Sex Pheromone of the Pine Sawfly, Macrodiprion nemoralis. Stereoselective Synthesis of the Sixteen Stereoisomers of 3,7,9-Trimethyl-2-tridecyl Acetate.

2006

Chemistry A European J

A new iterative strategy for the flexible preparation of any oligodeoxypropionate stereoisomer is presented which relies on an o-DPPB-directed copper mediated allylic substitution employing enantiomerically pure Grignard reagents; the reaction is working with perfect control over all aspects of the reaction selectivity. This key C--C bond-forming step features reversed polarity compared with established enolate alkylation methodology. It thus avoids existing problems of enolate alkylation strategies such as enolate reactivity as well as costs and problems associated with the chiral auxiliary. Practicability of this new method is demonstrated through application in natural product syntheses. Thus, an efficient synthesis of the northern part of the angiogenesis inhibitor borrelidin (28), the deoxypropionate building block 27, could be devised, representing a formal total synthesis.

Section: Resultsmentioning

confidence: 99%

“…Flash chromatography (pentane/diethyl ether 5:1) yielded alcohol (−)‐ 23 (19.9 mg, 0.126 mmol, 95 %) as a colorless oil. [ α ]${{{20\hfill \atop {\rm D}\hfill}}}$ =−23.6 ( c =0.83 in CHCl 3 , dr 97:3, lit 18…”

Section: Methodsmentioning

confidence: 99%

Iterative Deoxypropionate Synthesis Based on a Copper‐Mediated Directed Allylic Substitution: Formal Total Synthesis of Borrelidin (C3–C11 Fragment)

2006

Chemistry A European J

“…Thus, the reaction that leads to the 1,3-syn relative configuration (in (À)-14) appears to represent a matched case, whereas the reaction that leads to the 1,3-anti configuration (in (+)-13) represents a mismatched case. The relative and absolute configurations of the bis(deoxypropionate)s (+)-13 and (À)-14 were verified upon conversion into the known alcohols (À)-19 [13] and (+)-20, [14] respectively (Scheme 4).…”

mentioning

confidence: 99%

Iterative Deoxypropionate Synthesis Based on a Copper‐Mediated Directed Allylic Substitution

2004

Angew Chem Int Ed

Many biologically relevant natural products of polyketide origin contain a fully reduced 1,3,5,n("skip")-polymethylsubstituted carbon chain.[1] Such structures, referred to as "deoxypropionate oligomers", are usually constructed through an iterative asymmetric enolate alkylation of the type introduced by Evans et al. [2] Although the use of amide enolates based on pseudoephedrine [3] and azaenolates derived from (R)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP) hydrazones [4] have led to significant improvements in this methodology, disadvantages still include the often low reactivity of the enolate intermediate towards the alkylating agent, and the cost and removability of the chiral auxiliary. These drawbacks prohibit large-scale applications. We report herein an alternative iterative strategy based on a stereospecific copper-mediated directed allylic substitution. This flexible approach allows the preparation of any desired oligo(deoxypropionate) stereoisomer. The strategy is outlined in Scheme 1.The key step of our strategy is an S N 2' reaction of the organometallic reagent 3 with the electrophile 2 derived from an allylic alcohol, to furnish the bis(deoxypropionate) building block 1. Oxidative cleavage of the alkene in the bis(deoxypropionate) 1 followed by conversion of the product into a new organometallic nucleophile should then make it possible to carry out an iterative process. This approach is complementary to the known enolate-alkylation strategy, as the growing propionate chain is introduced as a nucleophile and not as an electrophile ("Umpolung"). Key to the success of this strategy is the availability of an allylic substitution reaction that occurs in acyclic systems with complete chemo-, regio-, and stereoselectivity, as well as complete 1,3-chirality transfer. Our recently developed "directed" copper-mediated allylic substitution reaction with o-diphenylphosphanylbenzoate (o-DPPB) as the reagent-directing leaving group meets these requirements.[5] However, its compatibility with enantiomerically pure Grignard reagents 3 that are branched in the b position remained untested. Furthermore, it was necessary to develop a practical route to enantiomerically pure building blocks 2 and 3.Enzyme catalysis was selected as a suitable method for the preparation of large quantities of both enantiomers of allylic electrophiles 2. Thus, the allylic alcohol rac-6 was subjected to enzymatic resolution with Novozym 435 (Scheme 2).[6] Enantiomerically pure (S)-6 was obtained at 55 % conversion (enantioselectivity factor E = 52). The acetate (R)-7 (82 % ee) formed in the reaction underwent hydrolysis (also catalyzed by Novozym 435) to furnish (R)-6 (96-97 % ee). Both enantiomers of 6 were transformed into the corresponding odiphenylphosphanylbenzoate compounds 8, which were purified by crystallization. In this way, gram quantities of both enantiomers of 8 could be prepared in enantiomerically pure form. The crystalline allylic o-DPPB esters 8 could be stored Scheme 1. Iterative strategy for the enantioselective const...

