, PPh3 O 4 spite significant efforts, structural determination of silyl enol TMSCHN2, i-PrOH, Dioxane, 60 ºC 5 ether 30 proved difficult. Ultimately, the tetracyclic structure 25 34 (65% yield) 6 of β-ketolactone 31, which was furnished by removing the TBS group, was confirmed by single crystal X-ray analysis 7 (Scheme 4). In solution, β-ketolactone 31 was spectroscopi- OH 8 AlR3 cally observed as a 10:1 mixture of keto/enol forms (i.e., 31 O 9 and 32) by 1H NMR. DIBAL, CH2Cl2 R3Al 10 O H H Scheme 4. An unexpected rearrangement 0 ºC - 23 ºC 11 24 h OH Me 12 OTBS O OTBS 35 36 O (59% yield) 13 hexane O 68 ºC O TBAF 14 36 h THF, 23 ºC 3.3. Mechanistic studies of the unexpected rear- 15 27 (50% yield) (57% yield) 16 30 rangement 17 In order to gain greater insight into this unexpected rearrangement, we examined several divinylcyclopropanes (Table 18 O O O OH H 1). The yield of the rearranged product is highest (57%) with 19 O O O a TES group, which undergoes complete desilylation (entry 1). 20 + O The TIPS group remains intact after rearrangement, with a 21 OTBS somewhat lower yield (39% yield, 20% recovered starting 22 31 (X-ray) 32 33 (Not Observed) material, entry 3). In contrast, vinyl lactone 34 did not under- (10:1 in CDCl3) 23 go the rearrangement to afford tetracycle (entry 4). Based on 24 these results, we envisioned that the silyl enol ether moiety 25 strongly affects or even participates in the transformation. 26 Table 1. The rearrangement of enol ethers. 27 O R O R O O 28 H O 29 O hexane, 68 ºC O + 30 36 h 31 32 entry R yield (%) 33 1 −OTES - 57 34 2 −OTBS 50 trace 35 Figure 2. X-ray structure of unexpected β−ketolactone 31. 3 −OTIPS 39 - 36 4 −Me not observed 37 We believed that ring strain from the lactone moiety pre- 38 vented the formation of the desired tricyclic system. To over- 39 come this obstacle, we imagined that the lactone moiety must We turned our attention to understanding the mechanism of 40 first be ruptured. Since previous attempts with silyl enol the unexpected rearrangement giving rise to 30. Thus, the ethers 26 and 27 were not satisfactory, we prepared divinylcy- rearrangement of 27 was repeated in toluene-d8 and monitored 41 1 1 13 42 clopropane 34 via Wittig-type olefination using Wilkinson’s by H NMR (Scheme 6) and H- C HMBC. While the NMR 43 catalyst and trimethylsilyl diazomethane as a methylene data showed smooth conversion to the rearranged product 30, source.11 The resulting divinylcyclopropane 34 was treated unfortunately no discernible intermediates were observed. 44 with DIBAL to reduce the lactone. Gratifyingly, reduction Scheme 6. NMR study 45 conditions also triggered the desired rearrangement, affording 46 a tricyclic system 36, likely via unstable bis-aluminum alkox- O OTBS O OTBS 47 ide intermediate 35 (Scheme 5). O O toluene-d8 48 49 80 ºC 27 1 1 13 50 H NMR and H- C HMBC spectra were collected 30 51 52 3.4. Computational studies 53 We undertook a computational study of the mechanism of 54 the rearrangement using both the “trial-and-error” approach 55 using standard transition-state search algorithms as imple- 56 mented in Gaussian 09,12 and automatic reaction path searches 57 using single-component AFIR simulations for intramolecular 58 59 60 ACS Paragon Plus Environment Page 5 of 12 Journal of the American Chemical Society

paths (SC-AFIR).2d In the latter method, reaction paths are while M06-2X led to much higher energies for transition states 1 explored automatically by applying an artificial force between with diradical character (see SI for details). 2 pairs of reactive atoms. Details on this method are given in The hypothesis that directed the trial-and-error approach 3 the Supporting Information. Here we describe how both was that the desired Cope rearrangement of 27 occurs, but 4 methods identified the same mechanism for the rearrangement cycloheptadiene 33 is unstable due to the presence of two 5 of 27 to form 30. bridgehead double bonds in a 9-membered ring (Scheme 8). 