Among 1,4-addition and 1,6-addition reactions, 1,4-addition reaction is the main reaction mode in the Michael reaction of α,β-γ,δ-diunsaturated aldehyde with several nucleophiles catalyzed by diphenylprolinol silyl ether via iminium ion intermediate. The 1,4-addition products, which possess excellent enantioselectivity and alkene moiety, are useful chiral building blocks. The ab initio calculation indicates that 1,4-addition reaction is preferable in terms of π-orbital coefficient and Mulliken/CHelpG atomic charge.
A microflow reaction of the Curtius rearrangement by using trimethylsilyl azide as an azide source, followed by trapping of the generated isocyanate with a nucleophile was established, which is safe, inexpensive, and suitable for large-scale synthesis. By this flow reaction in the Curtius rearrangement and recrystallization of the late-stage acetamide intermediate the third-generation synthesis of (–)-Oseltamivir has been established, which is efficient, practical, and safe.
The amine-catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid-catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4-NO2C6H4OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol-% (Tables 2–5). Fast formation of an amino-nitro-cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all-trans-isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid-catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino-nitro-cyclobutanes with H2O led to mixtures of 4-nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6–9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C-bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6, which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13. While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1–5). Various acid-catalyzed steps have been identified. The cyclobutanes 12 may be considered an off-cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3).
This review focuses on the synthetic strategies used for the construction of fumagillin, ovalicin, and other natural products of this family that are known angiogenesis inhibitors. These compounds are comprised of a cyclohexane framework, two epoxides, and five or six contiguous stereogenic centers. The first total syntheses of fumagillin and ovalicin were reported by Corey in 1972 and 1985, respectively. There were numerous studies directed at these natural products in the decades that followed with many reports appearing in the year 2000 or later. Despite the relatively small size of these molecules, their syntheses highlight the efficient construction of stereogenic centers in organic synthesis.
The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis-cis-trans-triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4-relationship is considered difficult, we have developed a notable 1,4-asymmetric induction that utilizes an alkyne–cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3-asymmetric induction with a higher-order alkynyl-zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis-cis-trans-triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.
The efficient asymmetric total synthesis of (−)-oseltamivir, an antiviral reagent, has been accomplished by using two “one-pot” reaction sequences, with excellent overall yield (60 %) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner–Wadsworth–Emmons reaction combined with retro-aldol/Horner–Wadsworth–Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (−)-oseltamivir has also been established.
Structures of the reactive intermediates (enamines and iminium ions) of organocatalysis with diarylprolinol derivatives have been determined. To this end, diarylprolinol methyl and silyl ethers, 1, and aldehydes, PhCH2CHO, tBuCH2CHO, PhCH=CHCHO, are condensed to the corresponding enamines, A and 3 (Scheme 2), and cinnamoylidene iminium salts, B and 4 (Scheme 3). These are isolated and fully characterized by melting/decomposition points, [α]D, elemental analysis, IR and NMR spectroscopy, and high-resolution mass spectrometry (HR-MS). Salts with BF4, PF6, SbF6, and the weakly coordinating Al[OC(CF3)3]4 anion were prepared. X-Ray crystal structures of an enamine and of six iminium salts have been obtained and are described herein (Figs. 2 and 4–8, and Tables 2 and 7) and in a previous preliminary communication (Helv. Chim. Acta2008, 91, 1999). According to the NMR spectra (in CDCl3, (D6)DMSO, (D6)acetone, or CD3OD; Table 1), the major isomers 4 of the iminium salts have (E)-configuration of the exocyclic NC(1′) bond, but there are up to 11% of the (Z)-isomer present in these solutions (Fig. 1). In all crystal structures, the iminium ions have (E)-configuration, and the conformation around the exocyclic N-CC-O bond is synclinal-exo (cf.C and L), with one of the phenyl groups over the pyrrolidine ring, and the RO group over the π-system. One of the meta-substituents (Me in 4b, CF3 in 4c and 4e) on a 3,5-disubstituted phenyl group is also located in the space above the π-system. DFT Calculations at various levels of theory (Tables 3–6) confirm that the experimentally determined structures (cf. Fig. 10) are by far (up to 8.3 kcal/mol) the most stable ones. Implications of the results with respect to the mechanism of organocatalysis by diarylprolinol derivatives are discussed.
trans-tert-Butyldimethylsiloxy-L-proline displays greater catalytic activity and affords higher enantioselectivity than the parent proline in the α-amination reaction of carbonyl compounds with azodicarboxylate. A quantum mechanical calculation reveals the structure of the transition state. In the presence of a catalytic amount of siloxyproline and water (3–9 equiv), α-amino carbonyl derivatives, which are important synthetic intermediates, are obtained in good yield and with excellent enantioselectivity.
