Abstract: In the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a
cascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition.
Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to
excellent yields

Barbe G.

Bélanger G.

Coelho R. M.

Coldham I.

Houk K. N.

Jones R. C. F.

Nicolaou K. C.

Smith R.

Tietze L. F.

Tsuge O.

Tóth G.

Wasserman H. H.

English

Levesque

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ChemInform Abstract: A Versatile Cascade of Intramolecular Vilsmeier-Haack and Azomethine Ylide 1,3-Dipolar Cycloaddition Toward Tricyclic Cores of Alkaloids.

A Versatile Cascade of Intramolecular Vilsmeier−Haack and Azomethine Ylide 1,3-Dipolar Cycloaddition toward Tricyclic Cores of Alkaloids

Lévesque, François

Bélanger, Guillaume

Savoirs UdeS

A Versatile Cascade of IntramolecularVilsmeier-Haack and Azomethine Ylide1,3-Dipolar Cycloaddition towardTricyclic Cores of Alkaloids†François Lévesque and Guillaume Bélanger*Département de Chimie, UniVersité de Sherbrooke, 2500 bouleVard UniVersité,Sherbrooke, Québec J1K 2R1, Canadaguillaume.belanger@usherbrooke.caReceived August 27, 2008ABSTRACTIn the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using acascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition.Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good toexcellent yields.The pursuit of synthetic efficiency has been driving syntheticchemists over the years. The rapid and controlled increasein molecular complexity constitutes an enormous challengefor the construction of polycyclic natural products. Reactionsin cascade certainly offer a powerful means to reach thisgoal, as several bonds can be formed in a single operation.1With this in mind, we became interested in exploring a newcascade of reactions that combines our recently developedVilsmeier-Haack cyclization methodology2 with the genera-tion of an azomethine ylide and a subsequent intramolecular1,3-dipolar cycloaddition (Scheme 1).3The versatility of our planned synthetic strategy isnoteworthy. The branches bearing the nucleophile and the† Dedicated to Professor Pierre Deslongchamps on the occasion of his70th birthday.(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions inOrganic Chemistry; WILEY-VCH: Weinheim, 2006; p 672. (b) Nicolaou,K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,7134.(2) (a) Bélanger, G.; Larouche-Gauthier, R.; Ménard, F.; Nantel, M.;Barabé, F. Org. Lett. 2005, 7, 4431. (b) Bélanger, G.; Larouche-Gauthier,R.; Ménard, F.; Nantel, M.; Barabé, F. J. Org. Chem. 2006, 71, 704.(3) For reviews on azomethine ylides, see: (a) Coldham, I.; Hufton, R.Chem. ReV. 2005, 105, 2765. (b) Tsuge, O.; Kanemasa, S. AdV. Heterocycl.Chem. 1989, 45, 231.Scheme 1. Planned Synthetic StrategyORGANICLETTERS2008Vol. 10, No. 214939-494210.1021/ol802010n CCC: $40.75  2008 American Chemical SocietyPublished on Web 10/09/2008dipolarophile can be attached anywhere about the amide.Upon the proposed key transformation, the various possibleassemblies for a starting material substrate will lead to verydiverse skeletons that belong to a wide range of alkaloidfamilies of pharmaceutical interest.We already demonstrated that iminium ions (cf. 2),generated from intramolecular Vilsmeier-Haack reactions,are stable and could sometimes be isolated.2 Addition of asuitable tethered dipolarophile should trap the ylide 3, itselfformed through a deprotonation of 2, and generate the secondand third cycles of the desired cascade product 4. Suchstructures are found in numerous steroidal alkaloids, suchas leptinidine,4 daphnane alkaloids, and others. The greatestchallenge in the development of this reaction sequence iscertainly the numerous chemoselectivity issues associatedwith each step of the desired cascade since the reactivityand the order of reaction of the four required functionalgroups must be perfectly controlled.In order to prove the viability of our planned syntheticstrategy, we prepared and then tested a first model compoundbearing a methyl enol ether as the nucleophile for theVilsmeier-Haack cyclization and a tethered dipolarophilefor the final 1,3-dipolar cycloaddition. Preparation of precur-sor 9 started with iodination of known alcohol 55 (Scheme2). Iodide 6 then served in the alkylation of formamide togenerate 7. The latter was alkylated again, this time withknown bromoester 8.6The possibility of generating three cycles in a singlesequence was then examined. When the highly function-alized model substrate 9 was treated with triflic anhydridein the presence of 2,6-di-tert-butyl-4-methylpyridine (DT-BMP), the