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The proline-catalysed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one with dimethoxyacetaldehyde is used as the key reaction according to the biomimetic C₃+C_n strategy for de novo carbohydrate synthesis. Based on the Whitesides inversion strategy, protected D-erythro-pentos-4-ulose (de>96 %, ee=94 %) was employed for a rapid and divergent entry to various selectively and partly orthogonal protected aldopentoses and derivatives, like amino sugars, thio sugars, deoxy sugars, 4-C-substituted (alkylated) aldopentoses and epoxy sugars.

The isoelectronic replacement of the α-carbon of enamines by nitrogen leads to the corresponding hydrazones, and thus, they can be termed “aza-enamines”. Hence, aldehyde N,N-dialkylhydrazones enable analogous electrophilic substitutions at the imine carbon that corresponds to the β-carbon of enamines. In addition, after hydrolysis of the product hydrazones to the parent ketones or aldehydes, these reactions constitute an umpolung of the classical carbonyl reactivity and overall a nucleophilic acylation or formylation. This review covers the aza-enamine chemistry from its very beginning in the late 1960s up to this year. In the first part, reactions of aromatic, aliphatic, and heterocyclic aldehyde N,N-dialkylhydrazones with highly reactive substrates such as the Vilsmeier and Mannich reagents, sulfonyl isocyanates, perfluoroacetic anhydride, and inorganic electrophiles such as halogens and phosphorus tribromide are described. The hydrazones of α,β-unsaturated aldehydes react as vinylogous aza-enamines at the terminal carbon providing unsaturated aldehydes. As electron-rich dienes and dienophiles, they also form Diels–Alder adducts and thus interesting N-heterocycles. The second part covers carbon–carbon bond formations of the sterically less-demanding formaldehyde N,N-dialkylhydrazones with synthetically very useful electrophiles such as various Michael acceptors and carbonyl compounds. Formaldehyde SAMP-hydrazone and related derivatives generally give excellent asymmetric inductions. Finally, first organocatalytic versions of the aza-enamine chemistry are presented. In summary, the rich chemistry of aldehyde N,N-dialkylhydrazones as neutral acyl anion, formyl anion, and cyanide equivalents is demonstrated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The asymmetric synthesis of the 2-trifluoromethylated 1,2,3-triols 5 starting from 2,2-dimethyl-1,3-dioxan-5-one (1) is described. The enantiomerically pure α-alkylated dioxanones 3 and 6 were obtained via the SAMP/RAMP hydrazone methodology. Trifluoromethylation of the monoalkylated dioxanones 3 with (trifluoromethyl)trimethylsilane in the presence of TBAF gave the 2-trifluoromethylated acetonide-protected triols 4 in high diastereo-and enantiomeric excesses (de ≥ 96 %, ee = 92 – ≥ 98 %) and good overall yields (52–97 %). Finally, deprotection of the triol under acidic conditions afforded the title compound 5 (de ≥ 96 %, ee = 95, 96 %) as a typical example. In addition, the methodology was extended to the trialkylated dioxanone 6 leading to the trifluoromethylated alcohol 7 with two neighbouring quaternarystereocenters in good yield (77 %) and very good diastereo- and enantiomeric excesses (de ≥ 96 %, ee = 98 %). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C₈–C₁₄2 and C₇–C₂15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric α-alkylation of diethyl ketone permitted the introduction of the C₁₀ stereogenic center of 2, whereas the stereocenters C₄ and C₅ of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the α,β-unsaturated δ-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.

Hitting the teens! Five CC bonds and eight stereocenters were formed in a one-pot asymmetric multicomponent domino reaction, which led to the functionalized tricyclic diterpenoid-type core structures (see scheme, IMDA=intramolecular Diels–Alder reaction).

The current status of organic synthesis is hampered by costly protecting-group strategies and lengthy purification procedures after each synthetic step. To circumvent these problems, the synthetic potential of multicomponent domino reactions has been utilized for the efficient and stereoselective construction of complex molecules from simple precursors in a single process. In particular, domino reactions mediated by organocatalysts are in a way biomimetic, as this principle is used very efficiently in the biosynthesis of complex natural products starting from simple precursors. In this Minireview, we discuss the current development of this fast-growing field.

Efficient and selective: An asymmetric nucleophilic glyoxylation has been achieved for the first time using a metalated glyoxylate aminonitrile derivative in Michael additions to nitroalkenes. After conversion of the aminonitrile back into the keto function with removal of the chiral auxiliary, the γ-nitro α-keto esters were available in good yields and excellent enantiomeric excesses (see scheme).

Jetzt schlägt's dreizehn! Fünf C-C-Bindungen und acht Stereozentren werden in einer asymmetrischen Mehrkomponenten-Domino/Diels-Alder-Sequenz gebildet, die zu mehrfach funktionalisierten, tricyclischen Diterpenoid-Grundgerüsten führt (siehe Bild; IMDA=intramolekulare Diels-Alder-Reaktion).

Der derzeitige Stand der organischen Synthese macht oft kostspielige Schutzgruppenstrategien und aufwändige Reinigungsschritte nach jeder Synthesestufe erforderlich. Um diese Probleme zu umgehen, werden zunehmend Mehrkomponentendominoreaktionen zum effizienten und stereoselektiven Aufbau von komplexen Molekülen aus einfachen Vorstufen in einem einzigen Prozess genutzt. Organokatalytische Dominoreaktionen sind in gewisser Weise biomimetisch, da dieses Prinzip bei der Biosynthese von komplexen Naturstoffen aus einfachen Bausteinen sehr effizient verwirklicht ist. In diesem Kurzaufsatz werden die aktuellen Entwicklungen des sich rasch entwickelnden Gebiets diskutiert.

