Research Article pubs.acs.org/acscatalysis
Amine-Catalyzed Cascade Reactions of Unprotected AldosesAn Operationally Simple Access to Defined Configured Stereotetrads or Stereopentads Celin Richter,‡ Michael Krumrey,‡ Marwa Bahri,‡ Sebastian Trunschke,‡ and Rainer Mahrwald* Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor Strasse 2, 12489 Berlin, Germany S Supporting Information *
ABSTRACT: An amine-catalyzed cascade reaction of unprotected carbohydrates with 1.3-diketones was elaborated. This cascade is based on a Knoevenagel reaction/intramolecular ketalization/retro-aldol reaction. By application of this operationally simple protocol, a direct access to optically active stereopentads or stereotetrads is given. Rules of configurative outcomes will be discussed. KEYWORDS: amine-catalysis, carbohydrates, cascade reactions, chiral stereopentads, stereoselectivity
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In contrast to such an amine-catalyzed execution, transformations of aldoses with acetylacetone were reported to yield C-glycosides. These reactions were carried out in aqueous sodium hydrogen carbonate at higher temperature and are known as the Lubineau reaction (eq 3, Scheme 1).5 Under these conditions, a Knoevenagel-condensation/retro-aldol reaction/intramolecular oxa-Michael cascade is observed, which yields the corresponding C-glycosides. The loss of an acetyl fragment of acetylacetone occurs during this reaction.6
rganocatalysis’s move into organic chemistry provides, among other advantages, extreme shortcuts for existing synthetic multistep routes and catalytic reactions, which have never been realized before. This applies also for the total synthesis of natural products.1 Recently we reported several organocatalyzed methods for stereoselective chain elongation of unprotected aldoses and ketoses. Very small changes of reaction conditions resulted in great differences of cascade paths and formation of products. Moreover, great differences were noticed when used with different substrates under the same reaction conditions (aldoses vs ketoses). These different behaviors are depicted in Scheme 1.2 By way of example, unprotected fructose
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RESULTS AND DISCUSSION A similar trend is observed in amine-catalyzed reactions of unprotected aldoses with acetylacetone. Initial experiments with ribose were carried out in water in the presence of catalytic amounts of pyrrolidine. Under these conditions, an inseparable mixture of α- and β-configured C-glycoside 1, the hemiketal 2, and small amounts of the chain elongated carbohydrate 3 was obtained (Scheme 2).
Scheme 1. Cascade Reactions of Unprotected Carbohydrates and 1.3-Dicarbonyl Compounds
Scheme 2. Pyrrolidine-Catalyzed Reaction of D-Ribose with Acetylacetone
Further optimizations of the reaction conditions revealed N-methylpiperidine (NMP) as the best catalyst to suppress the competitive and undesired dehydration, which is the source for the intramolecular oxa-Michael reaction to generate C-glycoside.7 When used with 20 mol % NMP in reactions with ribose and acetylacetone, the corresponding syn- and anti-configured hemiketales 3
reacts with acetylacetone to give a single stereoisomer of chainelongated ketoses containing a defined configured tertiary alcohol (eq 2, Scheme 1). This process is realized by an amine-catalyzed Knoevenagel reaction/retro-aldol cascade.3 Attempts to react unprotected aldoses with acetylacetone in the presence of catalytic amounts of DBU failed. A chain-elongation as observed in the ketose-series was not detected. Amine-catalyzed cascade reactions with aldoses were observed only when used with acetoacetate instead of acetylacetone (eq 1, Scheme 1).4 © XXXX American Chemical Society
Received: June 17, 2016 Revised: July 6, 2016
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DOI: 10.1021/acscatal.6b01699 ACS Catal. 2016, 6, 5549−5552
Research Article
ACS Catalysis Scheme 3. N-Methylpiperidine-Catalyzed Cascade Reaction of D-Ribose with Acetylacetone
The following reaction mechanism can be assumed. An initial Knoevenagel reaction of acetylacetone and ribose gives rise to the generation of the intermediate 1.3-dicarbonyl structure A. The successive hemikelatization yields furanoid or pyranoid structures B or C. As a consequence, a subsequent retro-aldol reaction generates C5- and C6-substituted acetates D and E. A simultaneously occurring acyl migration, under these basic reaction conditions, drives the acetate into the C-8 position (primary acetate F, Scheme 6).9 To overcome the problem with the isolation and
were obtained in good yields after 12 h at room temperature (Scheme 3).8 A Knoevenagel/ketalization/retro-aldol reaction is assumed as the reaction mechanism (see Scheme 6). With the optimized conditions in hand, we tested several unprotected aldopentoses in these reactions. The isolation and structure elucidation of the products were realized on the stage of their corresponding pentaacetates. The peracetylated ketones 10−14 were isolated with good to exceptionally high stereoselectivities. Results of these investigations are depicted in Scheme 4.