resulting triflyliminium ion reacted exclusivelywith the electron-rich alkene in a Vilsmeier-Haack-typecyclization (Scheme 3). Upon deprotonation, the azome-thine ylide 10 was generated and then reacted with theremaining electron-poor alkene in a highly diastereose-lective intramolecular 1,3-dipolar cycloaddition.The success of the reaction hinged on ylide generation at atemperature that could then promote the dipolar cycloaddition.Lower temperatures resulted in complete decomposition of thereactive ylide.7 The whole cascade of reactions occurred withperfect chemoselectivity. An 8:1 mixture of 11/12was obtainedin 77% overall yield, which is excellent for this one-pottricyclization from linear 9.8 The relative stereochemistry ofall four adjacent stereocenters in 11 was confirmed by single-crystal X-ray analysis (Figure 1) and is the result of an endotransition state for the cycloaddition of the ylide 10 in an Sconformation; endo/exo transition state preferences and ylideconformation are discussed in detailed below.With this especially encouraging result, we established thefeasibility of the rapid increase in molecular complexity inone operation using our synthetic strategy. For the followingidentification of the scope and limitations of the strategy,we opted for the study of easily accessible model compoundsin a Vilsmeier-Haack cyclization-intermolecular cycload-dition sequence.Preparation of precursors 14b-d is detailed in Scheme4.9 Acetamide was alkylated with iodide 6 to givecompound 13. Alkylation of the anion of either theformamide 7 or the acetamide 13 with ethyl bromoacetatefurnished the precursors 14b and 14d, respectively. Amethyl Grignard addition to 14b at low temperatureproduced the methylketone 14c.Since the first part of the cascade, the Vilsmeier-Haacktype cyclization, has already been successfully developed,2we concentrated our efforts on the azomethine ylide genera-tion and the subsequent 1,3-dipolar cycloaddition. Therefore,a series of bases was screened for the azomethine ylidegeneration (tested with substrate 14b). Although many baseswere either unreactive10a or caused the decomposition of thesubstrate,10b we found that DIPEA had the best balance ofScheme 2. Synthesis of Cascade Precursor 9Scheme 3. Cascade of IntramolecularVilsmeier-Haack-Azomethine Ylide Generation-1,3-DipolarCycloadditionFigure 1. ORTEP representation of the single-crystal X-raystructure of 11.4940 Org. Lett., Vol. 10, No. 21, 2008high basicity and low nucleophilicity.10c We also rapidlyconcluded that the azomethine ylide was unstable and neededto react immediately with a dipolarophile upon its genera-tion.11 To this end, N-phenylmaleimide was chosen as aprototypic highly reactive dipolarophile.In order to study the scope of the reaction cascade, theoptimized conditions were used with model compounds14a-e (Table 1). Both the silyl (14a) and methyl (14b) enolethers led to the desired cycloadducts (entries 1 and 2,respectively), although 14b gave a much better yield (92%),presumably because of the lower acid12 sensitivity of themethyl enol ether. Delightfully, excellent yields (82-92%)were obtained with either the ester (14b, entry 2) or theketone (14c, entry 3).2,13Finally, in order to verify the capacity of the reactioncascade to withstand steric hindrance, we replaced theformamide (14b, entry 2) with bulkier groups. In the caseof the acetamide (14d, entry 4), no cycloadduct wasobserved, even though the iminium ion intermediate wascompletely formed.14 We suspect that deprotonation leadingto the resulting enamine was preferred to the generation ofthe ylide.15 This competing deprotonation pathway wascircumvented by replacing the methyl with a phenyl (14e,entry 5). We were pleased to see that generation of aquaternary center was thus possible at this position (16e/17e, 63% combined yield), even though a higher cycload-dition temperature was required.The relative stereochemistry of all cycloadducts wasexamined. The relationship between C2 and C5 in thecycloadducts 15 and 16 could be rationalized on the basisof the geometry of the ylide (Scheme 5).When the substituent R3 on the amide was an hydrogen(entries 1-3), electrostatic stabilization in the S conformationprevails,16 leading preferentially to 15a-c. Closely relatedexamples showed that such substrates give endo and exoadducts resulting from a common S-ylide intermediate.17However, 14a-c furnished only endo adducts 15a-c and16a-c, regardless of the ylide geometry. In the case wherethe amide substituent R3 was a phenyl (entry 5), sterichindrance destabilized