CHIRALITY (2014)
Conference Report A Practical and Stereoselective Organocatalytic Alkylation of Aldehydes with Benzodithiolylium Tetrafluoroborate ANDREA GUALANDI, LUCA MENGOZZI, JESSICA GIACOBONI, STEVE SAULNIER, MOIRA CIARDI, AND PIER GIORGIO COZZI* Alma Mater Studiorum, Dipartimento di Chimica “G. Ciamician”, University of Bologna, Bologna, Italy
ABSTRACT Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved via SN1-type reactions with catalytic amounts of Brønsted or Lewis acids. When a new stereogenic center is formed most of these transformations produce the desired product as a racemate, as these reactions proceed through carbenium ions. The arsenal of activation modes available in organocatalysis can be used to set up suitable reaction conditions in which chiral nucleophiles (enamine catalysis) or chiral electrophiles (iminium catalysis, chiral counterion catalysis) can easily be generated. Recently, we have used stabilized carbenium ions, directly available or obtained from the corresponding alcohols, in new organocatalytic stereoselective SN1-type reactions. The commercially available carbenium ion benzodithiolylium tetrafluoroborate 1 can be used for the straightforward organocatalytic stereoselective alkylation of aldehydes. In this account we will illustrate the application of this methodology in the total synthesis of natural products and the preparation of valuable starting materials. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc. KEY WORDS: organocatalysis; aldehydes; alkylation; carbenium ion; SN1-type reactions INTRODUCTION
The organocatalytic stereoselective α-alkylation of aldehydes represents a challenging area of development in organocatalysis.1 This reaction has been the source of many innovative breakthroughs in organocatalysis,2 which has lead to the combination of transition metals with organocatalytic modes of activation.3–6 The combination of organocatalysis with photoredox reactions7 is particularly intriguing, allowing the establishment of a redox cycle by the action of light, which can be captured by a transition metal complex,8 or by an organic dye.9 The organocatalytic photoredox cycle can be used for practical alkylation of aldehydes using halides substituted with electron-withdrawing groups, such as α-haloketones or halomalonates (Scheme 1). The use of transition metals (particularly copper) in combination with organocatalysis has been used in remarkable examples of the alkenylation and arylation of aldehydes.10,11 MacMillan had the rather inspired idea of establishing a Cu(I)-Cu(III) cycle in which the electrophilic Cu(III) intermediate12–14 is attacked by a chiral enamine, followed by reductive elimination. Vinylboronic, arylboronic, and iodinated compounds can be used in this strategy, allowing the simple preparation of valuable intermediates using mild reaction conditions. Although the introduction of benzylic stereocenters is possible using photoredox reactions,15 the scope is limited. On the other hand, allylic alkylation can be realized using organocatalytic SOMO reactions,16 or palladium synergistic organocatalytic reactions.17 However, the methodology to simply alkylate using alkyl chains is still missing. This reaction is extremely important in academia and industry, as it is widely used to access key intermediates in the total synthesis of natural products or pharmaceutically active intermediates.18,19 A practical and robust way to prepare © 2014 Wiley Periodicals, Inc.
alkylated alcohols, aldehydes, or acids is to use the methodology developed by Evans that relies on the use of oxazolidinone chiral auxiliaries.20 Recently, we turned our attention towards the organocatalytic alkylation of aldehydes, which proceeds via an SN1-type mechanism,21 during which carbenium ions are generated from a precursor such as alcohols, or can be introduced as stable carbenium ions.22–26 We used the Mayr scale of reactivity extensively as a guide in order to choose suitable precursors of these stable carbenium ions (Fig. 1).27 Mayr recently summarized the application of his table of reactivity in organocatalysis, and how it is possible to understand and interpret chemical reactions using this scale based on electrophilicity and nucleophilicity.28 Stabilized carbenium ions can be compatible with water, which is essential in enamine organocatalytic cycles (Fig. 2). If the carbenium ions or cationic species generated do not irreversibly react with water and have moderate stability, the in situ formation of a chiral enamine can be used as the stereo-determining step in the alkylation reaction (Fig. 2, HNR2* catalyst). By combining this idea and the use of Lewis acids, we were able to extend the alkylation reaction to alcohols that form relatively stable carbenium ions, including allylic,29 propargylic,30 and benzylic alcohols.31 However, simple alkyl chains are still not accessible using this chemistry, as the corresponding carbenium ions are quite unstable.32 We questioned if suitable carbenium ions can be used to introduce alkyl chains in an organocatalytic stereoselective fashion, and in this account we illustrate our findings. *Correspondence to: Pier Giorgio Cozzi, Alma Mater Studiorum, University of Bologna, Dipartimento di Chimica “G. Ciamician,” Via Selmi 2, 40126 Bologna, Italy. E-mail: [email protected] Received for publication 18 October 2013; Accepted 13 January 2014 DOI: 10.1002/chir.22303 Published online in Wiley Online Library (wileyonlinelibrary.com).
