Total synthesis of (+)-scyphostatin featuring an enantioselective and highly efficient route to the side-chain via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)

All four stereoisomers (7-10) of ethyl undeca-2,4-dienoate were prepared in ≥98% isomeric purity by Pd-catalyzed alkenylation (Negishi coupling) using ethyl (E)-and (Z)-β-bromoacrylates. Although the stereoisomeric purity of the 2Z,4E-isomer (8) prepared by Suzuki coupling using conventional alkoxide and carbonate bases was ≤95%, as reported earlier, the use of CsF or n Bu4NF as a promoter base has now been found to give all of 7-10 in ≥98% selectivity. Other widely known methods reveal considerable limitations. Heck alkenylation was satisfactory for the syntheses of the 2E,4E and 2E,4Z isomers of ≥98% purity, but the purity of the 2Z,4E isomer was ≤95%. Mutually complementary HornerWadsworth-Emmons and Still-Gennari (SG) olefinations are also of considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer is readily prepared in ≥90% selectivity. In addition to (2Z,4E)-dienoic esters, some (2Z,4E,6E)-and (2Z,4E,6Z)-trienoic esters have been prepared in ≥98% selectivity by a newly devised Pd-catalyzed alkenylation-SG olefination tandem process. As models for conjugated higher oligoenoic esters, all eight stereoisomers for ethyl trideca-2,4,6-trienoate (23-30) have been prepared in ≥98% overall selectivity.highly selective synthesis | Pd-catalyzed Negishi coupling A lkenes represent a large number of natural products of bioactive and medicinally important compounds. Of interest in this study are those containing conjugated dienes and oligoenes (1-11) (Fig. 1). Among numerous known methods for the syntheses of alkenes including conjugated dienes and oligoenes (12, 13), carbonyl olefination reactions, notably Wittig olefination (14) and its variants, such as Horner-Wadsworth-Emmons (HWE hereafter) (15, 16), and Still-Gennari (SG hereafter) (17) as well as Ando (18) modifications have been widely used along with related Si-promoted (Peterson) (19) and S-promoted (Julia and Paris) (20) olefination reactions. As useful as these reactions are, they often lack very high (≥98%) stereoselectivity.In search for highly (≥98%) stereoselective alkene synthesis methodology, our attention was initially drawn to alkyne hydroboration, which generally proceeds in >99% syn-selectivity. Following some promising leads of Brown (21) and Zweifel and co-workers (22-25), we reported in 1973 a couple of highly selective routes to 1,4-disubstituted (E,E)-and (E,Z)-1,3-dienes (1, 3, 26), which appear to represent the earliest syntheses of unsymmetrically substituted conjugated dienes in very high (≥97%) selectivity via organometallic alkenylation.Despite highly selective and satisfactory results described above, our continued search for a more generally applicable and straightforward route to conjugated di-and oligoenes led to the discovery in 1976 of the Pd-catalyzed alkenyl-alkenyl coupling with alkenylalanes (27) and subsequently with alkenyl derivatives containing Zr (28) and Zn (29), collectively known as Negishi coupling (30,31). Along with the subsequently developed alkenylboron version (Suzuki coupling) (32-34), the Pd-catalyzed alken...

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“…Of interest in this study are those containing conjugated dienes and oligoenes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) (Fig. 1).…”

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confidence: 99%

Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation–Pd-catalyzed cross-coupling

Wang

Mohan

Negishi

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthesis of the side chain of scyphostatin by Pd-catalyzed alkenyl-alkenyl coupling and HWE olefination [117].…”

Section: Scheme 324mentioning

confidence: 99%

“…Vitamin E (2001 and 2002) [313,319] Vitamin K (2001 and 2007) [316,319] Phytol (2001) [319] Scyphostatin (2004 and 2010) [117,244] Siphonarienal (2004) [245] Siphonarienone (2004) [245] Siphonarienolone (2004) …”

