Indolynes as Electrophilic Indole Surrogates: Fundamental Reactivity, Regioselectivity, and Synthetic Applications

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1 Indolynes as Electrophilic Indole Surrogates: Fundamental eactivity, egioselectivity, and Synthetic Applications The indole heterocycle is observed in an astonishing number of medicinal agents and natural products. 1 Currently, over 0 drugs contain the indole moiety and another 10 indole-containing compounds are undergoing clinical trials. Given the value of indoles, the discovery of new methods that allow for their functionalization is critical. Although numerous methods for accessing C- and C-substituted products from indole building blocks have been discovered, access to C C-substituted indoles remains a significant challenge. ur approach to this issue contrasts with the usual paradigm of indole reactivity. The indole heterocycle is typically exploited for its nucleophilic character (1, Figure 1). Conversely, we reasoned that substitution of the benzenoid ring may proceed by rendering the indole susceptible to attack by nucleophiles (1 ). To this end, we sought to prepare indolynes, or aryne derivatives of indoles ( ). Indolyne species were first looked into in the 190 s with modest success, but were unexplored for several decades. In 00, both the Buszek group and our group independently re-examined the synthetic utility of the indolyne methodology. Buszek and coworkers demonstrated that C-substituted indolynes may be generated from dihaloindoles upon treatment with butyllithium reagents, and used in a variety of Diel Alder reactions. Despite these advances, my thesis research delves into previously unexplored areas in the chemistry of indolynes: (a) the use of indolynes as electrophilic indole surrogates, (b) sources of regioselectivity for nucleophilic attack on indolynes and other unsymmetrical arynes, and (c) methods to overturn the inherent regioselectivity of unsymmetrical arynes. Figure 1 Common Mode of Indole eactivity Indolyne Intermediates ' 1 1 E uc ' uc ' E eversal of Typical Indole eactivity Tf Indolyne Precursors Tf 8 Tf 9

2 1. Generation and eactivity of Indolynes,, Following extensive experimentation, we determined that indolynes could be accessed from silyltriflates 9 using the general Kobayashi approach. In turn, synthetic routes to indolyne precursors 9, with varying 1-substituents, were developed using hydroxyindole starting materials. Presented in Scheme 1 is our rapid, high yielding synthesis of our initial target,,-indolyne precursor 1. To confirm that silyltriflate 1 would function as a suitable precursor to the targeted,-indolyne, 1 was treated with TBAF in the presence of furan (1) to yield Diels Alder adduct 1. The reactivity of indolyne intermediates was further explored by performing experiments involving indolynes and nucleophilic trapping reagents. A sampling of the numerous nucleophiles that undergo smooth reaction with the indolyne intermediate is shown in Scheme. Indolyne precursor 1 could also be used in a variety of formal cycloaddition processes to access unique,-disubstituted indole derivatives (e.g., 18 0). Scheme 1 1. a, I DMS, DME i-pr C Scheme Tf 10 i. TBSTf, TMEDA, Et TF, 0Æ C ii. nbuli, 8 C; Cl 1 (8% yield)., Pd/C (9% yield, steps) ( equiv) 1 TBAF, C C (8% yield) Et, C Cl 11 (90% yield) 1 1 DBU, Et C C, 0 C then, PhTf, C (88% yield) 1 aniline TBAF Tf TBAF C C C C % yield % yield (1. : 1) TBAF CsF, C C C C 0 C 18 8% yield (. : 1) 19 1 nucleophiles and cycloaddition partners; 8 91% yield 1 8% yield (10 : 1) Figure Indolyne Precursors Tf Tf Tf 8 9 =, TIPS,, Boc =, TIPS,, Boc =,, Boc Selection of Indolyne Adducts Et C TIPS Boc 8 9 over 0 unique adducts prepared