Effizient und selektiv: Eine asymmetrische nucleophile Glyoxylierung konnte erstmals durch metallierte Glyoxylat-Aminonitril-Derivate in Michael-Additionen an Nitroalkene erzielt werden. Nach Rücküberführung der Aminonitril- in die Ketofunktion unter Abspaltung des chiralen Auxiliars wurden die γ-Nitro-α-ketoester in guten Ausbeuten und mit exzellenten Enantiomerenüberschüssen erhalten (siehe Schema).

An efficient and flexible asymmetric synthesis of various 3-substituted γ- and δ-sultams is described. The key step is a diastereoselective nucleophilic 1,2-addition of various organocerium compounds to the CN double bond of ω-SAMP-hydrazonosulfonates. The resulting hydrazines were obtained in good to excellent diastereomeric excesses (de = 78 to ≥ 96 %). Removal of the chiral auxiliary by reductive N,N-bond cleavage afforded the corresponding aminosulfonates without racemisation. Ester hydrolysis and subsequent treatment of the resulting sulfonic acids with phosgene in toluene led to the aminosulfonyl chlorides, which were cyclised to the title compounds in good to excellent overall yields (39–51 %) and high enantiomeric excesses (ee = 78–99 %). The absolute configuration was determined by X-ray structure analysis and is in accordance with the postulated mechanism for the diastereoselective 1,2-addition. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-1,3-dioxan-5-one (1) was performed with various nitro alkenes 2 using a number of proline-based catalysts (A–M) affording polyfunctional nitro ketones 3. Reverse diastereoselectivity was observed with the diphenylprolinol catalyst J, and the best diastereo- and enantiomeric excesses were achieved with the sulfonamide catalyst M (de = 84–98 %, ee = 81–86 %). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Geglückte Kreuzung: Mit chiralen N-heterocyclischen Carbenen als Katalysatoren ließen sich bei der Erzeugung eines quartären Stereozentrums in α-hydroxysubstituierten Tetralonen (siehe Bild) mithilfe einer enantioselektiven intramolekularen gekreuzten Benzoinreaktion ausgezeichnete asymmetrische Induktionen und sehr gute Ausbeuten erzielen. Die Synthese der entsprechenden α-Hydroxyindanone mit guten ee-Werten ist auf diesem Weg ebenfalls möglich.

Dihydroxyacetonphosphat (DHAP) dient der Natur als Methylenkomponente in verschiedensten enzymkatalysierten Aldolreaktionen. Das wohl wichtigste Beispiel in diesem Zusammenhang ist die Photosynthese, bei der d-Glucose, der mengenmäßig bedeutendste Naturstoff, ausgehend von DHAP in nur wenigen Stufen gebildet wird. In den vergangenen Jahren wurde eine Vielzahl von synthetischen DHAP-Äquivalenten entwickelt, die insofern besondere Aufmerksamkeit verdienen, als ihre Anwendbarkeit nicht auf (stereoselektive) Aldolreaktionen beschränkt ist. Die Reagentien stellten ihr Potenzial auch bei einer Reihe weiterer asymmetrischer elektrophiler α-Substitutionen in zahlreichen zielgerichteten Synthesen überzeugend unter Beweis. Die verwandten 1,3-Dioxine sind darüber hinaus nützliche Äquivalente 2-substituierter Acroleine.

In einem Schritt: Die biomimetische asymmetrische Synthese von Kohlenhydraten gelingt durch eine Prolin-katalysierte Aldolreaktion von 1 als Methylenkomponente mit Aldehyden. Die neue organokatalytische C₃+C_n-Strategie führt direkt zu selektiv geschützten einfachen Zuckern und Aminozuckern, aus denen wie am Beispiel der D-Psicose demonstriert durch einfaches Entschützen die Kohlenhydrate zugänglich sind.

Die ungewöhnliche [5.3.2]-Bicyclus-Struktur der insektiziden Amaryllis-Alkaloide Cripowellin A und B ist durch eine Kombination aus Sharpless-Dihydroxylierung, Ringschlussmetathese (RCM) und intramolekularer Heck-Reaktion zugänglich (siehe Schema). Die asymmetrische Synthese des 1-epi-Aglycons verläuft praktisch vollständig diastereo- und enantioselektiv (de, ee≥98 %) in 13 Stufen mit einer Gesamtausbeute von 5.6 %.

Ein leichter Weg zu Aminozuckern: Ausgehend von den käuflichen Vorstufen 1–3 erhält man durch Prolin-katalysierte Dreikomponenten-Mannich-Reaktion in einem Schritt selektiv geschützte, hoch diastereo- und enantiomerenreine Aminozucker und ihre Derivate (siehe Schema; LM=Lösungsmittel, PMP=para-Methoxyphenyl). Dieses effiziente organokatalytische Verfahren kann im Multigramm-Maßstab durchgeführt werden.

One small step for a catalyst: A biomimetic asymmetric synthesis of carbohydrates was accomplished by a proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one as the methylene component with various aldehydes. This new organocatalytic C₃+C_n strategy leads directly to selectively protected simple sugars and amino sugars.

Nature employs dihydroxyacetone phosphate (DHAP) as the donor component in various enzyme-catalyzed aldol reactions. Probably the most significant example in this regard is photosynthesis, in which D-glucose, the most widespread natural product, is formed in just a few steps from DHAP. In recent years a number of synthetic equivalents of DHAP have been reported that deserve particular attention, as their applicability in organic synthesis is not limited to (stereoselective) aldol reactions. The power of these reagents has also been demonstrated convincingly in numerous other asymmetric electrophilic α-substitution reactions in target-oriented syntheses. Furthermore, the related 1,3-dioxins are useful equivalents of 2-substituted acrolein derivatives.

The unusual [5.3.2]bicyclic structure of the insecticidal Amaryllidaceae alkaloids cripowellins A and B has been synthesized for the first time by a sequence of Sharpless dihydroxylation, ring-closing metathesis (RCM), and intramolecular Heck reaction (see scheme). The asymmetric synthesis of the 1-epi aglycon proceeds with virtually complete diastereo- and enantioselectivity (≥98 % de, ≥98 % ee) in 13 steps and an overall yield of 5.6 %.