6 The Morokuma group employed the single component SC- Further rearrangement occurs to alleviate strain, forming ob- 7 AFIR method as follows. Atoms that were deemed likely in- served product 30 (along with desilylation to 31). This rear- 8 volved in the rearrangement were defined as reactive atoms. rangement is formally a suprafacial 1,3-shift of the enol silane, 9 The AFIR algorithm simulates bond-formation by applying an which is disallowed by Woodward–Hoffmann rules. That is, artificial force between pairs of atoms, systematically evaluat- the necessary 1r,3s sigmatropic shift is the only way that 33 10 ing all pairs of reactive atoms. In cases where the active atoms could be transformed to 30, and this anti-aromatic cyclic 4 11 are initially bonded, a negative force can be applied to simu- electron transition state or the diradical alternative were found 12 late bond-breaking. In this way, possible reaction paths were to be prohibitively high in energy (see Figure 5 below). We 13 sampled using a relatively low level of theory (HF/3-21G) to therefore expected that a stepwise rearrangement would be the 14 allow for a large number of simulations. Energy maxima and favored pathway, through either diradical intermediates or a 15 minima were automatically optimized to locate transition series of pericyclic reactions. Although zwitterionic interme- 16 states and intermediates, respectively. diates could also be proposed, these should be disfavored in 17 Beginning with model 27a, in which the TBS group was nonpolar solvents. 18 truncated to TES, the seven carbon atoms of the divinylcyclo- Scheme 8. Mechanistic hypothesis 19 propane moiety were defined as reactive atoms (Scheme 7, 20 highlighted in blue). A large number of possible reaction 21 pathways were found, but only the desired Cope rearrange- 22 ment to 33a had a low enough barrier to be feasible (35 kcal/mol, likely overestimated due to the low level of theory). 23 Other reaction pathways included vinylcyclopropane rear- 24 rangements and hydrogen shifts with prohibitively high barri- 25 ers (>60 kcal/mol, see Supporting Information). Subsequent 26 rearrangement of 33a was also simulated with the reactive 27 atoms shown in Scheme 7, but no reasonable transition states 28 could be located. These initial studies suggested that the de- 29 sired Cope rearrangement was likely, but did not suggest a pathway to the observed product 30. It was determined that 30 Our DFT study began by examining the Cope rearrange- 31 other reactive atoms may be involved, which will be discussed later. ment of model compound 37, in which the TBS group is re- 32 placed by TMS (Figure 3). The Cope rearrangement proceeds 33 Scheme 7. Summary of initial AFIR simulations via boat-like TS38, which is very similar to prior computed 34 Cope transition states of divinylcyclopropanes.18 The free en- 35 ergy barrier is about 26 kcal/mol, which is reasonable for the 36 reaction conditions but somewhat higher than Cope rear- 18 37 rangement of a simple divinylcyclopropane. The reaction is endergonic by about 8 kcal/mol, despite the release of strain in 38 39 the cyclopropane ring of 37. A structural analysis of Cope While the AFIR studies were underway, the Houk group product 39 shows the strain incurred by the two bridgehead 40 explored this mechanism by the more conventional “trial and alkenes (Figure 3, right). The alkenes are bent out of planari- 41 error” approach, using density functional theory (DFT) calcu- ty, with C–C=C–C dihedral angles of 141 and 150 degrees, to 42 lations. Geometries were optimized using B3LYP/6-31G(d) in accommodate the bicyclic system. The calculations predict 43 the gas phase. Single-point energy calculations were per- that the Cope rearrangement can occur, but intermediate 39 is 44 formed with the dispersion-corrected functional B3LYP-D3 unstable and will either revert to 37 or undergo further rear- 45 using the larger 6-311++G(2d,2p) basis set and the IEF-PCM rangement. solvation model for n-hexane. The B3LYP functional was 46 selected because it has been successfully used to study a num- Experimentally, reduction of the ester in divinylcyclopro- 47 ber of diradical processes, and we suspected diradicals could pane 34 with DIBAL leads to spontaneous Cope rearrange- 48 be involved in the present rearrangement. We also computed ment to cycloheptadiene 36. We modeled this reaction using 49 single-point energies using M11-L and M06-2X. While the diol 40 as a model for the postulated aluminum alkoxide in- 50 M06-2X functional has been shown to give accurate barriers termediate 35 (Figure 4). Cope rearrangement of 40 is exer- 51 and thermodynamics for pericyclic reactions,13 it can give gonic by about 15 kcal/mol, with a free-energy barrier of 52 unreliable (overestimated) energies for diradical processes.14 about 19 kcal/mol. The stability of cycloheptadiene 36 relative to 39 highlights the torsional strain incurred by the two 53 In contrast, M11-L is a local functional that has better perfor- mance for multi-reference systems, such as diradicals.15,16 The bridgehead double bonds in the 9-membered ring of 39. 