GUALANDI ET AL.
Scheme 1. Examples of the bromides and aldehydes used to illustrate the substrate scope in the direct α-alkylation of aldehydes. DMF, N,N´dimethylformamide; Tf, triflate; Me, methyl; Et, ethyl.
+
Fig. 1. Electrophilicity parameters E for classes of compounds that have been used as electrophilic substrates (E ) in enamine catalysis.
DISCUSSION
Studying the stabilization of carbenium ion by heteroatoms, Mayr has extensively characterized the capability of a sulfur Chirality DOI 10.1002/chir
33
atom to stabilize a positively charged carbon. The dithiane and related groups have been used as masked aldehydes in 34 synthesis since their introduction by Corey and Seebach. An inspection of the Mayr scale (Fig. 3) allowed the
PG COZZI, ORGANOCATALYTIC SN1 REACTIONS
Fig. 2. The general mechanism of the organocatalyzed alkylation of aldehydes with electrophiles (E).
Fig. 3. Electrophilicity of various sulfur stabilized carbenium ion.
prediction that carbenium ions stabilized by two sulfur atoms in the α-positions were reactive and moderately stable, which would allow their use in an organocatalytic reaction. We have considerably explored the possibility of generating carbenium ions from 1,3-dithianes35, but we were unable to detect any reactivity in model reactions with stoichiometric
or catalytic quantities of enamines. However, we found that the commercially available benzodithiolylium tetrafluoroborate 1 was reactive and the chemistry of this compound is well documented. The reaction of this molecule with a variety of nucleophiles was described by Nakayama,36,37 while its use in carbonyl elongation was described by Degani.38 We studied the organocatalytic alkylation of aldehydes with 1 and we found general conditions required to obtain good stereoselectivity (Scheme 2). The reaction was general and gave good selectivity with various aldehydes. When the sterical hindrance of the aldehyde increases, the reaction does not proceed as well. We have recently discovered that it is possible to perform the organocatalytic alkylation conveniently using the commercially available MacMillan catalyst 2 in the presence of benzoic acid (Scheme 2), or as a hydrochloride salt 5 without the addition of a base (Scheme 3).39 The alkylated aldehydes can be isolated without any racemization after column, but for analytical purposes and easy separation from by-products, is convenient the reduction with NaBH4 performed at 0°C. High enantioselectivity was obtained using a combination of acetonitrile and water as the solvent. It is worth adding that the reaction is heterogeneous, limiting the extent of carbenium ion decomposition that can result in water. It is also worth mentioning that the carbenium ion can be weighed in open air and can be conveniently stored in closed vials at room temperature for months without any appreciable decomposition. This commercially available carbenium ion displays a rich chemistry in material science,40 where it is used as precursor of fulvalenes.41 The utility and versatility of this carbenium ion is fully realized when the simple elimination of the sulfur group is carried out with Ni-Raney. In addition, the benzodithiol is a chameleonic group as it can also stabilize negative charges.42 The simple metalation followed by alkylation of this group can be used to access a variety of useful intermediates (Scheme 4). Alkylation of benzodithiol group is not only possible with alkyl bromides/ iodides, but also with epoxides and other electrophiles.43 The chiral intermediates obtained after the alkylation of aldehydes are suitable for further reactions and it is possible to introduce different functional groups. This can be extremely advantageous in the synthesis of natural products. Using this
Scheme 2. Stereoselective alkylation of aldehydes with benzodithiolylium catalyzed by the MacMillan catalyst 2. Chirality DOI 10.1002/chir
GUALANDI ET AL.
Scheme 3. Efficient reaction conditions for the aldehydes alkylation reaction, using commercially available catalyst 5.
methodology we have recently completed the total synthesis of arundic acid,39 in one of the shortest and highest yielding syntheses reported to date.44 By using this chemistry, different natural compounds can also be readily accessible. Bisabolanes are interesting compounds that display remarkable biological activity.45 Total syntheses of bisabolanes using organometallic46 and organocatalytic strategies47 have been reported. Our approach to bisabolanes is illustrated in Figure 4.