Short and sweet: Starting from the commercially available precursors 1–3, selectively protected amino sugars and derivatives are obtained in one step and with high diastereo- and enantiomeric purity by means of a proline-catalyzed three-component Mannich reaction (see scheme, PMP=para-methoxyphenyl). This efficient organocatalytic procedure can be carried out smoothly on a multigram scale.

The asymmetric synthesis of protected 2-amino-1,3-diols (S,R)-5 starting from 2,2-dimethyl-1,3-dioxan-5-one is described. The stereogenic centres are generated by α-alkylation using the SAMP/RAMP hydrazone methodology and diastereoselective reduction of the ketones (S)-2 with L-selectride. The resulting alcohols (S,S)-3 are converted into the amines (S,R)-4 by nucleophilic substitution with sodium azide and subsequent reduction with lithium aluminium hydride. The products are obtained in high diastereomeric and enantiomeric excesses (de ⩾ 96%, ee = 90−94%). By employing this methodology, the ammonium salt of D-erythro-sphinganine (R,S)-11 was synthesised starting from RAMP-hydrazone (R)-1 in 47% overall yield and with excellent diastereomeric and enantiomeric excess (de, ee ⩾ 96%). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A versatile and efficient asymmetric synthesis of 2-mono- and 2,3-trans-disubstituted azetidines with excellent diastereomeric (de = 93 to ⩾ 96%) and enantiomeric excesses (ee ⩾ 96%) in good overall yields is described. Virtually stereoisomerically pure differently N,O-protected 3-amino-1-alkanols were prepared as intermediates. Key steps are a diastereoselective α-alkylation of aldehyde SAMP-hydrazones with benzyloxymethyl chloride as the electrophile, and a nucleophilic 1,2-addition of various organocerium reagents to the hydrazone CN double bond. An epimerisation-free reductive removal of the auxiliary gave O-benzyl-protected 3-amino-1-alkanols. After N-tosylation and hydrogenolytic cleavage of the benzylic protecting group, ring closure to the corresponding N-tosylazetidines was achieved in good yields under Mitsunobu conditions. Detosylation was easily accomplished employing sodium/naphthalene. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

We have discovered that α-[dimethyl(thexyl)silyl]acetaldehyde (=[dimethyl(1,1,2-trimethylpropyl)silyl]acetaldehyde; 31) has a strong, woody odor. Structural analysis has shown resemblance to known odorants with similar organoleptic properties. On the basis of structureodor relationships, new and more-powerful woody and ambery sila odorants were prepared. Further derivatization led to a set of compounds with very interesting organoleptic properties. Selected chiral compounds were also prepared stereoselectively. The influence of the absolute configuration on the olfactory properties was in agreement with theoretical assumptions. We also designed other groups of organosilicon odorants. The compounds discovered can be obtained in a few simple steps from commercially available reagents, and may find application in the fragrance and flavor industry. Their structures provide interesting data for further research on structureodor relationships.

An efficient and flexible asymmetric synthesis of various protected anti-1,2-sulfanyl amines bearing two adjacent stereogenic centres is described. Key steps are the diastereoselective α-alkylation of α-sulfanylated acetaldehyde-SAMP-hydrazones with various electrophiles and subsequent nucleophilic 1,2-addition of organocerium reagents to the hydrazone CN double bond. The resulting hydrazines were converted into the title compounds with excellent diastereomeric and enantiomeric excesses (de and ee values ⩾ 96%) by reductive N,N bond cleavage to remove the chiral auxiliaries and protection of the amino functions. The relative and absolute configurations were determined by NOE experiments and X-ray structure analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The first auxiliary controlled asymmetric synthesis of enantiopure α,γ-substituted γ-sultones via α-allylation of lithiated sulfonates by using 1,2:5,6-di-O-isopropylidene-α-D-allofuranose as chiral auxiliary is described. The high asymmetric inductions of the α-allylations were reached in good to excellent yields. Successive epimerization-free cleavage of the auxiliary and diastereoselective ring closure of the sulfonic acid intermediates in a one-pot procedure led to the title compounds in good to excellent yields and diastereo- and enantiomeric excesses (de, ee ≥ 98%). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

An efficient and straightforward ten-step asymmetric synthesis of the polyketide tarchonanthuslactone (1) in good overall yield (21% starting from chloro lactone 5) and with excellent diastereomeric and enantiomeric excesses (de, ee ⩾ 96%) is described. The new synthetic route is based on the α,β-unsaturated δ-lactone building block 5, available in enantiopure form (ee > 99%) through an enzymatic procedure, and its conversion into methyl ketone 11 by an Umpolung strategy. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The asymmetric synthesis of an aryltetralin lignan, (–)-lintetralin, was achieved with an overall yield of 29% with seven steps. Key features of the synthesis are an asymmetric Strecker reaction, a diastereoselective Michael addition of the lithiated amino nitrile product to 5H-furan-2-one, and an intramolecular carbocationic cyclization to provide the desired ring skeleton with the correct configuration. Chirality 15:510–513, 2003. © 2003 Wiley-Liss, Inc.

The asymmetric conjugate addition of various carbon and heteroatom nucleophiles to nitroalkenes as a tool for the construction of highly functionalized synthetic building blocks is presented. Diastereoselective, substrate-controlled 1,4-additions are also included. Besides auxiliary controlled asymmetric Michael additions, external asymmetric versions employing enantiopure additives, addition-elimination processes with enantiopure leaving groups, and catalytic asymmetric syntheses are described. The use of the highly reactive nitroalkenes as Michael acceptors opens the way to synthetically very useful C−C and C−X bond-forming reactions and subsequent transformations as is demonstrated by various applications. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A novel amine auxiliary for the asymmetric synthesis of α-substituted N-methylsulfonamides is described. The reaction of 4-([1,1′-biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine (16) with various aliphatic sulfonyl chlorides afforded the corresponding sulfonamides, which were lithiated and subsequently reacted with electrophiles to give the corresponding products in high yields and good-to-excellent asymmetric inductions (de 83–95%). Racemization-free cleavage of the auxiliary led to the α-alkylated N-methylsulfonamides in acceptable yields and high enantiomer purities (ee 91 to ≥98).