“…Dabei erwies es sich als essenziell, das verwendete Magnesium nach der Dry-Stir-Methode zu aktivieren. [11,12] [13] und (+)-20 [14] verifiziert (Schema 4).…”

Section: Bernhard Breit* Und Christian Herberunclassified

Iterative Desoxypropionat‐Synthese auf der Basis einer kupfervermittelten dirigierten allylischen Substitution

2004

Angewandte Chemie

Viele biologisch relevante, von Polyketiden abgeleitete Naturstoffe enthalten eine völlig reduzierte, 1,3,5,…,n("Skip")-Polymethyl-substituierte Kohlenstoffkette.[1] Solche Ketten, die als "Desoxypropionat-Oligomere" aufgefasst werden können, werden im Allgemeinen durch eine iterative asymmetrische Enolatalkylierung nach Evans et al. aufgebaut.[2] Deutliche Verbesserungen wurden durch die Verwendung von Amidenolaten auf der Basis von Pseudoephedrin [3] und durch den Einsatz von Azaenolaten ausgehend von (R)-1-Amino-2-(methoxymethyl)pyrrolidinHydrazonen (RAMP-Hydrazonen) erzielt.[4] Nachteile dieser Methode sind jedoch die oft geringe Enolatreaktivität gegenüber den Alkylierungsmitteln sowie der hohe Preis und die schwierige Abspaltung des chiralen Auxiliars, was eine Anwendung in größerem Maßstab behindert.Wir berichten hier über eine alternative iterative Strategie auf der Basis einer stereospezifischen kupfervermittelten dirigierten allylischen Substitution. Dieser Ansatz ermöglicht die flexible Synthese jedes gewünschten Oligo(desoxypropionat)-Stereoisomers. Das zugrundeliegende Konzept ist in Schema 1 dargestellt.Der Schlüsselschritt unserer Strategie ist eine S N 2'-Reaktion des metallorganischen Reagens 3 mit dem Allylelektrophil 2 unter Bildung des Bis(desoxypropionat)-Bausteins 1. Die Iteration gelingt durch eine oxidative Alkenspaltung von 1 und anschließende Metallierung zum neuen metallorganischen Nucleophil. Diese Methode ist somit das Gegenstück zur bekannten Enolatalkylierung: Die wachsende Propionatkette wird hier als Nucleophil und nicht als Elektrophil eingeführt ("Umpolung"). Die allylische Substitutionsreaktion muss unter vollständiger Kontrolle von Chemo-, Regiound Stereoselektivität mit vollständigem 1,3-Chiralitätstrans-fer an acyclischen Systemen ablaufen, damit diese Strategie gelingt. Die von uns kürzlich entwickelte "dirigierte" kupfervermittelte allylische Substitution unter Verwendung der ortho-Diphenylphosphanylbenzoat-Funktion (o-DPPB) als Reagens-dirigierender Abgangsgruppe erfüllt zwar diese Voraussetzungen, [5] bisher war allerdings unklar, ob diese Methode kompatibel mit enantiomerenreinen in b-Position verzweigten Grignard-Reagentien (3) sein würde. Außerdem musste ein praktikabler Zugang zu den enantiomerenreinen Bausteinen 2 und 3 entwickelt werden.Wir wählten die Enzymkatalyse, um größere Mengen beider Enantiomere des Allylelektrophils 2 zu gewinnen. Uns gelang ausgehend vom Allylalkohol rac-6 die enzymatische Racemattrennung mithilfe von Novozym 435 (Schema 2).