The organocatalytic alkylation of a variety of aldehydes was possible in high yields and excellent enantiomeric excess (ee) without issue. The intermediates obtained by alkylation with benzodithiolylium were transformed into the corresponding iodides using a straightforward reaction. Iodides 10f-i were then subjected to simple reaction with sodium malonate, as illustrated in Scheme 5.48 After successive decarboxylation using established reaction conditions, we obtained the desired intermediates 11f-j in good yields, as illustrated in Scheme 5. The compound 11j was previously used for the synthesis of curcumene. The straightforward alkylation of aldehydes gives access to important intermediates that are used in the fragrance industry.49 Lilial 12 is a key compound for the preparation of fragrances, with the optically enriched isomer known to be more potent. The application of our simple alkylation strategy gives easy access to this molecule, as illustrated in Scheme 6. The aldehyde 3k is used as the substrate for the alkylation step. This compound is not commercially available but can easily be prepared by the simple chemistry illustrated in Scheme 6. After the alkylation of 3k to give 4k, elimination of the sulfur groups by treatment with Nickel-Raney and successive oxidation with Dess-Martin periodinane allowed us to
Scheme 4. Selective metalation of the benzodithiol by nBuLi with successive alkylation and elimination of the benzodithiol group by Ni-Raney.
Fig. 4. Our approach to curcumene by alkylation with benzodithiolylium and successive functional group manipulation. Chirality DOI 10.1002/chir
PG COZZI, ORGANOCATALYTIC SN1 REACTIONS
Scheme 5. Preparation of a key intermediates for the synthesis of curcumene by alkylation and successive functional group manipulation.
obtain the desired compound in good isolated yield and with high optical purity. Unfortunately, the direct elimination of the benzodithiol on the aldehydic compound obtained after alkylation was not possible to perform.
The deoxypropionate class of compounds can also be accessed using our chemistry. Important natural substances such as (–)-borrelidin 16, (–)-doliculide 17, (–)-lardorue 18 (Fig. 5) belong to this class of natural products. In the synthesis of these natural products installation of the methyl groups with the correct relative and absolute configuration is a difficult task. This problem can be solved by iterative stereoselective strategies.50 In fact Feringa, Minnaard,51 and Negishi52 have published excellent chemistry in an attempt to address this problem. Recently, Minnaard described the total synthesis of a deoxypropionate chain used in the study of new antibiotics for Gram-negative bacteria.53 Sufficient quantities of the desired products are required to establish the relative and absolute configuration of many kinds of these natural products, as their structure is still not known or not completely assigned.54 We want to establish the absolute and relative configuration of the methyl groups in the deoxypropionate chains, using our relatively straightforward alkylation strategy. Contrary to the chemistry previously described by others, we make use of commercially available catalysts and precursors with mild reaction conditions. These alkylations can be performed without the use of a glove box and without the need of special skills. In Scheme 7 we illustrate a simple example of this chemistry in the preparation of a number of intermediates.55 This work is still in progress and will further demonstrate the potential of this alkylation methodology. Access to 1-3, 1-4, 1-5 (and in general 1-n) dimethyl groups is possible with control of their absolute and relative configuration by only
Scheme 6. Preparation of Lilial 12 by alkylation of aldehyde 3k. DIBAL-H, diisobutylaluminium hydride; DMP, Dess-Martin periodinane.
Fig. 5. Examples of deoxypolypropionate natural products. Chirality DOI 10.1002/chir
GUALANDI ET AL.
Scheme 7. Control in the syn or anti configuration of two stereogenic centers via alkylation of aldehydes performed with benzodithiolylium. LAH, lithium aluminum hydride, PCC, pyridinium chlorochromate.
changing the absolute configuration of the catalyst used. Our preliminary results indicate that the reaction is controlled mainly by the catalyst and only marginally influenced by the methyl group introduced in the previous reaction, which can diminish the diastereocontrol in a mismatched combination. In addition, the iterative introduction of the benzodithiolylium and the final elimination of all sulfur groups, can be useful for the simple analysis and purification of quite challenging substrates that are not UV-active. We want to establish a comprehensive protocol for this chemistry and work is in progress to this end. CONCLUSION
To conclude, a practical and stereoselective methodology for the alkylation of aldehydes using benzodithiolylium tetrafluoroborate has been developed and has a number of advantages over established procedures. The simple alkylation was carried out with commercially available materials and can be performed by undergraduate students in any laboratory56 without any extraordinary precautions or attention to dry conditions. Difficult techniques and unstable intermediates are avoided and the reaction proceeds in high yields and enantiomeric excesses. The chameleonic propensity of benzodithiol can be advantageously used to access many complex products using a variety of methodologies.