An efficient asymmetric total synthesis of the potent cytotoxic marine natural product (−)-callystatin A and its 20-epi analogue has been achieved. The synthetic pathway involved the preparation of three fragments to be coupled with each other at the end of the route. The first fragment 3 was obtained using a biocatalytic enantioselective reduction of a 3,5-dioxocarboxylate as the key step. For the second intermediate 4 the asymmetric α-alkylation of an O-protected derivative of 4-hydroxybutanal was performed exploiting the SAMP/RAMP hydrazone alkylation methodology, and followed by a highly Z-selective Horner–Wadsworth–Emmons reaction under modified conditions. For the synthesis of the polypropionate fragment 5 a diastereoselective syn-aldol reaction was employed between a chiral ethyl ketone and an α-substituted chiral aldehyde, both prepared in enantiopure form again by means of the asymmetric alkylation of their corresponding RAMP hydrazones. Finally, these three building blocks were coupled using highly E-selective Wittig reactions via allyltributylphosphonium ylides to afford the target compounds after a final oxidation/deprotection sequence.

Durch eine effiziente asymmetrische Totalsynthese wurde der stark cytotoxische marine Naturstoff (−)-Callystatin A und dessen 20-epi Analogon erhalten. Die Syntheseroute basiert auf der Darstellung von drei Fragmenten, die gegen Ende der Synthese miteinander gekuppelt werden. Das erste Fragment 3 wurde mittels einer biokatalytischen, enantioselektiven Reduktion eines 3,5-Dioxocarboxylats als Schlüsselschritt erhalten. Zur Darstellung des zweiten Intermediats 4 wurde eine asymmetrische α-Alkylierung eines O-geschützten 4-Hydroxybutanals unter Anwendung der SAMP/RAMP-Hydrazon-Methode durchgeführt, gefolgt von einer hoch Z-selektiven modifizierten Horner–Wadsworth–Emmons-Reaktion. Für die Synthese des Polypropionatfragments 5 wurde eine diastereoselektive syn-Aldol-Reaktion zwischen einem chiralen Ethylketon und einem α-substituierten chiralen Aldehyd, beide in enantiomerenreiner Form über asymmetrische Alkylierung der entsprechenden RAMP-Hydrazone hergestellt, verwendet. Schließlich wurden die drei Bausteine unter Verwendung von hoch E-selektiven Wittig-Reaktionen via Allyltributylphosphonium Ylide miteinander gekuppelt, um nach Oxidation und Entfernung der Schutzgruppe die Zielmoleküle zu erhalten.

The right choice of sugar auxiliary led to a breakthrough in the first asymmetric α-alkylations of sulfonic acid esters (see scheme). The high asymmetric inductions were reached with 1,2:5,6-di-O-isopropyliden-α-D-allofuranose as the auxiliary group, which can be cleaved off again under mild conditions. Enantiopure α-substituted methyl sulfonates are important building blocks and precursors of bioactive compounds.

The chiral bicyclic triazolium salt 1 is currently the most efficient precatalyst for the asymmetric benzoin condensation. The substituted acyloins 3 are obtained in moderate to good yields and with very good enantiomeric excesses from the corresponding aldehydes 2. The high asymmetric induction is presumably based on the conformational rigidity of the bicyclic nucleophilic carbene catalyst and on the steric hindrance of the tert-butyl group in the Breslow intermediate.

Das chirale bicyclische Triazoliumsalz 1 ist der bislang effizienteste Präkatalysator für die asymmetrische Benzoinkondensation. Die unterschiedlich substituierten Acyloine 3 werden in moderaten bis guten Ausbeuten und mit sehr guten Enantiomerenüberschüssen aus den entsprechenden Benzaldehyden 2 erhalten. Die hohe asymmetrische Induktion beruht vermutlich auf der konformativen Rigidität des bicyclischen nucleophilen Carben-Katalysators und der Abschirmung im Breslow-Intermediat durch die sterisch anspruchsvolle tert-Butylgruppe.

Die richtige Wahl eines Zucker-Auxiliars brachte den Durchbruch bei der ersten asymmetrischen α-Alkylierung von Sulfonsäureestern (siehe Schema). Die hohen asymmetrischen Induktionen wurden mit 1,2:5,6-Di-O-isopropyliden-α-D-allofuranose als Hilfsgruppe erreicht, die unter milden Bedingungen wieder abgespalten werden kann. Enantiomerenreine α-substituierte Methylsulfonate sind wichtige Synthesebausteine und Vorstufen für bioaktive Verbindungen.

Enantioselective electrophilic substitutions with Michael acceptors and alkylating agents at the α-positions of γ- and δ-lactams are presented. The asymmetric Michael addition of lactam 1a to nitroalkenes 2 was used as the key step for the synthesis, over three steps, of α-(β-aminoalkyl)-γ-lactams 5 in good overall yields (37−61%) and with very good diastereomeric and enantiomeric excesses (de ⩾ 96%, ee = 82 to ⩾ 96%). Conjugate addition to alkenylsulfones 6a and 6b afforded Michael adducts 7a and 7b in good yields, but with only moderate diastereoselectivities (de = 38−41%). α-Substituted N-dialkylamino lactams 9a−c were obtained by asymmetric alkylation of N-(dialkylamino)lactam 1a with functionalised electrophiles 8a−c in good yields (66−84%) and with moderate to excellent diastereomeric excesses (66 to ⩾ 96%). The auxiliary was removed by reductive N−N bond cleavage to afford the lactam 10 (ee = 83%). A second alkylation of α-alkylated d N-(dialkylamino)lactams 11 yielded α-disubstituted γ-butyrolactams (12a, 12b) in good yields and diastereomeric excesses (de = 83−88%) and α-disubstituted δ-valerolactams (12c−e) in good yields but with low to moderate diastereoselectivities (de = 6−52%). The α-silylated γ-lactam 15 was obtained in good yield (53% over two steps) and with an enantiomeric excess of 83% by α-silylation of N-(dialkylamino)lactam 1a and subsequent reductive removal of the auxiliary.