Section: Chiral Compounds Of Biological and Medicina Linterest (Year)mentioning

confidence: 99%

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

Kamada

Kim

et al. 2013

Metal‐Catalyzed Cross‐Coupling Reactions and More

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The Pd-or Ni-catalyzed cross-coupling reactions of organometals containing Zn, Al, Zr, and B as well as related reactions of those containing Mg and several other metals collectively have emerged as arguably the most widely applicable organic skeleton construction method discovered and developed over the past several decades, allowing synthetic chemists to prepare practically all types of organic compounds. In this chapter, some of the seminal and critically important discoveries and early developments in the 1970s as well as their current scope are briefly discussed. Some of the notable discoveries and developments include (i) identification of superior properties of Pd as a critical element for crosscoupling relative to Ni, (ii) the broad scope of Pd-or Ni-catalyzed cross-coupling with respect to metal countercations including Zn, Al, Zr, B, and Mg, (iii) the hydrometallation-Pd-catalyzed cross-coupling sequential processes for selective syntheses of alkenes, dienes, oligoenes, and oligoenynes, (iv) double metal catalysis involving Pd or Ni and added metal compounds containing Zn, In, Li, and others, and (v) realization of high turnover numbers (TONs) (≥10 3 -10 9 ) through the use of chelating phosphines, such as bis-[2-(diphenylphosphino)phenyl] ether (DPEphos) and 1,1 -Bis(diphenylphosphino)ferrocene (dppf).The Zr-catalyzed alkyne carboalumination and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction) have provided efficient and selective routes to (E)-trisubstituted alkenylalanes and 2-substituted chiral alkylalanes, respectively. These reactions provide two additional examples of prototypical transition metal-catalyzed organometallic reactions. Significantly, they can be readily combined with the Pd-or Ni-catalyzed cross-coupling for the synthesis of trisubstituted alkenes embracing a wide variety of natural products, such as terpenoids, carotenoids, and others, as well as various chiral organics including deoxypolypropionates and saturated terpenoids. The Zr-catalyzed alkyne carboalumination has been applied to the synthesis of a large number (>100) of natural products, while the ZACA reaction has been transformed from a mere scientific novelty to a full-fledged asymmetric synthetic method that is catalytic in both transition metal (Zr) and chiral auxiliaries through a series of breakthroughs.

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“…[98,100] 3) In Fällen, in denen die ZACA-Produkte als 2-chirale verzweigte 1-Alkohole durch einfache Oxidation von Alanen, normalerweise mit O 2 , erhalten werden, bietet die Lipasekatalysierte Acetylierung mit anschließender einfacher Säu-lenchromatographie eine allgemein anwendbare und bequeme Reinigungsmethode, wobei der in der ZACA-Reaktion gebildete ausreichend hohe Enantiomerenüberschuss (70-95 %) der Rohprodukte genutzt wird. [106] [99,111] Seitenkette [99] und Totalsynthese [111] 5…”

Section: Zusammenfassung Der Entwicklung Und Anwendung Der Zacareaktiunclassified

Die magische Kraft der Übergangsmetalle: Vergangenheit, Gegenwart und Zukunft (Nobel‐Aufsatz)

Negishi

2011

Angewandte Chemie

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183

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In meinem ersten Jahr an der Shonan errang damit den 123. Platz der schulischen Leistung unter etwas mehr als 400 Mitschülern. Nach einem kurzen Augenblick der Enttäu-schung erkannte ich, dass zwar etwas mehr als 100 Schüler vor mir lagen, aber auch fast 300 hinter mir. Damals wurden jährlich etwa 30-40 Schüler von Shonan einschließlich der einmaligen Wiederholer an der Universität Tokio aufgenommen. Mir wurde dann plötzlich klar, dass ich sogar eine berechtigte Chance hätte, an die bis dahin für mich unerreichbar scheinende Universität Tokio zu kommen, wenn ich so hart wie möglich lernte.

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Total synthesis of (+)-scyphostatin featuring an enantioselective and highly efficient route to the side-chain via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)

Cited by 30 publications

References 44 publications

Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation–Pd-catalyzed cross-coupling

Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation–Pd-catalyzed cross-coupling

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

Die magische Kraft der Übergangsmetalle: Vergangenheit, Gegenwart und Zukunft (Nobel‐Aufsatz)

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