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6. Gualandi A, Mengozzi L, Wilson CM, Cozzi PG. Synergy, compatibility and innovation: merging Lewis acid with stereoselective enamine catalysis. Chem Asian J 2014, DOI: 10.1002/asia.201301549. 7. Nicewicz D, MacMillan DWC. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 2008;322:77–80. 8. Prier CK, Rankic DA, MacMillan DWC. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem Rev 2013;113:5322–5363. 9. Neumann M, Füldner S, König B, Zeitler K. Metal-free, cooperative asymmetric organophotoredox catalysis with visible light. Angew Chem Int Ed 2011;50:951–954. 10. Stevens, JM, MacMillan DWC. Enantioselective α-alkenylation of aldehydes with boronic acids via the synergistic combination of copper(II) and amine catalysis. J Am Chem Soc 2013;135:11756–11759. 11. Skucas, E, MacMillan DWC. Enantioselective α-vinylation of aldehydes via the synergistic combination of copper and amine catalysis. J Am Chem Soc 2012;134:9090–9093. 12. Allen AE, MacMillan DWC. Enantioselective α-arylation of aldehydes via the productive merger of iodonium salts and organocatalysis. J Am Chem Soc 2011;133:4260–4263. 13. Allen AE, MacMillan DWC. The productive merger of iodonium salts and organocatalysis: A non-photolytic approach to the enantioselective αtrifluoromethylation of aldehydes. J Am Chem Soc 2010;132:4986–4987. 14. Hickman AJ, Sanford MS. High-valent organometallic copper and palladium in catalysis. Nature 2012;484:177–185. 15. Shih HW, Vander Wal MN, Grange RL, MacMillan DWC. Enantioselective α-benzylation of aldehydes via photoredox organocatalysis. J Am Chem Soc 2010;132:13600–13603. 16. Beeson TD, Mastracchio A, Hong J, Ashton K, MacMillan DWC. Enantioselective organocatalysis using SOMO activation. Science 2007;316:582–585. 17. For recent work, see: Deiana L, Afewerki S, Palo-Nieto C, Verho O, Johnston EV, Córdova A. Highly enantioselective cascade transformations by merging heterogeneous transition metal catalysis with asymmetric aminocatalysis. Sci Rep 2012;2:851. 18. Evans DA, Shaw JD. Recent advances in asymmetric synthesis with chiral imide auxiliaries. L’actualité chimique 2003;35–38. 19. For the use of organocatalysis see: Alemán J, Cabrera S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem Soc Rev 2013;42:774–793. 20. Ager DJ, Prakash I, Schaad DR. Chiral oxazolidinones in asymmetric synthesis. Aldrichimica Acta 1997;30:3–12. 21. Gualandi A, Cozzi PG. Stereoselective organocatalytic alkylations with carbenium ions. Synlett 2013;281–296.
PG COZZI, ORGANOCATALYTIC SN1 REACTIONS 22. Petruzziello D, Gualandi A, Grilli S, Cozzi PG. Direct and stereoselective alkylation of nitro derivatives with activated alcohols in trifluoroethanol. Eur J Org Chem 2012;6697–6701. 23. Guiteras-Capdevila M, Emer E, Gualandi A, Petruzziello D, Grilli S, Cozzi PG. Organocatalytic stereoselectiveα-formylation of ketones. ChemCatChem 2012;4: 968–971. 24. Gualandi A, Petruzziello D, Emer E, Cozzi PG. A general stereoselective enamine mediated alkylation of α-substituted aldehydes. Chem Comm 2012;48:3614–3616. 25. Benfatti F, Benedetto E, Cozzi PG. Organocatalytic stereoselective α-alkylation of aldehydes with stable carbocations. Chem Asian J 2010;5:2047–2052. 26. Cozzi PG, Benfatti F, Zoli L. Organocatalytic asymmetric alkylation of aldehydes by SN1-type reaction of alcohol. Angew Chem Int Ed 2009;48:1313–1316. 27. Mayr H, Kempf B, Ofial, AR. Nucleophilicity in carbon-carbon bondforming reactions. Acc Chem Res 2003;36:66–77. 28. Mayr H, Lakhdar S, Maji B, Ofial AR. A quantitative approach to nucleophilic organocatalysis. Beilstein J Org Chem 2012;8:1458–1478. 29. Guiteras Capdevila M, Benfatti F, Zoli L, Stenta M,. Cozzi PG. Merging organocatalysis with an indium(III)-mediated process: a stereoselective α-alkylation of aldehydes with allylic alcohols. Chem Eur J 2010:16;11237–11244. 30. Sinisi R, Vita MV, Gualandi A, Emer E, Cozzi PG. SN1-Type reactions in the presence of water: indium(III)-promoted highly enantioselective organocatalytic propargylation of aldehydes. Chem Eur J 2011;17:7404–7408. 31. Guiteras Capdevila M, Emer E, Benfatti F, Gualandi A, Wilson CM, Cozzi PG. Indium(III)-promoted organocatalytic enantioselective α-alkylation of aldehydes with benzylic and benzhydrylic alcohols. Asian J Org Chem 2012;1:38–42. 32. Ammer J, Mayr H. Photogeneration of carbocations: applications in physical organic chemistry and the design of suitable precursors. J Phys Org Chem 2013;26:956–969. 33. Mayr H, Henninger J, Siegmund T. Quantification of the electrophilicities of dithiocarbenium ions. Res Chem Intermed 1996;22:821–838. 34. Corey EJ, Seebach D. 1,3-Dithiane: organic syntheses, Coll. Vol. 6, 1988;50:556–556. 35. Gualandi A, Emer E, Cozzi PG. Carbenium ion prepared from alkyl and phenyl dithianes were decomposing under organocatalytic SN1-type reactions: Unpublished results. 36. Nakayama J. 2-Arylbenzo-1,3-dithioles. Reaction of 2-alkoxybenzo-1,3-dithioles with N,N-dialkylarylamines and polymethoxybenzenes. Synthesis 1975;170–172. 37. Nakayama J, Fujiwara K, Hoshino M. 1,3-Benzodithiolylium salts. Synthesis and reactions with nucleophilic reagents. Bull Soc Chim Jpn 1976;49:3567–3573. 38. Degani I, Fochi R. Pentaatomic heteroaromatic cations. VIII. A convenient method for the preparation of aromatic and aliphatic 1-deuterioaldehydes. Synthesis 1976;759–761. 39. Gualandi A, Emer E, Guiteras Capdevila M, Cozzi PG. Highly enantioselective α alkylation of aldehydes with 1,3- benzodithiolylium tetrafluoroborate: a formal organocatalytic α-alkylation of aldehydes by the carbenium ion. Angew Chem Int Ed 2011;50:7842–7846.