The aza-Michael addition of enantiopure 1-aminopyrrolidines to (E)-alkenyl sulfones in the presence of a catalytic amount of ytterbium trifluoromethanesulfonate [Yb(OTf)₃] yields β-hydrazino sulfones in moderate to good yields and with diastereoselectivities of up to ≥ 98%. The latter undergo reductive N-N bond cleavage with BH₃ · THF and, after N-protection with Boc₂O or benzyl bromide, afford N-protected β-amino sulfones with moderate to high enantiomeric excesses (ee = 42 to ≥96%) without racemization. Subsequent α-alkylation of the N,N-dibenzyl protected β-amino sulfones with various electrophiles yields α-alkyl-β-amino sulfones in excellent yields (88-97%) with high diastereomeric (de ≥96 to ≥98%) and enantiomeric purity (ee = 94 to ≥96%). The absolute configuration of the new stereogenic centre was determined by X-ray structural analysis and confirmed by NMR spectroscopy (NOE experiments). Possible reaction mechanisms for the conjugate addition and α-alkylation are presented.

An efficient asymmetric synthesis of α-substituted β-formyl δ-lactones 5 (de ≥ 98%, ee = 80-95%) and 4-substituted furofuran lactones 6 (de ≥ 98%, ee = 80->98%) in acceptable overall yields is reported. Key steps of the new procedure are an asymmetric Michael addition of formaldehyde SAMP-hydrazone (1) to 5,6-dihydro-2H-pyran-2-one (2) under neutral conditions, followed by trans-selective α-alkylation and subsequent cleavage of the auxiliary by ozonolysis or a hydrolytic domino reaction protocol, respectively. The absolute configurations given for the title compounds are based on three X-ray structure analyses and NOE measurements.

An efficient and flexible asymmetric synthesis of planar chiral ortho-functionalized ferrocenyl ketones in good overall yields (35−79%) and enantiomeric excesses (ee = 71−96%) is described. The key step of the procedure is the diastereoselective (de = 87−98%) orthometalation of ferrocenyl ketone SAMP hydrazones, followed by trapping with various electrophiles such as MeI, Me₃SiCl, Ph₂PCl, Ph₂CO, Me₂NCHO or I₂. Subsequent oxidative or reductive hydrazone cleavage leads to the title compounds.

The nucleophilic ring-opening of tosylaziridines with chiral aza-enolates is reported. The SAMP-/ RAMP-hydrazones 1a−h derived from aldehydes or ketones were reacted with tosylaziridine 2a to give the β-aminoethylated hydrazones 3a−h with good diastereoselectivity. Removal of the chiral auxiliary resulted in the formation of the γ-amino nitriles 4a−e or γ-amino ketones 6f−h in good yields and excellent enantiomeric excesses (ee ⩾ 98%). Ring-opening of the enantiopure, benzyl-substituted tosylaziridine 2b with aza-enolates was achieved selectively at the less-substituted ring-carbon atom, again with excellent diastereoselectivity. Subsequent cleavage of the chiral auxiliary yielded the γ-benzyl-substituted γ-amino nitrile 4j or γ-amino ketone 6i with de,ee ⩾ 98%, respectively. The relative and absolute configuration of the new stereogenic centre of the aminoethylated hydrazones 3a−j was determined by NOE measurements and confirmed by X-ray structure analysis on the Mosher amide of 6h.

An efficient and flexible asymmetric synthesis of planar chiral ferrocenyl ligands bearing a stereogenic centre at the β-position to the metallocene backbone is described. A variety of donor groups can be independently introduced as electrophiles, thus allowing electronic and steric fine-tuning of the ligands, which were investigated in Pd-catalyzed enantioselective allylic substitutions. By employing a P,S ligand, the alkylation of the standard test system (±)-1,3-diphenyl-2-propenyl acetate using dimethyl malonate/BSA as the nucleophile proceeded in a quantitative yield with an ee of 97%, which is the best value reported so far in this reaction for a P∪S ligand.

Alkylation of 1,4-cyclohexanedione monoethylene acetal SAMP-hydrazone with various electrophiles (10 examples given) and subsequent cleavage of the hydrazones with saturated oxalic acid furnished highly enantiomerically enriched α-alkylated mono-protected 1,4-cyclohexanedione derivatives in high yields and enantiomeric excesses of ee = 28, 80–≥99%. Reduction of the ketones gave the corresponding alcohols in good yields with high enantiomeric excesses (ee = 80–≥98%) and cis/trans-ratios of usually 85:15. Chirality 12:374–377, 2000. © 2000 Wiley-Liss, Inc.

Stigmatellin A (1) isolated from the myxobacterium Stigmatella aurantiaca is a powerful inhibitor of electron transport in mitochondria and chloroplasts. The first highly diastereo- and enantioselective total synthesis of this important natural product is described. Key steps in the synthesis are the alkylation of the SAMP-hydrazone (S)-13, a titanium mediated syn-diastereoselective aldol reaction, the anti-diastereoselective triacetoxyborohydride reduction of the aldol adduct (R,R,S)-16, formation of the chromone system via Baker-Venkataraman rearrangement and exclusive (E) CC double bond formation via Horner-Wadsworth-Emmons reaction.