3 ur strategy for preparing silyltriflates from hydroxyindole precursors proved amenable to the synthesis of,- and,-indolyne precursors, and allowed us to vary the 1-substituent. Thus, we readily gained access to indolyne precursors 9 (Figure ). Trapping indolyne intermediates with nucleophilic agents provided access to several novel substituted indoles (e.g., 9).. rigin of egioselectivity of ucleophilic Additions to Indolynes,,8 f note, our studies demonstrated that nucleophilic additions to indolynes can occur with significant regioselectivity. In collaboration with the ouk group at UCLA, we have shown that distortion energies control regioselectivities and have produced a simple, predictive model for nucleophilic additions to indolynes and other unsymmetrical arynes. ur predictive model advocates a comparison of the internal angles at the aryne termini of the geometry-optimized aryne. The BLYP/-1G(d)-optimized structures, obtained from Gaussian, of indolynes 0 are shown in Figure. In each case, the preferred site of nucleophilic attack is the flatter (i.e., larger internal angle), more electropositive carbon. Furthermore, the degree of regioselectivity was found to correlate to the magnitude of the internal angle difference. Figure preferred site of attack by nucleophiles ,-Indolyne (0),-Indolyne (1),-Indolyne () Bromo-,-Indolyne () -Bromo-,-Indolyne () predicted site of nucleophilic attack tudies demonstrated that nucleophilic additions to indolynes can occur with significant To test our model, we sought to control the regioselectivity of nucleophilic additions to indolynes. We laboration with the ouk group at UCLA, we have shown that distortion energies control have produced postulated a that simple, a bromide predictive substituent model at for C nucleophilic would increase additions the regioselective to indolynes preference and for nucleophilic attack rynes. ur predictive model advocates a comparison of the internal angles at the aryne ry-optimized at C aryne. of the The,-indolyne. BLYP/-1G(d)-optimized To support this hypothesis, structures, geometry obtained optimization from Gaussian, of -bromo-,-indolyne and e shown in Figure. In each case, the preferred site of nucleophilic attack is the flatter desbromo-indolyne 0 was performed (Figure ). The internal angles at C and C of were found to be 11 gle), more electropositive carbon. Furthermore, the degree of regioselectivity was found nitude and of the 1, internal respectively. angle difference. This finding suggests that bromoindolyne Scheme should display a greater preference for model, we sought to control the nucleophilic attack at C compared to 0 (for comparison, desbromo derivative 0 possesses internal angles of X X X cleophilic additions to indolynes. We Tf, F ide substituent 19 and at 1 ). C would Alternatively, increase we the hypothesized that C a bromide substituent at C would reverse regioselectivity C nce for nucleophilic attack at C of the X = (8% yield). : 1 support this hypothesis, geometry X = Br (% yield).8 : 1 heme optimization C-bromide leads to enhancement in regioselectivity of -bromo-,-indolyne Tf, F and

4 of the,-indolyne to favor nucleophilic attack at C. ur energy-minimized structure of validates this hypothesis, as C now possesses the larger internal angle. As shown in Scheme, both hypotheses were validated experimentally. Scheme X X X Tf, F C C X = (8% yield). : 1 X = Br (% yield).8 : 1 C-bromide leads to enhancement in regioselectivity Tf, F X C C X X X = (% yield) : 1 X = Br (% yield) 1 : C-bromide leads to reversal in regioselectivity. Application of the Indolyne thodology to Total Synthesis 8 To test our indolyne methodology in a complex setting, we undertook a total synthesis of indolactam V (0), a C-substituted indole that is both a tumor promoter and a stem cell differentiator. As shown in Scheme, treatment of silyltriflate with peptide in the presence of CsF furnished C-aminated product in % yield. Subsequent debromination and dehydration readily provided unsaturated ester 8. ZrCl -mediated cyclization gave the desired tricycle 9, after which C9 epimerization and reduction furnished indolactam V (0). Scheme Tf Br 1., Pd/C, Et,. Ac, Ac, C. K C, DMF, C (9% yield, steps) CsF, C C, 0 C rt (% yield) 8 Br ZrCl C Cl, 0 C (% yield and % recovered 8) 9 C9 epimerization & reduction 9 indolactam V (0)

