FULL PAPER DOI: 10.1002/chem.201302795
Towards the Core Structure of Strychnos Alkaloids Using Samarium Diiodide-Induced Reactions of Indole Derivatives Christine Beemelmanns,[a, b] Steffen Gross,[a, c] and Hans-Ulrich Reissig*[a] Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 80th birthday
Abstract: This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide-induced cycliza-
tions or a Barbier-type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our Keywords: alkaloids · Barbier reaction · cascade reaction · indole · samarium diiodide
first steps towards the development of an atom-economical samarium diiodide-induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide-induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.
Introduction Within the last century the syntheses of natural heterocyclic compounds, and in particular monoterpene indole alkaloids, have been crucial drivers for the development of modern organic chemistry.[1] Monoterpene indole alkaloids constitute a large and diverse class of natural products with all levels of molecular complexity, and a wealth of biological activities.[2] Especially, the challenging architecture of Strychnos alkaloids with strychnine as its flagship and most inspiring example has fascinated organic chemists since their discovery (Figure 1). With the first total synthesis by the group of Woodward in 1954,[3] strychnine has never lost its appeal to organic chemists, underlined by the fact that so far 16 (formal) total syntheses have been reported, each of them highlighting different synthetic methodologies and reflecting the progress of synthetic organic chemistry.[4–7] Planning an appropriate, efficient and atom-economical strategy for the total synthesis of monoterpene indole alkaloids is a challenging task. In an optimal case the best strategies allow access to a variety of different alkaloid structures with a minimum
[a] Dr. C. Beemelmanns, Dr. S. Gross, Prof. Dr. H.-U. Reissig Institut fr Chemie und Biochemie Freie Universitt Berlin, Takustr. 3, 14195 Berlin (Germany) E-mail: [email protected] [b] Dr. C. Beemelmanns BCMP, Harvard Medical School, Harvard University Longwood Avenue 240, 02115 Boston, MA (USA) [c] Dr. S. Gross BASF AG, GVA/ID-B009, 67056 Ludwigshafen (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302795.
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Figure 1. Representative examples of Strychnos alkaloids.[9, 10]
of steps. Radical chemistry offers a wide range of useful transformations for the construction of such complex molecular architectures. In particular the cyclization of carboncentered radicals onto unsaturated C=C bonds or functional groups has been considered as one of the most powerful strategy for C C bond formation and the fast generation of molecular complexity.[8] Ever since the introduction of samarium diiodide (SmI2) to organic synthesis,[11] the versatile electron-transfer reagent has played a key role in organic radical chemistry enabling the construction of previously inaccessible organic frameworks.[12] Its application in numerous elegant natural product syntheses has been reviewed recently.[13] Intrigued by the complex core structure of strychnine, we wondered whether our SmI2-induced ketyl–aryl[14, 15] and ketyl–hetaryl cyclizations[16, 17] could be employed to gain fast access to the complex core structure of Strychnos alkaloids. In particular we were inspired by the idea to develop an atom-economical cascade approach using functionalized indolyl ketones for the rapid stereoselective assembly of the ABGE substructure of strychnine.
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Figure 2. Retrosynthetic analysis of strychnine: Rawals pentacyclic compound I and intermediates II and III suggesting indole derivatives IV and V as precursors.
Results and Discussion Retrosynthetic analysis: All so far reported synthetic strategies towards strychnine are based on one of two precursors: isostrychnine[18] or the Wieland–Gumlich aldehyde.[19] Both compounds can be converted into strychnine in only one step by formation of either ring G or ring F in the very last stage of the synthesis. We commenced our retrosynthetic analysis of strychnine with the conversion of isostrychnine to strychnine, since our well-established SmI2-induced ketyl cyclization-trapping methodology should afford ring G during the first transformation of our anticipated synthetic sequence (Figure 2).[16] Rawals intermediate I allows closure of ring D by an intramolecular Heck reaction,[5d] and a reductive amination should generate ring C converting suitable precursors of type II into I. To generate the six-membered ring E of II we planned to take advantage of a SmI2induced Barbier reaction after suitable modifications of the side chain of cyclization product III. By judicious choice of substituents, intermediate III would already contain all atoms required for the construction of ring C and E. An even more attractive option was an atom-economical cascade approach using indolyl ketone V, which should generate the two six-membered rings G and E of II and three stereogenic centers, including a quaternary carbon, in one step. First approach: Our first experiment comprised the conversion of readily available indolyl ketone 1 to the highly functionalized dihydroindole derivative 2 by a SmI2-induced cyclization followed by trapping the intermediate Samariumenolate with allyl iodide (Scheme 1).[16a] After desilylation of 2 we converted the primary alcohol to an alkyl iodide in order to pursue the planned Barbier reaction. However, subsequent attempts to protect the tertiary alcohol prior to cyclization failed as the formation of a five-membered ring via enolate generation and an intramolecular alkylation was the faster process. The efficacy of the formation of 4 under the mild basic conditions employed is surprising. Reversal of the order of functionalization steps yielded alkyl bromide 5, which was subsequently subjected to a SmI2-induced Barbier reaction (Scheme 2). Unfortunately, all attempts to convert 5 into the desired tetracyclic com-
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Scheme 1. First approach to tetracyclic strychnine precursor II.
Scheme 2. Second approach to tetracyclic strychnine precursor III.
pound 7 failed with SmI2 ; instead only compound 6 was isolated in good yields. The lactam carbonyl group seems to be more electrophilic or better accessible by the intermediate samarium organyl compared to the methoxycarbonyl group.