40. Qin J, Qian CX, Zhou N, Zhu RM, Li YZ, Zuo JL, You XZ. Metal complexes based on tetrathiafulvalene-fused π-extended Schiff base ligands — syntheses, characterization, and properties. Eur J Inorg Chem 2012;234–245. 41. Jia HP, Ding J, Ran YF, Liu SX, Blum C, Petkova I, Hauser A, Decurtins S. Targeting π-conjugated multiple donor-acceptor motifs exemplified by tetrathiafulvalenel linked quinoxalines and tetrabenz[bc,ef,hi,uv] ovalenes: synthesis, spectroscopic, electrochemical, and theoretical characterization. Chem Asian J 2011;6:3312–3321. 42. Ncube S, Pelter A, Smith K, Blatcher P, Warren S. Generation and reactions of 2-lithio-2-substituted-1,3-benzodithioles: new, convenient acyl carbanion equivalents. Tetrahedron Lett 1978;19:2345–2348. 43. Saulnier S, Ciardi M, Lopez-Carrillo V, Cozzi PG. Selective difluorination of enantioenriched benzodithiol adducts. Manuscript in preparation. 44. Fernandes RA, Ingle AB. Arundic acid a potential neuroprotective agent: biological development and syntheses. Curr Med Chem 2013;20:2315–2329. 45. Asaoka M, Shima K, Fujii N, Takei H. Synthesis of (+)-α-curcumene, (+)curcumone, and (–)-methyl citronellate starting from optically pure 5-trime thylsilyl-2-cyclohexenone. Tetrahedron 1988;44:4757–4766. 46. Zhang A, Rajanbabu TV. Chiral benzyl centers through asymmetric catalysis. A three-step synthesis of (R)-(–)-alpha-curcumene via asymmetric hydrovinylation. Org Lett 2004;18:3159–3162, and ref. therein. 47. Afewerki S, Breistein P, Pirttilä K, Deiana L, Dziedzic P, Ibrahem I, Córdova A. Catalytic enantioselective β-alkylation of α,β-unsaturated aldehydes by combination of transition-metal- and amminocatalysis: total synthesis of bisabolane sesquiterpenes. Chem Eur J 2011;17:8784–8788. 48. Lee A., Michrowska A, Sulzer-Mosse S, List B. The catalytic asymmetric Knoevenagel condensation. Angew Chem Int Ed 2011;50:1707–1710. 49. Gualandi A; Emma MG; Giacoboni J, Mengozzi L, Cozzi PG. A highly stereoselective organocatalytic approach to lilial and muguesia. Synlett 2013;24:449–452. 50. Horst Bt, Feringa BL, Minnaard AJ. Catalytic asymmetric synthesis of mycocerosic acid. Chem Comm 2007;489–491. 51. van Summeren RP; Moody DB, Feringa BL, Minnaard AJ. Total synthesis of enantiopure β-D-mannosyl phosphomycoketides from mycobacterium tuberculosis. J Am Chem Soc 2006;128:4546 4547. 52. Xu S, Lee CT, Wang G, Negishi Ei. Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconiumcatalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling. Chem Asian J 2013;8:1829–1835. 53. Ferrer C, Fodran P, Barroso S, Gibson R, Hopmans EC, Damsté JS, Schouten S, Minnaard AJ. Asymmetric synthesis of cyclo-archaeol and β-glucosyl cyclo-archaeol. Org Biom Chem 2013;15:2482 2492. 54. Buter J, Yeh EAH, Budavich OW, Damodaran K, Minnaard AJ, Curran DP. Synthesis and analysis of the all(S) side chain of phosphomycoketides: a test of NMR predictions for saturated oligoisoprenoid stereoisomers. J Org Chem 2013;78:4913–4918. 55. Giacoboni J, Gualandi A, Cozzi PG. Iterative organocatalytic strategies for the stereoselective preparation natural products. Unpublished results. 56. The procedure of alkylation with benzodithiolylium is adopted as an undergraduate experiment in catalysis course ( Prof Cozzi PG, Prof Bandini M. : Catalysis in Organic Synthesis, MS Chemistry Degree, Bologna University, G. Ciamician Department of Chemistry).
