Asymmetric Total Synthesis of (+)-Pancratistatin

Trost, Barry M.; Pulley, Shon R.

doi:10.1021/ja00145a038

Cited by 152 publications

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“…8, the initial allylic azide 27 can be isolated in excellent yield and enantioselectivity. 29) This azide served as a key intermediate in an efficient synthesis of the antitumor agent pancratistatin. A similar reaction also led to a concise synthesis of the powerful analgesic (Ϫ)-epibatidine.…”

Section: Type B Enantiodiscriminationmentioning

confidence: 99%

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Trost

2002

Chem. Pharm. Bull.

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303

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Chiral compounds have many applications. None are more important than those related to biological targets. The chiral nature of biological receptors make chiral ligands common objectives as pharmaceuticals and agrichemicals. Thus, developing efficient synthetic methods to such compounds represents an important challenge. In spite of great advances, resolution methods still frequently represent the most economical method for commercial production in spite of the fact that the theoretical yield of the single desired enantiomer cannot exceed 50% unless the opposite enantiomer can be converted to the desired one. Using starting materials from the chiral pool also constitutes a common strategy. More recently, attention has shifted to inducing chirality into achiral precursors. Two tacts have been explored. In one, chiral auxiliaries, normally emanating from the chiral pool, are covalently attached to prochiral substrates.1) The advantage of this approach is the high degree of success in transmitting chiral information in this more controlled strategy. However, it suffers from numerous drawbacks. First, it requires stoichiometric amounts of the chiral auxiliary which ultimately is not part of the final product. It also requires additional steps to add and subsequently remove the chiral auxiliary. Clearly, the conceptually most attractive strategy is employing asymmetric catalytic reactions. 2)Some of these have achieved great success. Two of the most successful have been asymmetric catalytic hydrogenation and asymmetric catalytic oxidation of alkenes, notably epoxidation. These two reactions, in addition to virtually every other asymmetric catalytic reaction, share a common feature-the enantiodiscriminating event involves recognizing the enantiotopic faces of a prochiral p-unsaturation such as a carbonyl group or a double bond. Furthermore, each of these reactions also involve formation of just one bond type-a C-H bond in the case of hydrogenation and a C-O bond in the case of oxidation.Catalytic asymmetric allylic alkylation differs from virtually all other catalytic processes in two important ways. In the first, there are many enantiodiscriminating mechanisms, not just one. As shown in Fig. 1, there are at least five such mechanisms. As in most other catalytic asymmetric reactions, differentiating the enantiotopic faces of a p-unsaturation is one mechanism (Fig. 1, A). A second mechanism is differentiating enantiopic leaving groups (Fig. 1, B). Mechanism C involves differentiating enantiotopic termini of a pallylmetal intermediate. Since this intermediate derives from a chiral racemic precursor in which the chirality of the substrate is lost, this deracemization constitutes a dynamic kinetic asymmetric transformation (DYKAT). Mechanism D is a varient of mechanism A wherein the p-allylmetal intermediates interconvert faster than they are attacked by a nucleophile and asymmetric induction derives from differential rates of reaction of the two diastereomeric intermediates. This mechanism allows employment of either an ...

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Section: Type B Enantiodiscriminationmentioning

confidence: 99%

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Trost

2002

Chem. Pharm. Bull.

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303

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“…[7][8][9][10][11][12][13][14] Most remarkable is the synthesis by Trost and Pulley, whereby 1 is prepared in 11 % overall yield from conduritol A acetonide after only 12 steps. [9] Racemic 2 was first synthesised by Ohta and Kimoto in 1976 as an advanced intermediate in the total synthesis of another hydroxylated phenanthridone, lycoricidine. [15] A few years later, enantiopure 2 was prepared for the first time by Paulsen and Stubbe as an intermediate in their synthesis of Abstract: The stereocontrolled synthesis of (+)-7-deoxypancratistatin is described.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 7‐Deoxypancratistatin from Carbohydrates by the Use of Olefin Metathesis

Håkansson

Palmelund

Holm

et al. 2006

Chemistry A European J

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The stereocontrolled synthesis of (+)-7-deoxypancratistatin is described. The convergent synthesis has been achieved by two different strategies, both of which commence from a pentose and piperonal. The latter is converted into allylic bromide 7, which is then coupled with a protected methyl 5-deoxy-5-iodo-D-ribofuranoside in the presence of zinc metal. The first strategy involves a total of only 13 steps from D-ribose and piperonal, but suffers from a low yield in the zinc-mediated reaction between ribofuranoside 9, benzylamine, and bromide 7. The second strategy involves a total of 18 steps from D-xylose and piperonal. The former is converted into ribofuranoside 28, which is coupled with bromide 7 in the presence of zinc, and this is followed by ring-closing olefin metathesis. Subsequent Overman rearrangement, dihydroxylation, and deprotection then affords the natural product.

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“…70 Using our standard R,R ligand 31, trimethylsilyl azide reacted with dicarbonate 143 (R ) OCH 3 ) to give monoazide 142 (R ) OCH 3 ) of >95% ee in 82% yield. The synthesis as sketched in Scheme 26 was completed in 14 steps from meso-diester 143.…”

Section: Scheme 23 Retrosynthetic Analysis Of Calanolide Amentioning

confidence: 99%

Asymmetric Allylic Alkylation, an Enabling Methodology

Trost

2004

ChemInform

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The diversity of mechanisms for enantiodiscrimination and of bond types that can be formed make Pd-catalyzed asymmetric allylic alkylation a powerful key step for simplification of synthetic strategy to complex molecular targets. Using a wide range of different classes of compounds including alkaloids, polyhydrofurans, nucleosides and carbanucleosides, cyclohexitols and cyclopentitols, chromanes, cyclopentanoids, amino acids, barbiturates, etc., novel synthetic strategies emerge that provide short efficient asymmetric syntheses.Chemistry distinguishes itself from the other disciplines in approaching scientific questions by its ability to design structure for function unfettered by what is available. A key enabling aspect of this freedom is the effectiveness of synthetic methodology to solve problems of selectivity, a feature that is particularly noted when dealing with biological problems. Providing efficient synthesis to complex molecules requires minimizing the number of steps, any side reactions, and purification protocols. Among the most challenging issues is obtaining enantiomerically pure compounds for which asymmetric catalysis constitutes a core competency.Among asymmetric bond forming reactions, the metalcatalyzed asymmetric allylic alkylation (AAA) is unique for several reasons.

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Asymmetric Total Synthesis of (+)-Pancratistatin

Cited by 152 publications

References 0 publications

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Synthesis of 7‐Deoxypancratistatin from Carbohydrates by the Use of Olefin Metathesis

Asymmetric Allylic Alkylation, an Enabling Methodology

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