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Although disappointing, two conclusions can be drawn from the reaction outcome. First, the formation of a reactive samarium organyl from alkyl bromide 5 is possible, and secondly, the anticipated Barbier reaction will probably take place when a more reactive carbonyl group is offered. We next decided to synthesize a more reactive and conformationally fixed lactone in order to avoid the undesired lactam opening.[20] Starting with compound 8 as precursor,[16d] dihydroindole derivative 9 was obtained in multigram scale as single diastereomer by a SmI2-induced cyclization-trapping sequence using bromoacetonitrile as electrophile (Scheme 3). Strikingly, compound 9 already contains
FULL PAPER alcohol 11. We tried to convert tosylate 13 directly into the corresponding lactone 15 using various reaction conditions, but were again unsuccessful. We hence removed the Obenzyl group by hydrogenolysis to afford carboxylic acid 14 in very good yield. The subsequent intramolecular condensation of 14 with the tertiary alcohol was accomplished by using an excess of the coupling reagent EDAC. Again, we observed a partial in situ tosylate/chloride exchange due to the high concentration of chloride resulting in a mixture of compound 15 and 16. The desired cyclization precursor 17 was finally obtained in satisfactory yield by treatment of the 15/16 mixture with sodium iodide (Scheme 4). However, subsequent attempts
Scheme 3. Multistep synthesis of tetracyclic lactones 15/16. Scheme 4. Barbier-type reactions of alkyl iodide 17 to target ketone 18 and reductive aminations to strychnine precursors 19 and 20.
all atoms required for the construction of strychnine precursors I and II (Figure 2). Unfortunately, all attempts to directly convert dihydroindole 9 into the desired lactone 10 failed, and most often complete decomposition of starting material was observed. We then chose a sequence of steps to avoid incompatible functional group transformations. First, removal of the TBS group was performed under mild acidic conditions affording alcohol 11. Subsequent treatment with tosyl chloride afforded the desired sulfonic ester 13 in 67 % yield and seven-membered lactone 12 (11 %). Under these conditions 13 underwent, in part, spontaneous Finkelstein reaction with chloride and the corresponding alkyl chloride 13’ was formed as byproduct in low yield.[21] To our surprise only 12 was obtained in quantitative yield when tosyl anhydride was employed for the activation of primary
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to convert lactone 17 into tetracyclic product 18 by a SmI2induced Barbier reaction failed. We screened different reaction conditions by changing additives, temperature, and solvents but did not obtain even traces of the desired ketone 18 (Scheme 4). On the other hand, treatment of 17 with 4.6 equiv tBuLi at 78 8C afforded the target compound 18 in 63 % yield. This experiment confirmed our expectation that in substrates such as 17 the lactone carbonyl group shows higher reactivity compared to the lactam moiety. We assume that this fact is most probably caused by the higher ring strain of the g-lactone moiety and the favorable geometry of 17. It is further proposed that first, a metallated semiacetal is formed, which undergoes immediate ring opening
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to finally give ketone 18. As already reported[5n] reductive amination of tetracyclic intermediate 18 led to the potential strychnine precursors 19 and 20, which are already very close to the target structure I ( Figure 2). As an interim result, the transformations depicted in Schemes 3 and 4 demonstrate that we were able to transform simple indolyl ketones, such as 8, into highly functionalized dihydroindole derivatives using a SmI2-induced cyclization-trapping sequence as the crucial step. Subsequent reactions, including a g-lactone ring-opening by a transient lithium organyl led to the desired tetracyclic ketone 18 and finally to pentacyclic amine 20. This compound was later shown to be an excellent candidate for the formal total synthesis of strychnine in one of the shortest approaches towards the natural product reported.[5n] Nevertheless, we realized that the first-generation approach to compound 18 involved too many synthetic steps to be feasible on a larger scale. As a consequence, a shorter, more economical cascade strategy was envisioned, aiming for fewer steps and minimizing the use of protecting groups and activation reagents. In a second-generation approach, we continued to develop the concept based on the previously reported SmI2-induced cyclization of compound 21 (Scheme 5).[16a] Formation
Scheme 5. Example of a SmI2-induced cascade reaction leading to tetracyclic product 22.
of 22 under the given reaction conditions is intriguing because it demonstrates that the intramolecular alkylation step is considerably faster than the intermolecular allylation even in the presence of an excess of fairly reactive allyl iodide. Based on this encouraging result we chose “dimeric” 3’-alkoxycarbonyl-substituted indolyl ketones, such as 25–27, as cyclization precursors, which were available on multigram scale by a one-step acylation reaction of two indole units with 4-oxo-pimelic acid 24. Applying our standard cyclization protocol to methoxycarbonyl-substituted precursor 25 (addition of a THF solution of the substrate to the SmI2 solution in THF) afforded only traces of the expected tetracyclic compound 28.[22] We then reasoned that the low solubility of 25 in THF and the resulting high dilution hampered product formation. When the order of addition was reversed, we were delighted to find an increased yield of 28 (26 %), accompanied by lower amounts of spirolactone 29. Addition of HMPA[23] or tBuOH to the reaction mixture afforded predominantly 29 and no trace of tetracycle 28 was observed. A screen of various reaction conditions was conducted, but we failed to exceed yields higher than 55 % of 28. We then examined indolyl ketone 26 now bearing an allylACHTUNGREoxyACHTUNGREcarbonyl group and were delighted to find consistent
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yields of tetracycle 30 (40–45 %). The higher efficacy and reproducibility were most likely caused by the increased solubility of precursor 26. On the other hand, cyano-substituted indolyl ketone 27 completely decomposed after treatment with SmI2, presumably due to the higher electron-deficient nature of the indole moiety. At this point, we want to emphasize that no additives, such as HMPA, were required for a successful cyclization towards 28 and 30. The examples shown in Scheme 6 demonstrate the feasibility of a rapid
Scheme 6. SmI2-induced cascade reactions of “dimeric” indolyl ketones 25 and 26 leading to tetracyclic indolines 28 and 30 or spirolactones 29 and 30.