The asymmetric total synthesis of epoxyquinols A, B, and C and epoxytwinol A, and computational analysis of the key biomimetic oxidative dimerization procedure are described. In the first-generation synthesis, a HfCl4-mediated diastereoselective Diels–Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone using acryloyl chloride as the dienophile in the Diels–Alder reaction of furan and a lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale synthesis. A biomimetic cascade reaction involving oxidation, 6π-electrocyclization, and then Diels–Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction involving oxidation, 6π-electrocyclization, and formal [4+4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6π-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Drei zur Auswahl: Die Tandem-Michael-Henry-Reaktion eines Nitroalkens mit Pentan-1,5-dial (in situ erzeugt) führt unter Verwendung eines Diphenylprolinolsilylethers als Organokatalysator hoch diastereo- und enantioselektiv zu substituierten Nitrocyclohexancarbaldehyden (siehe Schema; TMS: Trimethylsilyl). Isomerisierung im Sauren oder Basischen überführt das Produkt diastereoselektiv in zwei Stereoisomere, ohne dabei die Enantioselektivität zu beeinträchtigen.
A choice of three: The tandem Michael/Henry reaction of a nitroalkene and pentane-1,5-dial (generated in situ) proceeded efficiently when diphenylprolinol silyl ether was used as an organocatalyst to afford substituted nitrocyclohexanecarbaldehydes with high diastereo- and enantioselectivity (see scheme; TMS: trimethylsilyl). Isomerization under basic or acidic conditions diastereoselectively converts the product into two stereoisomers, without compromising the enantioselectivity.
Proline-based organocatalysts have been developed for a highly enantioselective, direct aldol reaction of aldehydes and ketones in the presence of water. While several surfactant–proline combined catalysts have proved effective, proline derivatives with a hydrophobic moiety such as trans-siloxy-L-proline and cis-siloxy-D-proline, both of which are easily prepared from the same commercially available 4-hydroxy-L-proline, have been found to be the most effective organocatalysts examined in this study, affording the aldol product with excellent diastereo- and enantioselectivities, these two catalysts generating opposite enantiomers. Water affects the selectivity, and poor results are obtained under neat reaction conditions or in dry organic solvents. More than three equivalents of water are required for the best diastereo- and enantioselectivities, while three equivalents is the recommended amount from a synthetic point of view. The reaction proceeds in the organic phase, and also proceeds in the presence of a large amount of water. The large-scale preparation of aldols with the minimal use of an organic solvent, including in the purification step, is described.
Grüne Chemie: Aldolreaktionen, die in vielen Synthesen eine wichtige Rolle spielen, verlaufen auch in Wasser und ohne Metallkatalysator mit ausgezeichneten Enantioselektivitäten. Entscheidend für diese umweltverträgliche Synthese chiraler Verbindungen ist ein synthetischer Organokatalysator mit trans-Hydroxyprolin-Gerüst und einer Siloxygruppe (siehe Bild; TBDPS=tert-Butyldiphenylsilyl).
Why not combine the two? The asymmetric direct aldol reaction of two different aldehydes was catalyzed by a combined proline–surfactant organic catalyst in the presence of water. A stable emulsion was formed in the reaction mixture, and the aldols were obtained with excellent diastereo- and enantioselectivities (see scheme).
A clue to the origin of chirality? A solution of proline with high enantiomeric excess (85–99 % ee) was obtained from solid proline of only 10 % ee through novel dissolution and crystallization processes (see scheme). This observation may be an explanation for the origin of chirality on Earth.
What expression best conveys the recent examples of “aqueous” organocatalyzed aldol reactions? It is suggested that a reaction occurs “in water” if the participating reactants are dissolved homogeneously in water (or buffer), or “in the presence of water” if it proceeds in a concentrated organic phase with water present as a second phase that influences the reaction in the former.
The opposite result: A diphenylprolinol silyl ether promotes an intermolecular enantioselective ene reaction of α,β-enals with cyclopentadiene. This is the first example of cyclopentadiene acting as the ene component, and not the diene, with α,β-enals.
Ein Hinweis auf den Ursprung der Chiralität? Eine Lösung von Prolin mit hohem Enantiomerenüberschuss (85–99 % ee) wurde aus festem Prolin mit nur 10 % ee mithilfe eines neuartigen Lösungs- und Kristallisationsverfahrens erhalten (siehe Schema). Diese Beobachtung könnte den Ursprung der Chiralität auf der Erde erklären.
Welche Beschreibung passt am besten auf die neuen „wässrigen“ organokatalysierten Aldolreaktionen? Es wird vorgeschlagen, von einer Reaktion „in Wasser“ zu sprechen, wenn die beteiligten Reaktanten homogen in Wasser (oder einem Puffer) gelöst sind, und von einer Reaktion „in Gegenwart von Wasser“, wenn sie in konzentrierter organischer Phase abläuft, wobei Wasser als eine zweite Phase die Reaktion in der organischen Phase beeinflusst.
Eine ganz neue Eigenschaft: Ein Diphenylprolinolsilylether erwies sich als Katalysator für die intermolekulare enantioselektive En-Reaktion zwischen α,β-Enalen und Cyclopentadien. Hier fungiert Cyclopentadien gegenüber einem α,β-Enal erstmals als En- und nicht als Dienkomponente. TBS=tert-Butyldimethylsilyl.