Stigmatellin A (1), isoliert aus dem Myxobakterium Stigmatella aurantiaca, ist ein starker Inhibitor des Elektronentransports in Mitochondrien und Chloroplasten. Die erste hoch diastereo- und enantioselektive Totalsynthese dieses wichtigen Naturstoffs wird beschrieben. Schlüsselschritte der Synthese sind die Alkylierung des SAMP-Hydrazons (S)-13, eine Titan-unterstützte syn-diastereoselektive Aldol-Reaktion, die anti-diastereoselektive Triacetoxyborhydrid-Reduktion des Aldol-Addukts (R,R,S)-16, Aufbau des Chromonsystems durch Baker-Venkataraman-Umlagerung und (E)-selektive CC-Doppelbindungsbildung über eine Horner-Wadsworth-Emmons-Reaktion.

Asymmetrische C-P-Verknüpfungen durch Phospha-analoge Michael-Addition an Nitroalkene führen unter hoher asymmetrischer Induktion zu α-substituierten β-Nitrophosphonsäuren [Gl. (1)], präparativ wertvollen difunktionellen Synthesebausteinen, die insbesondere als direkte Vorstufen von β-Aminophosphonsäuren anzusehen sind. Der Schlüssel zum Erfolg ist ein P-Nucleophil-gebundenes TADDOL-Auxiliar, das leicht wieder entfernt werden kann.

The asymmetric synthesis of (+)-streptenol A was carried out in ten steps and with high enantioselectivity (ee ≥ 96%). The key steps are the α-alkylation of 2,2-dimethyl-1,3-dioxan-5-one RAMP hydrazone A (1), subsequent deoxygenation and elaboration of the side chain via aldehyde B to furnish (+)-streptenol A in 23% overall yield. In analogy, the enantiomer (–)-streptenol A was synthesized using the corresponding SAMP hydrazone in 18% overall yield.

A stereogenic center at the position β to the metallocene backbone is present in ferrocenyl ligands 2, which are interesting for asymmetric catalysis. These planar-chiral compounds are accessible for the first time by a highly diastereoselective and enantioselective synthesis (de=93–97 %; ee≥96 %) from the ferrocenyl ketones 1. A variety of donor groups (E¹=Ph₂P⋅BH₃, SMe, SiPr; E²=SMe, STol, SePh, Ph₂P⋅BH₃, iPr₂P⋅BH₃) can be introduced as electrophiles. Tol=tolyl=CH₃C₆H₄.

Regardless of whether SAMP or RAMBO (or their enantiomers RAMP or SAMBO) are used, the asymmetric synthesis of N-protected β-amino sulfones 4 by conjugate addition of a chiral nitrogen nucleophile (S)-1 (SAMP) or (R,R,R)-2 (RAMBO) to (E)-alkenyl sulfones 3 proceeds with high enantiomeric excesses. The title compounds are obtained after removal of the chiral auxiliary by reductive N−N bond cleavage.

Ob SAMP oder RAMBO oder deren Enantiomere RAMP bzw. SAMBO als chirale Ammoniakäquivalente verwendet werden: Die asymmetrische Synthese von N-geschützten β-Aminosulfonen 4 gelingt stets mit sehr hohen Enantiomerenüberschüssen durch Addition eines Stickstoff-Nucleophils ((S)-1 oder (R,R,R)-2) an (E)-Alkenylsulfone 3 und anschließende reduktive N-N-Spaltung zur Entfernung des chiralen Auxiliars.

Ein Stereozentrum inβ-Stellung zum Metallocenfragment haben die Ferrocenylliganden 2, die für den Einsatz in der asymmetrischen Katalyse interessant sind. Diese planar-chiralen Verbindungen sind nun durch eine hochdiastereo- und -enantioselektive Synthese (de = 93–97 %; ee≥96 %) aus den Ferrocenylketonen 1 zugänglich, wobei sehr variabel eine Vielzahl von Donorgruppen (E¹ = Ph₂P⋅BH₃, SMe, SiPr; E² = SMe, STol, SePh, Ph₂P⋅BH₃, iPr₂P⋅BH₃) elektrophil eingeführt werden kann. Tol = Tolyl = CH₃C₆H₄.

Investigations aimed at elucidating the structure of lithiated α-amino nitriles B have led to the identification of N-lithio α-amino nitrile anions as characteristic structural features. Their preparations, crystal structures, and solution structures under the reaction conditions, are described. X-ray crystal structure analyses of crystalline 3 and (S, S)-4 reveal the presence of dimeric aggregates B4 with C_i symmetry, held together by four-membered NLiNLi rings, coordinatively saturated at lithium by four THF ligands. The crystal structure of (S, S)-6 shows polymeric aggregation with dimeric subunits similar to those of 3 and (S, S)-4. The solution structure has been investigated by IR and Raman spectroscopy of 2, (S, S)-4 and (S, S)-6, by NMR spectroscopy of 3, (S, S)-5 and (S, S)-6, and by cryoscopic measurements of (S, S)-6 in THF. Trapping experiments complement the results. In THF, which constitutes the principal reaction medium, the lithiated amino nitriles B are found to exist as monomeric species B6 between −110 and +25°C. In less polar solvents, higher aggregation is presumed. NMR spectroscopic studies of 3 show that the favored orientations of the amine and phenyl groups are similar to their conformations in the solid state. In the light of the results obtained, a transition state is proposed to account for the relative topicity observed in the 1,4-additions of enantiopure lithiated α-amino nitriles (S, S)-4, (S, S)-5, and (S, S)-6 to Michael acceptors.