and fairly efficient approach to tetracyclic ketones 28 and 30 by SmI2-induced cascade reactions. Nevertheless, the requirement of an electron-withdrawing substituent R at the indole core and the loss of one indole moiety as leaving group in the second cyclization step are obvious drawbacks of this approach. Subsequent transformations: With the desired tetracyclic compounds 28 and 30 in hand new options to approach the core structure of strychnine alkaloids were examined. The most promising candidate, tetracyclic allyl ester 30 was subjected to a Pd-catalyzed decarboxylation-allylation protocol yielding compound 34 in good yields as single diastereomer (Scheme 7).[24] We then planned to oxidize the allyl group to an aldehyde, which should allow the introduction of a variety of other functional groups. The envisaged aldehyde 35 was easily obtained in an overall yield of 60 % using a two-step protocol, including a mCPBA-mediated epoxidation, followed by H5IO6-induced ring-opening and oxidative C C bond cleavage. Subsequent reductive amination[25] would lead us to compound 20 in a much shorter way compared to our first-generation approach. In addition, allyl-substituted
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Scheme 7. Subsequent transformations of tetracyclic compound 30.
compound 34 was successfully subjected to a metathesis reaction with Grubbs II catalyst in the presence of tert-butyl acrylate yielding compound 36 in 89 %. These transformations demonstrate the versatility of compounds such as 30 and 34 for approaching highly functionalized indole derivatives. Possible mechanisms of cascade reaction: The model reaction with “dimeric” indolyl ketones caused us to take a closer look to the possible mechanisms. One scenario, known as “carbonyl-first” mechanism,[12d] is initiated by the reversible single electron transfer (SET) from the SmI2 complex to the carbonyl group forming a samarium ketyl radical VI (Figure 3). Here, it is assumed that the nucleophilic radical adds in 6-exo-trig fashion to the double bond of the pyrrole moiety (transition state VII). The subsequent C C bond formation leads to VIII and after the second electron transfer to XIII results in the observed cis-orientation of the hydroxyl group and the adjacent bridge-head hydrogen in major product 28. A plausible second scenario is described in general as the “alkene-first”,[12d] or in this case better as “indole-first” mechanism, in which reduction of the indole moiety occurs first (intermediate IX and transition state X). This pathway may be more dominant when highly activated electron acceptors, such as indole derivative 25 are involved, in which the methoxycarbonyl and the N-carbonyl groups significantly lower the redox potential of the indole derivative. DFT calculations for similar indole derivatives indicate that after the first electron transfer the reactive intermediate of 3-methoxycarbonyl substituted indole derivatives should have the character of a radical anion, such as IX.[17d,e, 26] The addition
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Figure 3. Proposed mechanisms (“carbonyl-first” left side, “indole-first” right side) of the SmI2-induced cyclization sequence of indolyl ketone 25 leading to tetracyclic compound 28 and to lactone 29.
of the stabilized radical anion to the carbonyl group forms the crucial new C C bond under formation of intermediate XI. For both mechanistic scenarios the subsequent irreversible SET by the second equivalent SmI2 to either VIII or XI forms the identical samarium enolate intermediate XIII. Finally, it is also possible that radical anion X is first reduced to XII (formally a “dianion”) by the second equivalent of SmI2, and that the resulting allyl anion moiety then adds to the activated carbonyl group affording the identical stabilized intermediate XIII as described before.
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The high degree of diastereoselectivity in all described mechanistic scenarios may be explained by chelation and steric effects due to the formed SmACHTUNGRE(III) species. Most likely, steric reasons force the bulky samarium alcoholate to occupy an equatorial position, which leaves the side chain in an axial position.[27,28] We assume that chelate formation involving the carbonyl and the methoxycarbonyl groups with SmACHTUNGRE(III) as bridging cation,[29] as well as the steric bulk of the SmACHTUNGRE(III) moiety dominate the geometry of the transition state. This assumption is supported by the fact, that lower diastereoselectivities were observed when no chelating or directing agents are present, as discussed in the case of the electrochemical reductive cyclizations of indolyl alkanones.[17d] In those cases, it is assumed that the energy difference between a pseudoaxial and pseudoequatorial orientation of the carbonyl group is less pronounced resulting in a lower selectivity of the C C bond forming process. In the final step of the reaction intermediate XIII undergoes an intramolecular acylation (pathway a, Figure 3) by attacking the carbonyl group (COXR), to form, after protonation of XIV, product 28. A second possible reaction of intermediate XIII involves an attack of the samarium alkoxy group to COXR providing, after protonation of XV, spirolactone 29. Alternatively, rearrangement of primarily formed intermediate XIV (Figure 3) to spirolactone 29 could take place (retro-Claisen addition). The attack of the tertiary alkoxy group to the carbonyl group of XIV should be facilitated by the present basic reaction conditions and the adjacent methoxycarbonyl group, which considerably weakens the C C bond between the quaternary center and the ketone. The exact nature of this rearrangement is debatable, but is supported by the fact that during an attempt to protect 28, treatment of this compound with triethylamine exclusively furnished lactone 29.