Warum nicht zwei zusammen? Die asymmetrische direkte Aldolreaktion zweier verschiedener Aldehyde wird von einem kombinierten Prolin-Tensid-System in Gegenwart von Wasser katalysiert. In der Reaktionsmischung bildet sich eine stabile Emulsion, und die Aldole wurden mit ausgezeichneten Diastereo- und Enantioselektivitäten erhalten (siehe Schema).
L-Prolin-vermittelte α-Aminoxylierung ist ein Schlüsselschritt in den enantio- und diastereoselektiven Totalsynthesen von Fumagillin, Ovalicin und verwandten Verbindungen (siehe Schema). Diese Verbindungen enthalten einen Cyclohexanring, zwei Epoxide sowie fünf oder sechs benachbarte stereogene Zentren und haben Anti-Angiogenese- oder immunsuppressive Eigenschaften.
In the proline-mediated Mannich and aldol reactions of propanal as a nucleophile, the aldimine prepared from benzaldehyde and p-anisidine is about 7 times more reactive than the corresponding aldehyde, benzaldehyde, as an electrophile. This higher reactivity of aldimine over aldehyde is attributed to the carboxylic acid of proline protonating the basic nitrogen atom of the aldimine more effectively than the oxygen atom of the aldehyde, an explanation which has been both experimentally and theoretically verified.
The direct, catalytic, asymmetric Michael addition of aldehydes to nitroolefins in the presence of a chiral diphenylprolinol silyl ether organocatalyst is described (see scheme). The desired 1,4-addition products were obtained in nearly optically pure form in good yield with high syn diastereoselectivity. TMS=trimethylsilyl.
A biomimetic pathway to lucilactaene (1) from NG-391 has been developed which involves stereoselective reactions under very mild conditions. It was demonstrated that 1 racemizes rapidly, and the conditions under which racemization occurs were elucidated. Lucilactaene (1) isolated under neutral conditions is racemic, which suggests that either the natural product is racemized rapidly in the mycelia, or racemic 1 is biosynthesized.
Ein biomimetischer Weg führt unter sehr milden Bedingungen stereoselektiv von NG-391 zu Lucilactaen (1). Es wurde gezeigt, dass 1 rasch racemisiert, und die Bedingungen, unter denen Racemisierung eintritt, wurden aufgeklärt. Lucilactaen (1), das unter neutralen Bedingungen isoliert wird, ist racemisch, was dafür spricht, dass entweder der Naturstoff in den Mycelien rasch racemisiert oder bei der Biosynthese racemisches 1 entsteht.
Die direkte, katalytische, asymmetrische Michael-Addition von Aldehyden an Nitroolefine in Gegenwart eines chiralen Diphenylprolinolsilylether-Organokatalysators (siehe Schema) liefert hoch syn-diastereoselektiv die gewünschten 1,4-Addukte in nahezu optisch reiner Form und guter Ausbeute. TMS=Trimethylsilyl.
trans-4-tert-Butyldimethylsiloxy-L-proline displays a greater catalytic activity than the parent proline without compromising the enantioselectivity, which widens the substrate scope in the α-aminoxylation of carbonyl compounds, as well as O-nitroso-aldol/Michael, and Mannich reactions.
A chiral diamine, easily prepared from proline, is an effective, asymmetric organic catalyst for the Baylis–Hillman reaction of aldehydes and methyl vinyl ketone, affording adducts with enantioselectivities up to 75%.
Nitrosobenzene is the oxygen source in the direct catalytic enantioselective α-aminoxylation of ketones catalyzed by L-proline [Eq. (1)]. Versatile α-aminoxylated ketones are obtained in high yield and with excellent enantioselectivities.
A double-crossed reaction: The use of proline as an organocatalyst enables a one-pot, direct, cross-Mannich reaction to be performed between two different aldehydes and 4-methoxyaniline in a highly syn-diastereo- and enantioselective manner (see scheme).
Zweifach über Kreuz: Der Einsatz von Prolin als organischem Katalysator ermöglicht eine direkte gekreuzte Eintopf-Mannich-Reaktion zwischen zwei unterschiedlichen Aldehyden und 4-Methoxyanilin, die hochgradig syn-diastereo- und enantioselektiv abläuft.
Schwieriges Substrat, aktiver Katalysator: Bei der Diels-Alder-Reaktion von Furan oder substituierten Furanen bildet sich das Cycloaddukt mit hoher Ausbeute und endo-Selektivität, wenn als Katalysator HfCl4 verwendet wird (siehe Schema). Wie am Beispiel der diastereoselektiven Diels-Alder-Reaktion eines chiralen Acrylats gezeigt wird, verläuft die Reaktion schon bei niedrigen Temperaturen unter kinetischer Kontrolle.
High yields and high endo selectivity of the cycloadducts formed from the Diels–Alder reaction of furan or substituted furans occurs with an HfCl4 catalyst (see scheme). The use of the catalyst allows reactions to be performed at low temperature under kinetic control, as shown for the highly diastereoselective Diels–Alder reaction of a chiral acrylate.
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