54 Overall, these calculations are consistent with the hypothesis 55 ubiquitous functional B3LYP has also frequently been employed successfully in studies of radical processes.17 In the that bridging ester must be removed in order to forge the tricy- 56 current study, B3LYP-D3 and M11-L gave similar results, clic core via a divinylcyclopropane rearrangement. 57 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 6 of 12

1 2 3 4 5 6 7 8 9 10 11 12 13 Figure 3. Cope rearrangement of divinylcyclopropane 37 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Figure 4. Computed structures for Cope rearrangement of reduced divinylcyclopropane 40. 28 29 We next considered the possibility of a formal [1,3]-shift of ate 39 to the product 44. This surface involves breaking of C– 30 the enol silane in 39 to form 44, including the three limiting C bond a and formation of C–C bond b (Figure 5). This anal- 31 cases of concerted, dissociative, and associative processes ysis shows that a 70 kcal/mol barrier separates intermediate 39 32 (Scheme 9). We could not locate a transition state for the con- from product 44. Associative and dissociative processes are 33 certed process, which would violate Woodward–Hoffmann also ruled out, as the diradical intermediates 42 and 43 both 34 rules. The dissociative process involves C–C bond homolysis appear on the potential energy surface at about 70 kcal/mol. 35 to generate the allylic/vinylic diradical 42, while the associative process involves first C–C bond-formation to give the 36 cyclobutylcarbinyl diradical 43. Neither diradical could be 37 located as a minimum using unrestricted DFT calculations. 38 Scheme 9. Possible mechanisms for formal 1,3-shift 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Figure 5. Potential energy surface directly connecting in- 53 termediates 39 and 44 calculated using UB3LYP/6-31G(d). 54

55 While the silyl protecting group remains intact in the ob- 56 In order to conclusively rule out diradical processes, we calculated the potential energy surface connecting the intermedi- served product 44, the experiments presented in Table 1 estab- 57 lish that a silyl group is crucial for the reaction. We therefore 58 59 60 ACS Paragon Plus Environment Page 7 of 12 Journal of the American Chemical Society

considered participation of the silyl group in the rearrange- Scheme 10. AFIR simulations involving silyl migration 1 ment process. The 1,5-migration of silyl groups in protected 2 1,3-dicarbonyls has been reported to be rapid.19 Our calcula- 3 tions indicate that 1,5-silyl migration in 39 occurs in a con- 4 certed manner via distorted square pyramidal transition state 5 TS45 (Figure 6). The formation of silyl ketene acetal 46 is 6 endergonic with a barrier of 25.7 kcal/mol, making it competi- tive with the preceding Cope rearrangement. 7 8 Silyl ketene acetal 46 is poised to undergo an Ireland– 9 Claisen rearrangement to form the C–C bond (b) present in observed product 44. The Claisen rearrangement is predicted 10 to occur with a relatively low barrier of 20.3 kcal/mol to form 11 alkylidene cyclobutane 48 (Figure 7). Transition state TS47 12 corresponds to a concerted process, but has significant diradi- 13 cal character and is characterized by a very long breaking C–O 14 bond. We were also able to locate a stepwise process leading 15 through a diradical intermediate with a very similar barrier 16 (within about 1 kcal/mol). The structures and energetics of this 17 stepwise pathway are shown in the Supporting Information. 18 While alkylidene cyclobutane 48 is a relatively stable inter- 19 mediate, it undergoes an unusually facile retro-Claisen rear- 20 rangement via TS49 (14 kcal/mol). The formation of 50 is 21 exergonic due to release of the significant strain associated 22 with fused bicyclo[3.2.0]heptene system in 48. Importantly, the Claisen/retro-Claisen sequence 46→50 represents a formal 23 suprafacial 1,3-shift of the enol silane. A second 1,5-silyl shift 24 affords the observed product 44. 