Conclusion In summary, we were able to apply the SmI2-induced cyclization–trapping methodology to easily construct highly functionalized dihydroindole derivatives. A series of interesting transformations including an intramolecular Barbier-type reaction of a transient lithium organyl led to the formation of a tetracyclic key building block for the synthesis of the ABCEG ring system of Strychnos alkaloids. An atom-economical synthetic approach was developed employing SmI2induced cascade reactions of “dimeric” indolyl ketones affording selectively the ABGE core structure in one step.[30] Here we want to emphasize that very often no additives, such as HMPA, were required for a successful cyclization. Subsequent transformations of tetracyclic products leading to highly functionalized indole derivatives proved their synthetic versatility. A full account of an even more efficient approach to highly substituted tetracyclic and pentacyclic derivatives allowing a stream-lined synthesis of Strychnos alkaloids will be reported in due course.
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Experimental Section The Experimental Section can be found in the Supporting Information and includes full compound characterization.
Acknowledgements Support of this work by the Volkswagen Stiftung, the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the Studienstiftung des Deutschen Volkes (PhD fellowships for C.B.), the Ernst Schering Research Foundation (PhD fellowship for S.G.), and Bayer HealthCare is most gratefully acknowledged. We thank Dr. R. Zimmer for his assistance during the preparation of this manuscript. The help of C. Groneberg for HPLC separations and the NMR spectroscopy service team of Dr. A. Schfer for numerous NOE experiments is also gratefully acknowledged. We also thank Prof. Dr. B. Paulus and Priv.-Doz. Dr. D. Andrae for DFT calculations.
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[27]
51, 70 – 74; for a related publication on electrochemical cyclizations of indolyl ketones, see: d) N. Kise, T. Mano, T. Sakurai, Org. Lett. 2008, 10, 4617 – 4620; for related intermolecular reactions, see: e) N. Kise, A. Sueyoshi, S.-i. Takeuchi, T. Sakurai, Org. Lett. 2013, 15, 2746 – 2749. a) H. Wieland, R. G. Jennen, Liebigs Ann. Chem. 1940, 545, 99 – 112; b) V. Prelog, J. Battegay, W. I. Taylor, Helv. Chim. Acta 1948, 31, 2244 – 2246. For a reference that includes the conversion of Wieland–Gumlich aldehyde to strychnine and vice versa, see: a) H. Wieland, W. Gumlich, Liebigs Ann. Chem. 1932, 494, 191 – 200; b) H. Wieland, K. Kaziro, Liebigs Ann. Chem. 1933, 506, 60 – 76; c) F. A. L. Anet, R. Robinson, J. Chem. Soc. 1955, 2253 – 2262. For selected examples, see: a) G. L. Carroll, R. D. Little, Org. Lett. 2000, 2, 2873 – 2876; b) G. A. Molander, M. S. Quirmbach, L. F. Silva Jr., K. C. Spencer, J. Balsells, Org. Lett. 2001, 3, 2257 – 2260; c) J. T. Lowe, J. S. Panek, Org. Lett. 2008, 10, 3813 – 3816; d) Y. Ito, K. Takahashi, H. Nagase, T. Honda, Org. Lett. 2011, 13, 4640 – 4643. Depending upon reaction time and concentration, we observed differing ratios of tosylate 13, the corresponding alkyl chloride 13’ and lactone 12. For related SmI2-induced cascade reactions, see: a) I. Shinohara, M. Yamada, H. Nagaoka, Tetrahedron Lett. 2003, 44, 4649 – 4652; b) A. Kishida, H. Nagaoka, Tetrahedron Lett. 2008, 49, 6393 – 6397. Selected publications for the role of HMPA, see: a) J. Inanaga, M. Ishikawa, M. Yamaguchi, Chem. Lett. 1987, 1485 – 1486; b) Z. Hou, Y. Wakatsuki, J. Chem. Soc. Chem. Commun. 1994, 1205 – 1206; c) E. Prasad, R. A. Flowers II, J. Am. Chem. Soc. 2002, 124, 6895 – 6899; d) A. Dahln, G. Hilmersson, Eur. J. Inorg. Chem. 2004, 3393 – 3403; e) T. Inokuchi, J. Org. Chem. 2005, 70, 1497 – 1500; f) R. A. Flowers II, Synlett 2008, 1427 – 1439; g) D. V. Sadasivam, P. K. S. Antharjanam, E. Prasad, R. A. Flowers II, J. Am. Chem. Soc. 2008, 130, 7228 – 7229; h) H. Farran, S. Hoz, Org. Lett. 2008, 10, 865 – 867; i) K. A. Choquette, D. V. Sadasivam, R. A. Flowers II, J. Am. Chem. Soc. 2010, 132, 17396 – 17398; j) D. V. Sadasivam, K. A. Choquette, R. A. Flowers II, J. Vis. Exp. 2013, 72, 4323 – 4325. For a substitute of carcinogenic HMPA, see: k) C. McDonald, J. D. Ramsey, D. G. Sampsell, J. A. Butler, M. R. Cecchini, Org. Lett. 2010, 12, 5178 – 5181; l) M. Berndt, A. Hçlemann, A. Niermann, C. Bentz, R. Zimmer, H.-U. Reissig, Eur. J. Org. Chem. 2012, 1299 – 1302. For decarboxylative couplings of b-ketoesters, see: a) I. Shimizu, T. Yamada, J. Tsuji, Tetrahedron Lett. 1980, 21, 3199 – 3202; b) T. Tsuda, Y. Chujo, S.