the S conformation, and the cycload-ducts 16e and 17e obtained both stem from a W-ylide, viaendo and exo cycloaddition transtition states, respectively.Structures of 16e and 17e were proven by single crystalX-Ray diffraction.Note that in all of the cycloadducts, the enol ether had atrans geometry, as a result of the initial Vilsmeier-Haackreaction. For instance, after amide 18 is activated, thenucleophilic addition of the tethered enol ether gerenates aScheme 4. Synthesis of Cascade Precursor 14b-dTable 1. Scope of the Key Reaction Cascadeaa Reagent and conditions: (i) DTBMP, Tf2O, CH2Cl2, 0 °C, 5 min; (ii) N-phenylmaleimide; (iii) DIPEA, 15 min. (b) Ratio determined by NMR analysisof crude material. (c) Combined yield of diastereoisomers. (d) Step (iii) conducted in refluxing toluene.Org. Lett., Vol. 10, No. 21, 2008 4941carboxonium ion 19 (Scheme 6). The latter gets deprotonatedto give the less sterically congested trans enol ether 20,leading to unsaturated iminium ion 21 upon triflate expulsion.In conclusion, we demonstrated that a new syntheticstrategy that exploits our recently developed Vilsmeier-Haackcyclization coupled to the generation and cycloaddition ofits azomethine ylide is a powerful, rapid, and efficientapproach to polycyclic alkaloid cores. The generation ofbicyclic and tricyclic adducts occurred in a single operationfrom an acyclic substrate with perfect chemoselectivity.Diastereoselectivity of the process is fully rationalized.Applications of our strategy to the total synthesis of alkaloidsare now in progress.Acknowledgment. This research was supported by theNatural Science and Engineering Research Council (NSERC)of Canada, FQRNT (Québec), the Canadian Fund forInnovation (CFI), and the Université de Sherbrooke. TheUniversité de Sherbrooke is acknowledged for Ph. D.fellowship to F.L.Supporting Information Available: Experimental detailsand spectra for all new compounds, including CIF files. Thismaterial is available free of charge via the Internet athttp://pubs.acs.org.OL802010N(4) Coelho, R. M.; De Souza, M. C.; Sarragiotto, M. H. Phytochemistry1998, 49, 893.(5) Methyl enol ether 5 is obtained from a Wittig olefination ofγ-butyrolactol. See: Wasserman, H. H.; Cook, J. D.; Vu, C. B. J. Org. Chem.1990, 55, 1701.(6) Jones, R. C. F.; Howard, K. J.; Nichols, J. R.; Snaith, J. S. J. Chem.Soc., Perkin Trans. 1 1998, 13, 2061.(7) The electron withdrawing group (CO2Et) on the dipolarophile wasfound to be necessary for the success of the cycloaddition. The unsubstitutedterminal alkene proved to not be reactive enough, in accordance with themajor HOMOazomethine ylide-LUMOdipolarophile interaction in such 1,3-dipolarcycloadditions. See: Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am.Chem. Soc. 1968, 90, 543.(8) The increased thermal stability of methyl enol ether over silyl enolether was dramatic: for substrate 9, when the methyl group is substitutedfor a TBDMS, only 29% overall yield of tricyclic adduct was obtained.(9) Preparation of models 14a and 14e is described in SupportingInformation.(10) (a) DTBMP, DABCO, Cs2CO3. (b) KHMDS, LTMP, and NaH.(c) Nucleophilic bases (such as DBU) initiated undesired anionic polym-erization of N-phenylmaleimide presumably via Michael addition of thebase onto N-phenylmaleimide.(11) Any attempts to form the azomethine ylide prior to the addition ofthe dipolarophile led to low yield of cycloadduct.(12) Compounds 15a/16a decomposed slowly upon purification on silicagel.(13) For another example of chemoselective amide activation in thepresence of a ketone, see: Barbe, G.; Charette, A. B. J. Am. Chem. Soc.2008, 130, 18.(14) Confirmed by 1H NMR spectroscopy (see Supporting Informa-tion).(15) Even though the resulting enamine was not observed, its formationhas been proven in several occasions. For example, see: Smith, R.;Livinghouse, T. Tetrahedron 1985, 41, 3559.(16) Tsuge, O.; Kanemasa, S.; Takenaka, S. Chem. Lett. 1985, 355.(17) Tóth, G.; Frank, J.; Bende, Z.; Weber, L.; Simon, K. J. Chem. Soc.,Perkin Trans. 1 1985, 1961.Scheme 5. Geometry of the Azomethine Ylide and endo/exoTransition StatesScheme 6. Geometry of Enol Ether in Cycloadducts4942 Org. Lett., Vol. 10, No. 21, 2008

A Versatile cascade of intramolecular vilsmeier-haack and azomethine ylide 1,3-dipolar cycloaddition toward tricyclic cores of alkaloids

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A Versatile cascade of intramolecular vilsmeier-haack and azomethine ylide 1,3-dipolar cycloaddition toward tricyclic cores of alkaloids

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