25 26 The free energy profile for the overall rearrangement of divinylcyclopropane 37 to give 44 is shown in Figure 8. The 27 initial Cope rearrangement and 1,5-silyl migration have simi- 28 lar overall barriers of about 26 kcal/mol, while the 29 Claisen/retro-Claisen steps have significantly lower barriers. 30 Although the Cope rearrangement and [1,5]-silyl shift are en- 31 dergonic, subsequent intermediates are significantly more 32 stable due to a sequential release of strain. The Cope rear- 33 rangement is predicted to be rate-limiting such that no subse- 34 quent intermediates build up over the course of the reaction, 35 consistent with experimental observations. 36 Amazingly, the Morokuma group arrived at the same con- 37 clusions at nearly the same time as the Houk group. After fail- 38 ing to find a pathway to 30 using the divinylcyclopropane 39 moiety as reactive atoms, several silyl shifts were tested using the AFIR approach. From TES-protected 33a, AFIR simula- 40 tions led to 39a via the same 1,5-silyl shift discussed above 41 (Scheme 10, atoms circled in blue are defined as reactive at- 42 oms). From 39a, with the three carbon atoms involved in the 43 apparent 1,3-shift defined as reactive atoms, the Claisen/retro- 44 Claisen sequence discussed above was also found from the 45 AFIR simulations. A single AFIR simulation located both 46 Claisen transition states and led to 44a. In this case, the AFIR 47 approach still required a chemist to define the correct target 48 atoms before a reasonable pathway was found, and both AFIR 49 and the “trial-and-error” approach independently converged to the same answer. 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 8 of 12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Figure 6. 1,5-silyl shift of enol silane 39. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Figure 7. Formation and ring-opening of alkylidene cyclobutane 48. 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Figure 8. Free-energy profile for formation of 44 by a [1,5]-silyl shift/Claisen/retro-Claisen rearrangement cascade. 57 58 59 60 ACS Paragon Plus Environment Page 9 of 12 Journal of the American Chemical Society

1 2 The alkylidene cyclobutane 48 represents a critical, and strained alkene in 48d. Importantly, 48d is predicted to be 3 somewhat surprising intermediate in the Claisen/retro-Claisen completely unreactive toward retro-Claisen rearrangement 4 sequence predicted by our DFT studies. Observation of 48 (TS49d), with a barrier of over 40 kcal/mol. Therefore, Cope 5 would provide conclusive validation of the proposed rear- rearrangement of 37d, or other derivatives lacking the fused 6 rangement cascade, but unfortunately 48 is predicted to under- cyclopentane, is predicted to give 48d as an observable prod- 7 go a very fast retro-Claisen rearrangement. As shown in Fig- uct. 8 ure 9, the trisubstituted alkene in 48 (the experimental system) In fact, a thorough examination of the literature for related is distorted from planarity with a C–C=C–C dihedral angle of 9 reactions revealed that this precise rearrangement was carried 146 degrees. This angle distortion in addition to the already out by Davies and coworkers in 1997!20 Upon heating, divi- 10 strained fused cyclobutene illustrate why 48 is reactive enough 11 nylcyclopropane 52 (a TBS derivative of 37d) undergoes rear- to undergo a highly unusual retro-Claisen rearrangement. rangement to methylidene cyclopropane 54 (Scheme 11). 12 Derivatives of 48 were investigated in hopes of finding a Though the mechanism was not known at the time, it was pro- 13 system where the alkylidene cyclobutane would be stable posed to involve a Cope rearrangement to the desired but un- 14 enough to be observable. Several derivatives are shown in observed [4.3.1]-bicycle 53, followed by further rearrange- 15 Figure 9, along with with free energies computed with respect ment. Amazingly, experimental validation of our computed 16 to the corresponding divinylcyclopropane 37. Removal of the mechanism was obtained 20 years ago. 17 fused cyclohexane stabilizes cyclobutane 48b slightly com- pared to 48. However, removal of the two methylenes of the 18 Scheme 11. Rearrangement reported by Davies 19 cyclopentene ring makes cyclobutanes 48c and 48d more sta- 20 ble by more than 10 kcal/mol. This modification removes the 21 strain associated with the alkene, allowing C–C=C–C dihedral angles near 180 degrees. In addition, the ring system flattens 22 out such that the alkene is no longer poised to engage the car- 23 bonyl in a retro-Claisen rearrangement. We were intrigued 24 whether these derivatives would be stable enough to be ob- 25 servable or even isolable. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