-i. Nishi, K. Tawara, T. J. Saegusa, J. Am. Chem. Soc. 1980, 102, 6381 – 6384; c) E. C. Burger, J. A. Tunge, Org. Lett. 2004, 6, 4113 – 4115; d) J. T. Mohr, D. C. Behenna, A. W. Harned, B. M. Stoltz, Angew. Chem. 2005, 117, 7084 – 7087; Angew. Chem. Int. Ed. 2005, 44, 6924 – 6927; e) B. M. Trost, R. N. Bream, J. Xu, Angew. Chem. 2006, 118, 3181 – 3184; Angew. Chem. Int. Ed. 2006, 45, 3109 – 3112. a) A. Azzouzi, B. Perrin, M.-E. Sinibaldi, J.-C. Gramain, C. Lavaud, Tetrahedron Lett. 1993, 34, 5451 – 5454; b) G. A. Kraus, D. Bougie, Tetrahedron 1994, 50, 2681 – 2690; c) S. H. Tan, M. G. Banwell, A. C. Willis, T. A. Reekie, Org. Lett. 2012, 14, 5621 – 5623; d) T. A. Reekie, M. G. Banwell, A. C. Willis, J. Org. Chem. 2012, 77, 10773 – 10781. DFT calculations (GAUSSIAN 09, Rev. A.02/basis set VTZ) by B. Paulus and D. Andrae (Freie Universitt Berlin) indicate that a compound such as 25 should have a LUMO energy of about 2.0 eV whereas the simple ketone moiety has a LUMO energy of approximately 3.5 eV. These values indicate that the electron transfer should clearly favor the indole moiety. Nevertheless, these gas phase calculations completely neglect the influence of the solvent and most importantly the highly oxophilic nature of samarium(II). More detailed theoretical studies are in progress and will be reported. Calculations of the transition states of neutral radical additions to simple double bond systems indicate a preferred equatorial position due to steric reasons, see: a) A. L. J. Beckwith, Tetrahedron 1981, 37,
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3073 – 3100; b) D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959 – 974. [28] For a review comparing neutral versus radical anions and cations, see: A. N. Hancock, J. M. Tanko, in Radical Cation/Anion and Neutral Radicals: A Comparison, Encyclopedia of Radicals in Chemistry, Biology and Materials, John, New York, 2012. [29] The proposed SmIII-chelate results in a sterically demanding 11membered cyclic transition state with a certain degree of conforma-
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tional flexibility. For examples of SmI2-induced medium-sized ring formation and SmII/III-chelate formation, see refs. [12] and [13]. [30] For the economy of syntheses, see: a) T. Newhouse, P. S. Baran, R. W. Hoffmann, Chem. Soc. Rev. 2009, 38, 3010 – 3021; b) R. W. Hoffmann, Russ. J. Org. Chem. 2012, 48, 625 – 637.
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Received: July 17, 2013 Published online: November 22, 2013
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Towards the Core Structure of Strychnos Alkaloids Using Samarium Diiodide-Induced Reactions of Indole Derivatives Christine Beemelmanns,[a, b] Steffen Gross,[a, c] and Hans-Ulrich Reissig*[a] Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 80th birthday
Abstract: This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide-induced cycliza-
tions or a Barbier-type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our Keywords: alkaloids · Barbier reaction · cascade reaction · indole · samarium diiodide
first steps towards the development of an atom-economical samarium diiodide-induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide-induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.
Introduction Within the last century the syntheses of natural heterocyclic compounds, and in particular monoterpene indole alkaloids, have been crucial drivers for the development of modern organic chemistry.[1] Monoterpene indole alkaloids constitute a large and diverse class of natural products with all levels of molecular complexity, and a wealth of biological activities.[2] Especially, the challenging architecture of Strychnos alkaloids with strychnine as its flagship and most inspiring example has fascinated organic chemists since their discovery (Figure 1). With the first total synthesis by the group of Woodward in 1954,[3] strychnine has never lost its appeal to organic chemists, underlined by the fact that so far 16 (formal) total syntheses have been reported, each of them highlighting different synthetic methodologies and reflecting the progress of synthetic organic chemistry.[4–7] Planning an appropriate, efficient and atom-economical strategy for the total synthesis of monoterpene indole alkaloids is a challenging task. In an optimal case the best strategies allow access to a variety of different alkaloid structures with a minimum
[a] Dr. C. Beemelmanns, Dr. S. Gross, Prof. Dr. H.-U. Reissig Institut fr Chemie und Biochemie Freie Universitt Berlin, Takustr. 3, 14195 Berlin (Germany) E-mail: [email protected] [b] Dr. C. Beemelmanns BCMP, Harvard Medical School, Harvard University Longwood Avenue 240, 02115 Boston, MA (USA) [c] Dr. S. Gross BASF AG, GVA/ID-B009, 67056 Ludwigshafen (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302795.