Chirality DOI 10.1002/chir
Conference Report A Practical and Stereoselective Organocatalytic Alkylation of Aldehydes with Benzodithiolylium Tetrafluoroborate ANDREA GUALANDI, LUCA MENGOZZI, JESSICA GIACOBONI, STEVE SAULNIER, MOIRA CIARDI, AND PIER GIORGIO COZZI* Alma Mater Studiorum, Dipartimento di Chimica “G. Ciamician”, University of Bologna, Bologna, Italy
ABSTRACT Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved via SN1-type reactions with catalytic amounts of Brønsted or Lewis acids. When a new stereogenic center is formed most of these transformations produce the desired product as a racemate, as these reactions proceed through carbenium ions. The arsenal of activation modes available in organocatalysis can be used to set up suitable reaction conditions in which chiral nucleophiles (enamine catalysis) or chiral electrophiles (iminium catalysis, chiral counterion catalysis) can easily be generated. Recently, we have used stabilized carbenium ions, directly available or obtained from the corresponding alcohols, in new organocatalytic stereoselective SN1-type reactions. The commercially available carbenium ion benzodithiolylium tetrafluoroborate 1 can be used for the straightforward organocatalytic stereoselective alkylation of aldehydes. In this account we will illustrate the application of this methodology in the total synthesis of natural products and the preparation of valuable starting materials. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc. KEY WORDS: organocatalysis; aldehydes; alkylation; carbenium ion; SN1-type reactions INTRODUCTION
The organocatalytic stereoselective α-alkylation of aldehydes represents a challenging area of development in organocatalysis.1 This reaction has been the source of many innovative breakthroughs in organocatalysis,2 which has lead to the combination of transition metals with organocatalytic modes of activation.3–6 The combination of organocatalysis with photoredox reactions7 is particularly intriguing, allowing the establishment of a redox cycle by the action of light, which can be captured by a transition metal complex,8 or by an organic dye.9 The organocatalytic photoredox cycle can be used for practical alkylation of aldehydes using halides substituted with electron-withdrawing groups, such as α-haloketones or halomalonates (Scheme 1). The use of transition metals (particularly copper) in combination with organocatalysis has been used in remarkable examples of the alkenylation and arylation of aldehydes.10,11 MacMillan had the rather inspired idea of establishing a Cu(I)-Cu(III) cycle in which the electrophilic Cu(III) intermediate12–14 is attacked by a chiral enamine, followed by reductive elimination. Vinylboronic, arylboronic, and iodinated compounds can be used in this strategy, allowing the simple preparation of valuable intermediates using mild reaction conditions. Although the introduction of benzylic stereocenters is possible using photoredox reactions,15 the scope is limited. On the other hand, allylic alkylation can be realized using organocatalytic SOMO reactions,16 or palladium synergistic organocatalytic reactions.17 However, the methodology to simply alkylate using alkyl chains is still missing. This reaction is extremely important in academia and industry, as it is widely used to access key intermediates in the total synthesis of natural products or pharmaceutically active intermediates.18,19 A practical and robust way to prepare © 2014 Wiley Periodicals, Inc.
alkylated alcohols, aldehydes, or acids is to use the methodology developed by Evans that relies on the use of oxazolidinone chiral auxiliaries.20 Recently, we turned our attention towards the organocatalytic alkylation of aldehydes, which proceeds via an SN1-type mechanism,21 during which carbenium ions are generated from a precursor such as alcohols, or can be introduced as stable carbenium ions.22–26 We used the Mayr scale of reactivity extensively as a guide in order to choose suitable precursors of these stable carbenium ions (Fig. 1).27 Mayr recently summarized the application of his table of reactivity in organocatalysis, and how it is possible to understand and interpret chemical reactions using this scale based on electrophilicity and nucleophilicity.28 Stabilized carbenium ions can be compatible with water, which is essential in enamine organocatalytic cycles (Fig. 2). If the carbenium ions or cationic species generated do not irreversibly react with water and have moderate stability, the in situ formation of a chiral enamine can be used as the stereo-determining step in the alkylation reaction (Fig. 2, HNR2* catalyst). By combining this idea and the use of Lewis acids, we were able to extend the alkylation reaction to alcohols that form relatively stable carbenium ions, including allylic,29 propargylic,30 and benzylic alcohols.31 However, simple alkyl chains are still not accessible using this chemistry, as the corresponding carbenium ions are quite unstable.32 We questioned if suitable carbenium ions can be used to introduce alkyl chains in an organocatalytic stereoselective fashion, and in this account we illustrate our findings. *Correspondence to: Pier Giorgio Cozzi, Alma Mater Studiorum, University of Bologna, Dipartimento di Chimica “G. Ciamician,” Via Selmi 2, 40126 Bologna, Italy. E-mail: [email protected] Received for publication 18 October 2013; Accepted 13 January 2014 DOI: 10.1002/chir.22303 Published online in Wiley Online Library (wileyonlinelibrary.com).