An enantioselective synthesis of N-protected amino diols has been accomplished by employing a diastereoselective inter- and intramolecular 1,3-dipolar cycloaddition reaction of optically active nitrile oxides as a key step. The nitro alkane starting materials were obtained by diastereoselective oxa Michael addition of (1R,2S)-(–)-N-formylnorephedrine (1) to aliphatic (E)-nitro alkenes 2, 6a, b (de = 96 – ≥ 98%). Subsequent diastereo- and regioselective cycloaddition reactions to highly substituted 4,5-isoxazolines 5a–e, 8a, b (52-81%) and reductive ring opening led – after cleavage of the auxiliary – to amino diols 13, 14 in good overall yields (27-40%, over five steps) and with excellent diastereomeric and enantiomeric excesses (de,ee ≥ 96%).

The first intermolecular asymmetric oxa Michael additions with removable chirality information within the hydroxide source are reported. As enantiopure oxygen nucleophile functioning as chiral hydroxide equivalent N-formylnorephedrine (7) was used and conjugate additions to aliphatic (E)-nitro alkenes 2a–j were carried out in good yields (35-87%) and excellent diastereomeric excesses (de = 94–≥98%). After reduction of the nitro group and protection of the amino function (11a–h, 73-87%, both steps), the cleavage of the auxiliary occurred without epimerisation (69-99%) using Na/NH₃. The Boc-protected 2-amino alcohols 12a–h could be obtained in good overall yields (30-58 %, four steps) and excellent diastereomeric and enantiomeric excesses (de, ee = 94–≥98%). Transition states explaining the overall stereochemical outcome are presented based on the absolute configuration determined by X-ray structure analysis on 8b.

An efficient asymmetric synthesis of protected anti-1,3-diols 5 (de ≥ 98%, ee = 92-98%) from 2,2-dimethyl-1,3-dioxan-5-one SAMP hydrazone 1 is described. The key steps are the diastereo- and enantioselective α,α′-bisalkylation followed by reduction of the ketones 2 and a variant of the Barton–McCombie deoxygenation. The new method allows the synthesis of acetonide-protected anti-1,3-diols with a broad range of substituents in good overall yields (31-69%).

The aldehydes 1 and 5 were converted to the corresponding SAMP hydrazones 2 and 6, respectively. Subsequent nucleophilic 1,2-addition of organolithium reagents to the C−N double bonds and cleavage of the N−N hydrazine bond using an excess of BH₃·THF afforded (1-ferrocenylalkyl)amines (N-protection 4) and 1,1′-bis(1-aminoalkyl)ferrocenes (N-protection 8) in good overall yields (32−88%), with very high enantiomeric excesses (ee = 90−98%) and dl/meso ratios of up to 95:5.

Deprotonation of chiral triazolium salts 1 and reaction of the resulting nucleophilic carbenes with [(COD)RhCl]₂ or [(NBD)RhCl]₂ afforded square-planar complexes 2–6 in yields of 65–95%. The complexes contain an axis of chirality and a diastereomeric excess of up to 97% was achieved. The relative and absolute configurations of these complexes were determined by NMR spectroscopic investigations and X-ray structure analysis. The application of the rhodium(COD) complexes as catalysts in an asymmetric hydrosilylation reaction has been examined, resulting in enantiomeric excesses of up to 44%. Similar results were achieved for aromatic and aliphatic ketones and a nonlinear temperature effect (principle of isoinversion) was observed.

Als Homoenolatäquivalente werden erstmals Zirconocen-1-aza-1,3-dienkomplexe in der stereoselektiven Synthese eingesetzt. Durch Insertion unsymmetrischer Ketone in die Zr-C-σ-Bindung werden sterisch anspruchsvolle trisubstituierte Dihydro- und Tetrahydrofurane in guten Gesamtausbeuten und mit hohen Diastereoselektivitäten zugänglich (siehe unten).

The first highly diastereo- and enantioselective synthesis of isotetronic acids (de, ee>98 %) is reported. Key steps in the reaction sequence are the diastereoselective aldol reaction of the 2-oxoester 1 (as the SAEP hydrazone) with aldehydes, followed by base-promoted lactonization to the corresponding hydrazonolactones. Subsequent oxidative cleavage of the hydrazone moiety afforded the enantiomerically pure O-protected isotetronic acids (R)-/(S)-2.

As homoenolate equivalents, zirconocene-1-aza-1,3-diene complexes were used for the first time in stereoselective synthesis. By insertion of an unsymmetrical ketone in the Zr–C σ bond, sterically demanding trisubstituted dihydro- and tetrahydrofuran derivatives were prepared in good overall yields and with high diastereoselectivities (see below).

An efficient, highly enantioselective methodology for the synthesis of α-phosphanyl ketones 7 and 2-phosphanyl alcohols 12 and 13, important hemilable ligands for enantioselective homogeneous catalysis and chiral building blocks in general, has been developed. The key step of this first enantio-selective synthesis of α-phosphanyl ketones is the diastereo-selective phosphanylation of SAMP hydrazones 2 to produce α-phosphanyl hydrazones, isolated as the more stable borane adducts 6. Subsequent ozonolysis afforded α-phosphanyl ketones 7. The enantioselective synthesis of 2-phosphanyl alcohols 12 and 13 has been accomplished by two fundamentally different procedures: the phosphanylation of unsubstituted chiral aldehyde hydrazones 9 and the alkylation of α-diphenylphopshanyl acetaldehyde SAMP hydrazone 10. After separation of the minor diastereomer, the borane-protected α-phosphanyl aldehyde hydrazones 11 were converted to unprotected 2-phosphanyl alcohols 13 by ozonolysis, reduction and removal of the borane group. The absolute configuration of the functionalized phosphanes was determined by X-ray analysis, NOE experiments or polarimetry.

The synthesis of (R,S)-(–)-dehydroiridodiol(dial) [(R,S)-6b], isolated from the plant Actinidia polygama Miq., and its analogues, in high diastereo- and enantiomeric purity (ee ⩾ 96%) is described. Key steps of the synthesis are the Michael addition of metallated SAMP hydrazones [(S)-1] to the 2-cyclopentenecarboxylate 2 and subsequent conversion to the 5-substituted 2-methylcyclopentenecarboxylates 5.