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Figure 1. Representative examples of Strychnos alkaloids.[9, 10]
of steps. Radical chemistry offers a wide range of useful transformations for the construction of such complex molecular architectures. In particular the cyclization of carboncentered radicals onto unsaturated C=C bonds or functional groups has been considered as one of the most powerful strategy for C C bond formation and the fast generation of molecular complexity.[8] Ever since the introduction of samarium diiodide (SmI2) to organic synthesis,[11] the versatile electron-transfer reagent has played a key role in organic radical chemistry enabling the construction of previously inaccessible organic frameworks.[12] Its application in numerous elegant natural product syntheses has been reviewed recently.[13] Intrigued by the complex core structure of strychnine, we wondered whether our SmI2-induced ketyl–aryl[14, 15] and ketyl–hetaryl cyclizations[16, 17] could be employed to gain fast access to the complex core structure of Strychnos alkaloids. In particular we were inspired by the idea to develop an atom-economical cascade approach using functionalized indolyl ketones for the rapid stereoselective assembly of the ABGE substructure of strychnine.
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Figure 2. Retrosynthetic analysis of strychnine: Rawals pentacyclic compound I and intermediates II and III suggesting indole derivatives IV and V as precursors.
Results and Discussion Retrosynthetic analysis: All so far reported synthetic strategies towards strychnine are based on one of two precursors: isostrychnine[18] or the Wieland–Gumlich aldehyde.[19] Both compounds can be converted into strychnine in only one step by formation of either ring G or ring F in the very last stage of the synthesis. We commenced our retrosynthetic analysis of strychnine with the conversion of isostrychnine to strychnine, since our well-established SmI2-induced ketyl cyclization-trapping methodology should afford ring G during the first transformation of our anticipated synthetic sequence (Figure 2).[16] Rawals intermediate I allows closure of ring D by an intramolecular Heck reaction,[5d] and a reductive amination should generate ring C converting suitable precursors of type II into I. To generate the six-membered ring E of II we planned to take advantage of a SmI2induced Barbier reaction after suitable modifications of the side chain of cyclization product III. By judicious choice of substituents, intermediate III would already contain all atoms required for the construction of ring C and E. An even more attractive option was an atom-economical cascade approach using indolyl ketone V, which should generate the two six-membered rings G and E of II and three stereogenic centers, including a quaternary carbon, in one step. First approach: Our first experiment comprised the conversion of readily available indolyl ketone 1 to the highly functionalized dihydroindole derivative 2 by a SmI2-induced cyclization followed by trapping the intermediate Samariumenolate with allyl iodide (Scheme 1).[16a] After desilylation of 2 we converted the primary alcohol to an alkyl iodide in order to pursue the planned Barbier reaction. However, subsequent attempts to protect the tertiary alcohol prior to cyclization failed as the formation of a five-membered ring via enolate generation and an intramolecular alkylation was the faster process. The efficacy of the formation of 4 under the mild basic conditions employed is surprising. Reversal of the order of functionalization steps yielded alkyl bromide 5, which was subsequently subjected to a SmI2-induced Barbier reaction (Scheme 2). Unfortunately, all attempts to convert 5 into the desired tetracyclic com-
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Scheme 1. First approach to tetracyclic strychnine precursor II.
Scheme 2. Second approach to tetracyclic strychnine precursor III.
pound 7 failed with SmI2 ; instead only compound 6 was isolated in good yields. The lactam carbonyl group seems to be more electrophilic or better accessible by the intermediate samarium organyl compared to the methoxycarbonyl group.
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Although disappointing, two conclusions can be drawn from the reaction outcome. First, the formation of a reactive samarium organyl from alkyl bromide 5 is possible, and secondly, the anticipated Barbier reaction will probably take place when a more reactive carbonyl group is offered. We next decided to synthesize a more reactive and conformationally fixed lactone in order to avoid the undesired lactam opening.[20] Starting with compound 8 as precursor,[16d] dihydroindole derivative 9 was obtained in multigram scale as single diastereomer by a SmI2-induced cyclization-trapping sequence using bromoacetonitrile as electrophile (Scheme 3). Strikingly, compound 9 already contains
FULL PAPER alcohol 11. We tried to convert tosylate 13 directly into the corresponding lactone 15 using various reaction conditions, but were again unsuccessful. We hence removed the Obenzyl group by hydrogenolysis to afford carboxylic acid 14 in very good yield. The subsequent intramolecular condensation of 14 with the tertiary alcohol was accomplished by using an excess of the coupling reagent EDAC. Again, we observed a partial in situ tosylate/chloride exchange due to the high concentration of chloride resulting in a mixture of compound 15 and 16. The desired cyclization precursor 17 was finally obtained in satisfactory yield by treatment of the 15/16 mixture with sodium iodide (Scheme 4). However, subsequent attempts
Scheme 3. Multistep synthesis of tetracyclic lactones 15/16. Scheme 4. Barbier-type reactions of alkyl iodide 17 to target ketone 18 and reductive aminations to strychnine precursors 19 and 20.