47 48 Figure 9. Stability of alkylidene cyclobutane 48 and derivatives. 49 The rearrangement cascade for the simplest (and most sta- 50 ble) methylidene cyclobutane 48d was calculated to compare 51 to the experimental system (Figure 10). The first three steps 52 of the sequence (Cope rearrangement/[1,5]-silyl shift/ Claisen 53 rearrangement) are very similar to the experimental system, 54 with somewhat lower barriers. The formation of methylidene 55 cyclobutane 48d is predicted to be exergonic and irreversible. 56 This is attributed to release of the strain associated with 57 strained alkenes in 39d and 46d to form the relatively un- 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 10 of 12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure 10. Free-energy surface for formation of alkylidene cyclobutane 48d, which is unable to undergo further rearrangement. 26 27 28 4. Conclusion Experimental procedures, characterization data, single crystal X- ray analysis, detailed computational methods, Cartesian coordi- 29 In summary, a unique reaction cascade of divinylcyclopro- nates, and complete reference for Gaussian 09. This material is 30 panes containing silyloxy groups was computationally sug- available free of charge via the Internet at http://pubs.acs.org. 31 gested, involving a quintet of five sequential thermally al- 21 32 lowed sigmatropic shifts. Both traditional “trial-and-error” AUTHOR INFORMATION 33 and the automatic AFIR method were successful in predicting 34 the same mechanism that has some precedent in the literature. Corresponding Author 35 Figure 8 summarizes this mechanism. Surprisingly, the cas- [email protected] 36 cade was found to include a cycloheptadiene intermediate with [email protected] 37 two bridgehead olefins via a [3,3]-Cope rearrangement. The intermediate was converted to the fused cyclobutane interme- 38 diate via a [1,5]-silyl shift followed by an Ireland–Claisen Present Addresses 39 rearrangement. Finally, the tetracyclic compound was formed ║ Corporate R&D, LG Chem, 188 Munji-ro, Yuseong-gu, Dae- 40 via a retro-Claisen rearrangement of the cyclobutane interme- jeon, 34122, Korea 41 diate and subsequent [1,5]-silyl shift. Based on the mecha- ∇ Department of Chemistry, University of Portland, 5000 N. 42 nism and free-energy analysis, divinylcyclopropanes with a Willamette Blvd., Portland, Oregon 97203 small-sized ring would result in unstable strained cyclobutane # 43 Department of Chemistry and Biochemistry, University of Cali- 44 intermediates that should undergo a retro-Claisen/[1,5]-silyl fornia at San Diego, La Jolla, California 92093 45 shift sequence to afford tetracycles. In contrast, the rearrangement cascade of divinylcyclopropanes without fused 46 carbocycles is expected to give a fused cyclobutane as an iso- 47 Author Contributions lated product. This was observed in the earlier Davies work.20 48 Computation has been found to be useful in the elucidation of §These authors contributed equally. 49 a complex mechanism, and with current computer power, both 50 the trial-and-error, and the automatic AFIR method were ACKNOWLEDGMENT 51 found to be similar effective in identifying a mechanism for B.M.S. and C.W.L. thank NSF (CHE-1800511), Amgen, and 52 this rearrangement. Details of the synthesis of Curcusone C Caltech for support of this research. K.N.H. thanks the NSF 53 will be reported from the Stoltz lab in due course. (CHE-1361104 and 1764238) for financial support of this re- 54 search. B.L.H.T. gratefully acknowledges the National Institutes 55 of Health for a postdoctoral fellowship (F32GM106596). Calcula- tions were performed on the Hoffman2 Cluster at UCLA and the 56 ASSOCIATED CONTENT Extreme Science and Engineering Discovery Environment 57 Supporting Information (XSEDE), which is supported by the NSF (OCI-1053575). The 58 59 60 ACS Paragon Plus Environment Page 11 of 12 Journal of the American Chemical Society

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