The stereoselective conjugate addition of (S)-(–)-1-(trimethylsilylamino)-2-(methoxymethyl)pyrrolidine (TMS-SAMP) to ω-halide-substituted α,β-unsaturated esters 1 is utilized to prepare carbocyclic and heterocyclic β-amino acids 2 and 5 of high diastereo- and enantiomeric purity via the corresponding β-hydrazino esters by selective intramolecular alkylation of the intermediate ester enolate or the hydrazino moiety. The auxiliary is removed by reductive NN bond cleavage. The stereochemistry of the resulting trans-2-aminocycloalkanecarboxylic acids (2) and azacycloalk-2-ylacetic acid esters (5) is confirmed by NMR spectroscopy and polarimetry. A transition-state model for the highly diastereoselective conjugate addition of TMS-SAMP to enoates is presented.

A new efficient method for the asymmetric epoxidation of α-enones with oxygen in the presence of diethylzinc and a chiral amino alcohol is presented. The epoxidation proceeds in moderate to excellent yields, complete diastereoselectivity and enantiomeric excesses of up to >99% by using enantiomerically pure (1R,2R)-N-methylpseudoephedrine 7 as a chiral additive. The amino alcohol auxiliary 7 employed can be almost completely recovered with unchanged enantiomeric purity.

The aldehydes 1 or 5 are converted to the SAMP hydrazones 2 or the α-alkylated SAMP hydrazones 7 and treated with organolithium compounds at low temperature. Cleavage of the NN bond of the resulting hydrazines 3 and 8 with Raney-Ni/H₂, or of the N-methoxycarbonylhydrazines 9 with Li/NH₃, yield the amines 4 with 61–90% ee, the amines 11 with 45–96% de and 93 99% ee. The absolute configuration of the amines 11 was established by X-ray analysis of an appropriate MTPA derivative.

A convenient, versatile and highly diastereo- and enantioselective synthesis of 4,5,6-trisubstituted piperidin-2-ones 1 in satisfactory overall yields is described. The procedure involves the efficient and highly anti-diastereo- and enantioselective Michael addition of aldehydes to enoates via their lithiated SAMP hydrazones, followed by nucleophilic 1,2-addition of organometallic reagents to the CN double bond of the corresponding aldehyde SAMP hydrazone-lithium ester enolate and subsequent lactamisation. In addition, 6-monosubstituted piperidin-2-ones 8 are prepared with enantiomeric excesses of ee = 79–92% via a similar three-step sequence starting from ethyl 5-oxovalerate (9).

Starting from chiral α-amino nitriles (S,S,R/S)-3, we prepared β-aroyl-γ-butyrolactones (S)-5 as well as 2,3-disubstituted γ -butyrolactones (S,S)- or (R,S,R)-6 in high yields and with high enantiomeric excesses by conjugate addition to butenolide, followed by protonation, α-alkylation or α-aldol addition, respectively. The introduction of one up to three stereogenic centers opens a flexible and highly efficient diastereo- and enantioselective route to 2,3-dibenzylated γ-butyrolactones 6, which proved to be important lignan building blocks.

The first asymmetric Carroll rearrangement opens up an efficient access to highly functionalised ketones 4 and 7 with vicinal quaternary and tertiary stereogenic centres of excellent diastereo- and enantiomeric purity (de =89–96%, ee =82 to >98%) by using the SAMP/RAMP hydrazone methodology. Starting from hydrazones (S)-2, we describe a dianionic and a Lewis acid-mediated variant of the [3.3]-sigmatropic Carroll rearrangement. The relative and absolute configuration of the new stereogenic centres created by C–C bond formation were assigned by X-ray crystallographic analysis of the hydrazones 3h and 3j.

The employment of 2-amino substituted 1,3-dienes in cycloaddition reactions has recently extended the scope of Diels-Alder methodologies. In this review, the preparation of a variety of 2-amino-1,3-dienes is presented, and the use of these cross conjugated enamines in normal as well as hetero Diels-Alder reactions is depicted. Diastereo- and enantioselective variations show new aspects for the preparation of cyclic carbonyl compounds in a highly stereoselective fashion. Further cyclisation reactions e.g. cyclopropanation reactions are also considered in this account.

Starting from easily available 2-acetoxy aldehyde dimethylhydrazones rac-2, we prepared various alkyl- and aryl-substituted 1H-pyrroles 6 in good overall yield. The titariummediated a²-umpolung reaction of rac-2 with different acyclic and cyclic silyl enol ethers 3 leads directly or via 4-oxo hydrazones rac,anti-4 to 1-(dimethylamino)-1H-pyrroles 5. A novel method for the reductive removal of the dimethylamino group affording 1H-pyrroles 6 is presented.

The reaction of three equiv. of a chiral imidazolium or triazolium perchlorate with one equiv. of Pd(OAc)₂, an excess of NaI and a base leads to the corresponding chiral dicarbenediiodopalladium(II) complexes in chemical yields up to 98% and with the trans isomer as the major product (1, 2). If only one equiv. of the imidazolium or triazolium perchlorate is used, then dinuclear complexes with bridging iodine atoms are formed (3, 4, chemical yield 92—94%). The latter can add Lewis basic ligands, e.g. amines, phosphanes or other carbenes, to give mononuclear complexes with one carbene ligand coordinated to the PdI₂ fragment (5, 6). Preliminary test experiments with these Pd(II) complexes as catalysts for an enantioselective Heck-type reaction have been carried out.

The title compound 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene (1), a stable carbene, is chemically characterized via its reactivity towards a multitude of organic substrates. Its behaviour in insertion, addition and cycloaddition reactions allows its classification as a typical representative of nucleophilic carbenes.