all atoms required for the construction of strychnine precursors I and II (Figure 2). Unfortunately, all attempts to directly convert dihydroindole 9 into the desired lactone 10 failed, and most often complete decomposition of starting material was observed. We then chose a sequence of steps to avoid incompatible functional group transformations. First, removal of the TBS group was performed under mild acidic conditions affording alcohol 11. Subsequent treatment with tosyl chloride afforded the desired sulfonic ester 13 in 67 % yield and seven-membered lactone 12 (11 %). Under these conditions 13 underwent, in part, spontaneous Finkelstein reaction with chloride and the corresponding alkyl chloride 13’ was formed as byproduct in low yield.[21] To our surprise only 12 was obtained in quantitative yield when tosyl anhydride was employed for the activation of primary
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to convert lactone 17 into tetracyclic product 18 by a SmI2induced Barbier reaction failed. We screened different reaction conditions by changing additives, temperature, and solvents but did not obtain even traces of the desired ketone 18 (Scheme 4). On the other hand, treatment of 17 with 4.6 equiv tBuLi at 78 8C afforded the target compound 18 in 63 % yield. This experiment confirmed our expectation that in substrates such as 17 the lactone carbonyl group shows higher reactivity compared to the lactam moiety. We assume that this fact is most probably caused by the higher ring strain of the g-lactone moiety and the favorable geometry of 17. It is further proposed that first, a metallated semiacetal is formed, which undergoes immediate ring opening
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to finally give ketone 18. As already reported[5n] reductive amination of tetracyclic intermediate 18 led to the potential strychnine precursors 19 and 20, which are already very close to the target structure I ( Figure 2). As an interim result, the transformations depicted in Schemes 3 and 4 demonstrate that we were able to transform simple indolyl ketones, such as 8, into highly functionalized dihydroindole derivatives using a SmI2-induced cyclization-trapping sequence as the crucial step. Subsequent reactions, including a g-lactone ring-opening by a transient lithium organyl led to the desired tetracyclic ketone 18 and finally to pentacyclic amine 20. This compound was later shown to be an excellent candidate for the formal total synthesis of strychnine in one of the shortest approaches towards the natural product reported.[5n] Nevertheless, we realized that the first-generation approach to compound 18 involved too many synthetic steps to be feasible on a larger scale. As a consequence, a shorter, more economical cascade strategy was envisioned, aiming for fewer steps and minimizing the use of protecting groups and activation reagents. In a second-generation approach, we continued to develop the concept based on the previously reported SmI2-induced cyclization of compound 21 (Scheme 5).[16a] Formation
Scheme 5. Example of a SmI2-induced cascade reaction leading to tetracyclic product 22.
of 22 under the given reaction conditions is intriguing because it demonstrates that the intramolecular alkylation step is considerably faster than the intermolecular allylation even in the presence of an excess of fairly reactive allyl iodide. Based on this encouraging result we chose “dimeric” 3’-alkoxycarbonyl-substituted indolyl ketones, such as 25–27, as cyclization precursors, which were available on multigram scale by a one-step acylation reaction of two indole units with 4-oxo-pimelic acid 24. Applying our standard cyclization protocol to methoxycarbonyl-substituted precursor 25 (addition of a THF solution of the substrate to the SmI2 solution in THF) afforded only traces of the expected tetracyclic compound 28.[22] We then reasoned that the low solubility of 25 in THF and the resulting high dilution hampered product formation. When the order of addition was reversed, we were delighted to find an increased yield of 28 (26 %), accompanied by lower amounts of spirolactone 29. Addition of HMPA[23] or tBuOH to the reaction mixture afforded predominantly 29 and no trace of tetracycle 28 was observed. A screen of various reaction conditions was conducted, but we failed to exceed yields higher than 55 % of 28. We then examined indolyl ketone 26 now bearing an allylACHTUNGREoxyACHTUNGREcarbonyl group and were delighted to find consistent
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yields of tetracycle 30 (40–45 %). The higher efficacy and reproducibility were most likely caused by the increased solubility of precursor 26. On the other hand, cyano-substituted indolyl ketone 27 completely decomposed after treatment with SmI2, presumably due to the higher electron-deficient nature of the indole moiety. At this point, we want to emphasize that no additives, such as HMPA, were required for a successful cyclization towards 28 and 30. The examples shown in Scheme 6 demonstrate the feasibility of a rapid
Scheme 6. SmI2-induced cascade reactions of “dimeric” indolyl ketones 25 and 26 leading to tetracyclic indolines 28 and 30 or spirolactones 29 and 30.
and fairly efficient approach to tetracyclic ketones 28 and 30 by SmI2-induced cascade reactions. Nevertheless, the requirement of an electron-withdrawing substituent R at the indole core and the loss of one indole moiety as leaving group in the second cyclization step are obvious drawbacks of this approach. Subsequent transformations: With the desired tetracyclic compounds 28 and 30 in hand new options to approach the core structure of strychnine alkaloids were examined. The most promising candidate, tetracyclic allyl ester 30 was subjected to a Pd-catalyzed decarboxylation-allylation protocol yielding compound 34 in good yields as single diastereomer (Scheme 7).[24] We then planned to oxidize the allyl group to an aldehyde, which should allow the introduction of a variety of other functional groups. The envisaged aldehyde 35 was easily obtained in an overall yield of 60 % using a two-step protocol, including a mCPBA-mediated epoxidation, followed by H5IO6-induced ring-opening and oxidative C C bond cleavage. Subsequent reductive amination[25] would lead us to compound 20 in a much shorter way compared to our first-generation approach. In addition, allyl-substituted
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FULL PAPER
Scheme 7. Subsequent transformations of tetracyclic compound 30.