5 . egioselectivity: Distortion vs. Steric Factors 9 ur aryne distortion model does not take steric factors into consideration. As a means to further probe the model, we examined the influence of inductively donating silyl substituents on aryne regioselectivities. C of the geometry optimized -triethylsilylbenzyne structure, obtained using DFT methods (BLYP/-1G*), is severely distorted (1, Figure ). Following the aryne distortion model, nucleophilic addition at C is favored electronically; however meta substitution should be preferred based on steric considerations. Silylaryne 1, obtained upon treating with a fluoride source, was trapped with a variety of nucleophiles and cycloaddition partners (Scheme ). The preference for initial attack was found to vary as a function of the trapping agent. rtho-substituted products were formed when the nucleophile possessed minimal steric hindrance (e.g., benzylamine) as a result of aryne distortion. owever, when bulky nucleophiles (e.g., aniline) were used, meta substitution predominated. In the case of -t-butylbenzyne (), which does not possess considerable aryne distortion, nucleophilic addition gives meta-substituted products. These studies suggest that aryne distortion can play an important role in governing regioselectivity in reactions of unsymmetrical arynes. Figure 1 δ δ 11 1 Tf Et Si Et Si -triethylsilylbenzyne (1) predicted site of nucleophilic attack (distortion factors) t-bu -t-butyl benzyne () Tf t-bu predicted site of nucleophilic attack (steric factors). Application of Distortion Model to ther eterocyclic Arynes 10 More recently, in collaboration with the ouk laboratory, we have developed an efficient computational approach for evaluating the synthetic potential of heterocyclic arynes. We have found that rapid calculations of arene dehydrogenation energies can effectively predict the likelihood that a given hetaryne can be generated. Additionally, we have used our aryne angle distortion model to predict the degree of regioselectivity that can be expected in a reaction between a given hetaryne and nucleophilic trapping agent. This analysis was applied to

6 over 10 heterocyclic arynes. Comparisons between calculations and experimental data were used to validate the utility of this predictive tool. In conclusion, our studies elucidate the factors that govern the regioselectivity of nucleophilic addition to unsymmetrical arynes, a subject that once confounded synthetic chemists. By allowing these reactions to proceed with predictable regioselectivity, it is expected that the classic field of heterocyclic arynes will realize more practical application in the modern field of synthetic chemistry. Current research efforts in the Garg lab are focused on continuing to probe the aryne distortion model in complex molecule synthesis. eferences: (1) a) Sundberg,. J. The Chemistry of Indoles; Academic Press: ew York, 190. b) Sundberg,. J. Pyrroles and Their Benzoderivatives: Synthesis and Applications. In Comprehensive eterocyclic Chemistry; () a) Julia, M.; Goffic, F. L.; Igolen, J.; Baillarge, M. Tetrahedron Lett. 199, 10, b) Julia, M.; uang, Y.; Igolen, J. C.. Acad. Sci., Ser. C 19,, c) Igolen, J.; Kolb, A. C.. Acad. Sci., Ser. C 199, 9,. For related studies, see: d) Julia, M.; Goffic, F. L.; Igolen, J.; Baillarge, M. C.. Acad. Sci., Ser. C 19,, e) Julia, M.; Igolen, J.; Kolb, M. C.. Acad. Sci., Ser. C 191,, 1 1. () a) Buszek, K..; Luo, D.; Kondrashov, M.; Brown,.; VanderVelde, D. rg. Lett. 00, 9, 1 1. b) Brown,.; Luo, D.; Vander Velde, D.; Yang, S.; Brassfield, A.; Buszek, K.. Tetrahedron Lett. 009, 0,. c) Buszek, K..; Brown,.; Luo, D. rg. Lett. 009, 11, d) Brown,.; Luo, D.; Decapo, J. A.; Buszek, K.. Tetrahedron Lett. 009, 0, e) Garr, A..; Luo, D.; Brown,.; Cramer, C. J.; Buszek, K..; VanderVelde, D. rg. Lett. 010, 1, f) Thornton, P. D.; Brown,.; ill, D.; euenswander, B.; Lushington, G..; Santini, C.; Buszek, K.. ACS Comb. Sci. 011, 1, 8. () Bronner, S. M.; Bahnck, K. B.; Garg,. K. rg. Lett. 009, 11, () Cheong, P..-Y.; Paton,. S.; Bronner, S. M.; Im, G-Y. J.; Garg,. K.; ouk, K.. J. Am. Chem. Soc. 010, 1, () Im, G-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton,. S.; Cheong, P..-Y.; ouk, K..; Garg,. K. J. Am. Chem. Soc. 010, 1, () imeshima, Y.; Sonoda, Y.; Kobayashi,. Chem. Lett. 198, 1, (8) Bronner, S. M.; Goetz, A. E.; Garg,. K. J. Am. Chem. Soc. 011, 1, 8 8. (9) Bronner, S. M.; Mackey, J. L.; ouk, K..; Garg,. K. J. Am. Chem. Soc. 01, 1,

7 (10) Goetz, A. E.; Bronner, S. M.; Cisneros, J. D.; lamed, J. M.; Paton,. S.; ouk, K..; Garg,. K. Angew. Chem. Int. Ed. 01,, 8.