GUALANDI ET AL.
Scheme 1. Examples of the bromides and aldehydes used to illustrate the substrate scope in the direct α-alkylation of aldehydes. DMF, N,N´dimethylformamide; Tf, triflate; Me, methyl; Et, ethyl.
+
Fig. 1. Electrophilicity parameters E for classes of compounds that have been used as electrophilic substrates (E ) in enamine catalysis.
DISCUSSION
Studying the stabilization of carbenium ion by heteroatoms, Mayr has extensively characterized the capability of a sulfur Chirality DOI 10.1002/chir
33
atom to stabilize a positively charged carbon. The dithiane and related groups have been used as masked aldehydes in 34 synthesis since their introduction by Corey and Seebach. An inspection of the Mayr scale (Fig. 3) allowed the
PG COZZI, ORGANOCATALYTIC SN1 REACTIONS
Fig. 2. The general mechanism of the organocatalyzed alkylation of aldehydes with electrophiles (E).
Fig. 3. Electrophilicity of various sulfur stabilized carbenium ion.
prediction that carbenium ions stabilized by two sulfur atoms in the α-positions were reactive and moderately stable, which would allow their use in an organocatalytic reaction. We have considerably explored the possibility of generating carbenium ions from 1,3-dithianes35, but we were unable to detect any reactivity in model reactions with stoichiometric
or catalytic quantities of enamines. However, we found that the commercially available benzodithiolylium tetrafluoroborate 1 was reactive and the chemistry of this compound is well documented. The reaction of this molecule with a variety of nucleophiles was described by Nakayama,36,37 while its use in carbonyl elongation was described by Degani.38 We studied the organocatalytic alkylation of aldehydes with 1 and we found general conditions required to obtain good stereoselectivity (Scheme 2). The reaction was general and gave good selectivity with various aldehydes. When the sterical hindrance of the aldehyde increases, the reaction does not proceed as well. We have recently discovered that it is possible to perform the organocatalytic alkylation conveniently using the commercially available MacMillan catalyst 2 in the presence of benzoic acid (Scheme 2), or as a hydrochloride salt 5 without the addition of a base (Scheme 3).39 The alkylated aldehydes can be isolated without any racemization after column, but for analytical purposes and easy separation from by-products, is convenient the reduction with NaBH4 performed at 0°C. High enantioselectivity was obtained using a combination of acetonitrile and water as the solvent. It is worth adding that the reaction is heterogeneous, limiting the extent of carbenium ion decomposition that can result in water. It is also worth mentioning that the carbenium ion can be weighed in open air and can be conveniently stored in closed vials at room temperature for months without any appreciable decomposition. This commercially available carbenium ion displays a rich chemistry in material science,40 where it is used as precursor of fulvalenes.41 The utility and versatility of this carbenium ion is fully realized when the simple elimination of the sulfur group is carried out with Ni-Raney. In addition, the benzodithiol is a chameleonic group as it can also stabilize negative charges.42 The simple metalation followed by alkylation of this group can be used to access a variety of useful intermediates (Scheme 4). Alkylation of benzodithiol group is not only possible with alkyl bromides/ iodides, but also with epoxides and other electrophiles.43 The chiral intermediates obtained after the alkylation of aldehydes are suitable for further reactions and it is possible to introduce different functional groups. This can be extremely advantageous in the synthesis of natural products. Using this
Scheme 2. Stereoselective alkylation of aldehydes with benzodithiolylium catalyzed by the MacMillan catalyst 2. Chirality DOI 10.1002/chir
GUALANDI ET AL.
Scheme 3. Efficient reaction conditions for the aldehydes alkylation reaction, using commercially available catalyst 5.
methodology we have recently completed the total synthesis of arundic acid,39 in one of the shortest and highest yielding syntheses reported to date.44 By using this chemistry, different natural compounds can also be readily accessible. Bisabolanes are interesting compounds that display remarkable biological activity.45 Total syntheses of bisabolanes using organometallic46 and organocatalytic strategies47 have been reported. Our approach to bisabolanes is illustrated in Figure 4.