compound 34 was successfully subjected to a metathesis reaction with Grubbs II catalyst in the presence of tert-butyl acrylate yielding compound 36 in 89 %. These transformations demonstrate the versatility of compounds such as 30 and 34 for approaching highly functionalized indole derivatives. Possible mechanisms of cascade reaction: The model reaction with “dimeric” indolyl ketones caused us to take a closer look to the possible mechanisms. One scenario, known as “carbonyl-first” mechanism,[12d] is initiated by the reversible single electron transfer (SET) from the SmI2 complex to the carbonyl group forming a samarium ketyl radical VI (Figure 3). Here, it is assumed that the nucleophilic radical adds in 6-exo-trig fashion to the double bond of the pyrrole moiety (transition state VII). The subsequent C C bond formation leads to VIII and after the second electron transfer to XIII results in the observed cis-orientation of the hydroxyl group and the adjacent bridge-head hydrogen in major product 28. A plausible second scenario is described in general as the “alkene-first”,[12d] or in this case better as “indole-first” mechanism, in which reduction of the indole moiety occurs first (intermediate IX and transition state X). This pathway may be more dominant when highly activated electron acceptors, such as indole derivative 25 are involved, in which the methoxycarbonyl and the N-carbonyl groups significantly lower the redox potential of the indole derivative. DFT calculations for similar indole derivatives indicate that after the first electron transfer the reactive intermediate of 3-methoxycarbonyl substituted indole derivatives should have the character of a radical anion, such as IX.[17d,e, 26] The addition
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Figure 3. Proposed mechanisms (“carbonyl-first” left side, “indole-first” right side) of the SmI2-induced cyclization sequence of indolyl ketone 25 leading to tetracyclic compound 28 and to lactone 29.
of the stabilized radical anion to the carbonyl group forms the crucial new C C bond under formation of intermediate XI. For both mechanistic scenarios the subsequent irreversible SET by the second equivalent SmI2 to either VIII or XI forms the identical samarium enolate intermediate XIII. Finally, it is also possible that radical anion X is first reduced to XII (formally a “dianion”) by the second equivalent of SmI2, and that the resulting allyl anion moiety then adds to the activated carbonyl group affording the identical stabilized intermediate XIII as described before.
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The high degree of diastereoselectivity in all described mechanistic scenarios may be explained by chelation and steric effects due to the formed SmACHTUNGRE(III) species. Most likely, steric reasons force the bulky samarium alcoholate to occupy an equatorial position, which leaves the side chain in an axial position.[27,28] We assume that chelate formation involving the carbonyl and the methoxycarbonyl groups with SmACHTUNGRE(III) as bridging cation,[29] as well as the steric bulk of the SmACHTUNGRE(III) moiety dominate the geometry of the transition state. This assumption is supported by the fact, that lower diastereoselectivities were observed when no chelating or directing agents are present, as discussed in the case of the electrochemical reductive cyclizations of indolyl alkanones.[17d] In those cases, it is assumed that the energy difference between a pseudoaxial and pseudoequatorial orientation of the carbonyl group is less pronounced resulting in a lower selectivity of the C C bond forming process. In the final step of the reaction intermediate XIII undergoes an intramolecular acylation (pathway a, Figure 3) by attacking the carbonyl group (COXR), to form, after protonation of XIV, product 28. A second possible reaction of intermediate XIII involves an attack of the samarium alkoxy group to COXR providing, after protonation of XV, spirolactone 29. Alternatively, rearrangement of primarily formed intermediate XIV (Figure 3) to spirolactone 29 could take place (retro-Claisen addition). The attack of the tertiary alkoxy group to the carbonyl group of XIV should be facilitated by the present basic reaction conditions and the adjacent methoxycarbonyl group, which considerably weakens the C C bond between the quaternary center and the ketone. The exact nature of this rearrangement is debatable, but is supported by the fact that during an attempt to protect 28, treatment of this compound with triethylamine exclusively furnished lactone 29.
Conclusion In summary, we were able to apply the SmI2-induced cyclization–trapping methodology to easily construct highly functionalized dihydroindole derivatives. A series of interesting transformations including an intramolecular Barbier-type reaction of a transient lithium organyl led to the formation of a tetracyclic key building block for the synthesis of the ABCEG ring system of Strychnos alkaloids. An atom-economical synthetic approach was developed employing SmI2induced cascade reactions of “dimeric” indolyl ketones affording selectively the ABGE core structure in one step.[30] Here we want to emphasize that very often no additives, such as HMPA, were required for a successful cyclization. Subsequent transformations of tetracyclic products leading to highly functionalized indole derivatives proved their synthetic versatility. A full account of an even more efficient approach to highly substituted tetracyclic and pentacyclic derivatives allowing a stream-lined synthesis of Strychnos alkaloids will be reported in due course.
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Experimental Section The Experimental Section can be found in the Supporting Information and includes full compound characterization.
Acknowledgements Support of this work by the Volkswagen Stiftung, the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the Studienstiftung des Deutschen Volkes (PhD fellowships for C.B.), the Ernst Schering Research Foundation (PhD fellowship for S.G.), and Bayer HealthCare is most gratefully acknowledged. We thank Dr. R. Zimmer for his assistance during the preparation of this manuscript. The help of C. Groneberg for HPLC separations and the NMR spectroscopy service team of Dr. A. Schfer for numerous NOE experiments is also gratefully acknowledged. We also thank Prof. Dr. B. Paulus and Priv.-Doz. Dr. D. Andrae for DFT calculations.
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Towards the Core Structure of Strychnos Alkaloids
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Received: July 17, 2013 Published online: November 22, 2013
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