Scheme 6. Proposed Reaction Mechanism
Scheme 4. Amine-Catalyzed Reactions of Aldopentoses with Acetylacetone
characterization of these products, the crude reaction mixtures were acetylated and identified as the peracetylated products. The Knoevenagel reaction of the aldoses and acetylacetone dictates the installation of configuration at C4, the former anomeric carbon atom of the carbohydrates. There are two aspects which influence the configurative outcome of this cascade reaction. This is demonstrated for lyxose (Scheme 7) and arabinose (Scheme 8). Scheme 7. Stereochemical Course of Cascade Reactions of D-Lyxose with Acetylacetone On the basis of these results, this new cascade reaction was extended to various aldohexoses. A further optimization revealed that higher yields can be achieved when used with catalytic amounts of diisopropylethylamine (DIPEA) instead of NMP in these transformations (Scheme 5). Scheme 5. Amine-Catalyzed Reactions of Aldohexoses with Acetylacetone
On the one hand, the configuration at C6 (formerly C3 in the carbohydrate numbering) dictates via hydrogen bonds the conformation of the carbohydrate in the transition state. By adopting the classical nomenclature for conformation of carbohydrates a 3 CO and 3CO conformation can be assumed for transition-state model G and H (for lyxose, Scheme 7). The extent of formation 5550
DOI: 10.1021/acscatal.6b01699 ACS Catal. 2016, 6, 5549−5552
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ACS Catalysis Scheme 8. Stereochemical Course of Cascade Reactions of D-Arabinose with Acetylacetone
Scheme 9. Stereochemical Course of Reactions of Acetylacetone with Deoxyribose and Deoxy-D-glucose
methyl-2.4-pentandione as substrate in reactions with deoxyThus, an access to propionate aldol adducts is given (Scheme 10). Nearly the same high yields and diastereoselectivities D-galactose.
Scheme 10. Amine-Catalyzed Cascade Reactions of Deoxy-Dgalactose 19 with Methyl-pentanedione
of these conformers depends on the configuration at C3 and C2 of the starting carbohydrate. The 2.3-diaxial configuration of lyxose and steric interactions with acetylacetone in intermediate structure H drives the equilibrium to the more favored structure G. A subsequent preferred Si-side attack during the C−C bond formation process with acetylacetone install the (S)-configuration at C4 (formerly anomeric carbon atom). As a result the 4.5-syn-, 4.6-anti-configured 12 was detected as the main product in reactions with lyxose. Similar considerations can be made for the stereochemical outcome of cascade reactions of arabinose with acetylacetone (Scheme 8). The 3CO configuration of intermediate structure J causes problems due to steric interactions. The avoidance of these interactions resulted in the preferred formation in the intermediate structure I (3CO conformation). The following Re-side attack gives access to the (4R)-configured product anti-11 (4.5-anti-, 4.6-anti-11). The corresponding (4S)-configured product syn-11 was not detected under these conditions. These more or less difficult to read stereochemical observations and considerations lead to the following rough rule of thumb. Independent of the configuration of the deployed aldoses, high degrees of 4.6-anti-configuration are detected in all compounds 10−14 and 20−24. By deployment of 2.3-syn-configured aldoses, extremely high degrees of 4.6-anti-selectivities are detected in the products. Only one diastereoisomer was obtained in reactions with arabinose, xylose, or galactose. When used with 2.3-anti-configured carbohydrates, a decrease of this high 4.6-anti-selectivity is observed. Thus, ratios of approximately 7/3 were detected by deployment of ribose, lyxose, or mannose. This rule is supported by results of reactions with 2-deoxy carbohydrates. Without any influence of the hydroxyl group at C2 from the carbohydrates deployed, an unhindered attack onto the carbonyl group takes place. Only the configuration of the hydroxyl group at C3 dictates the direction of this attack (Si-side attack for deoxyribose or Re-side attack for deoxy-D-glucose, Scheme 9). The corresponding 4.6-anti-configured products 14, 24, and 25 were detected as a single stereoisomer and with the highest yields obtained in these experiments. These cascade reactions can be expanded to other substrates. To demonstrate the applicability to other substrates, we tested
were obtained using the same reaction conditions as described for transformations with acetylacetone (see Scheme 5). During this process, an additional stereogenic carbon atom is created. For this reason, the relative and the internal diastereoselectivity have to be considered. A ratio of about 3/1 was detected for the relative 3.4-syndiastereoselectivity. The extremely high internal 4.6-anti-diastereoselectivity was not affected during this process. The 4.6-anticonfiguration was detected again as the only one in the 3.4-syn- and 3.4-anti-configured ketones 25.
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CONCLUSIONS In conclusion, an amine-catalyzed cascade reaction of 1.3-diketones with unprotected aldopentoses and aldohexoses was elaborated. This new methodology provides an operationally simple and elegant access to defined configured stereotetrads and stereopentads and thus extreme shortcuts of existing synthetic methods.10 Existing methods to stereoeselectively construct polyketide structures by multistep routes are connected with the extensive use of protective groups. To compare the reported results with the manual of these existing methods, see reviews in reference 11. Moreover, these stereopentads or tetrads represent suitable and valuable chiral building blocks for natural product synthesis.12
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01699. X-ray structure analysis (CIF) Experimental procedures, characterization data for all compounds, proof of configuration, copies of spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. 5551
DOI: 10.1021/acscatal.6b01699 ACS Catal. 2016, 6, 5549−5552
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ACS Catalysis Author Contributions ‡
These authors contributed equally (C.R., M.K., M.B., and S.T.).
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS B. Braun is gratefully acknowledged for the X-ray structure analysis. REFERENCES
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