The organocatalytic alkylation of a variety of aldehydes was possible in high yields and excellent enantiomeric excess (ee) without issue. The intermediates obtained by alkylation with benzodithiolylium were transformed into the corresponding iodides using a straightforward reaction. Iodides 10f-i were then subjected to simple reaction with sodium malonate, as illustrated in Scheme 5.48 After successive decarboxylation using established reaction conditions, we obtained the desired intermediates 11f-j in good yields, as illustrated in Scheme 5. The compound 11j was previously used for the synthesis of curcumene. The straightforward alkylation of aldehydes gives access to important intermediates that are used in the fragrance industry.49 Lilial 12 is a key compound for the preparation of fragrances, with the optically enriched isomer known to be more potent. The application of our simple alkylation strategy gives easy access to this molecule, as illustrated in Scheme 6. The aldehyde 3k is used as the substrate for the alkylation step. This compound is not commercially available but can easily be prepared by the simple chemistry illustrated in Scheme 6. After the alkylation of 3k to give 4k, elimination of the sulfur groups by treatment with Nickel-Raney and successive oxidation with Dess-Martin periodinane allowed us to
Scheme 4. Selective metalation of the benzodithiol by nBuLi with successive alkylation and elimination of the benzodithiol group by Ni-Raney.
Fig. 4. Our approach to curcumene by alkylation with benzodithiolylium and successive functional group manipulation. Chirality DOI 10.1002/chir
PG COZZI, ORGANOCATALYTIC SN1 REACTIONS
Scheme 5. Preparation of a key intermediates for the synthesis of curcumene by alkylation and successive functional group manipulation.
obtain the desired compound in good isolated yield and with high optical purity. Unfortunately, the direct elimination of the benzodithiol on the aldehydic compound obtained after alkylation was not possible to perform.
The deoxypropionate class of compounds can also be accessed using our chemistry. Important natural substances such as (–)-borrelidin 16, (–)-doliculide 17, (–)-lardorue 18 (Fig. 5) belong to this class of natural products. In the synthesis of these natural products installation of the methyl groups with the correct relative and absolute configuration is a difficult task. This problem can be solved by iterative stereoselective strategies.50 In fact Feringa, Minnaard,51 and Negishi52 have published excellent chemistry in an attempt to address this problem. Recently, Minnaard described the total synthesis of a deoxypropionate chain used in the study of new antibiotics for Gram-negative bacteria.53 Sufficient quantities of the desired products are required to establish the relative and absolute configuration of many kinds of these natural products, as their structure is still not known or not completely assigned.54 We want to establish the absolute and relative configuration of the methyl groups in the deoxypropionate chains, using our relatively straightforward alkylation strategy. Contrary to the chemistry previously described by others, we make use of commercially available catalysts and precursors with mild reaction conditions. These alkylations can be performed without the use of a glove box and without the need of special skills. In Scheme 7 we illustrate a simple example of this chemistry in the preparation of a number of intermediates.55 This work is still in progress and will further demonstrate the potential of this alkylation methodology. Access to 1-3, 1-4, 1-5 (and in general 1-n) dimethyl groups is possible with control of their absolute and relative configuration by only
Scheme 6. Preparation of Lilial 12 by alkylation of aldehyde 3k. DIBAL-H, diisobutylaluminium hydride; DMP, Dess-Martin periodinane.
Fig. 5. Examples of deoxypolypropionate natural products. Chirality DOI 10.1002/chir
GUALANDI ET AL.
Scheme 7. Control in the syn or anti configuration of two stereogenic centers via alkylation of aldehydes performed with benzodithiolylium. LAH, lithium aluminum hydride, PCC, pyridinium chlorochromate.
changing the absolute configuration of the catalyst used. Our preliminary results indicate that the reaction is controlled mainly by the catalyst and only marginally influenced by the methyl group introduced in the previous reaction, which can diminish the diastereocontrol in a mismatched combination. In addition, the iterative introduction of the benzodithiolylium and the final elimination of all sulfur groups, can be useful for the simple analysis and purification of quite challenging substrates that are not UV-active. We want to establish a comprehensive protocol for this chemistry and work is in progress to this end. CONCLUSION
To conclude, a practical and stereoselective methodology for the alkylation of aldehydes using benzodithiolylium tetrafluoroborate has been developed and has a number of advantages over established procedures. The simple alkylation was carried out with commercially available materials and can be performed by undergraduate students in any laboratory56 without any extraordinary precautions or attention to dry conditions. Difficult techniques and unstable intermediates are avoided and the reaction proceeds in high yields and enantiomeric excesses. The chameleonic propensity of benzodithiol can be advantageously used to access many complex products using a variety of methodologies.
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Chirality DOI 10.1002/chir
