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Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis

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Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis molecules Review Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis Martin Cordes and Markus Kalesse * Institute of Organic Chemistry, Gottfried Wilhelm Leibniz University of Hannover, Schneiderberg 1b, 30167 Hannover, Germany * Correspondence: [email protected]; Tel.: +49-(0)511-7624688 Academic Editor: Ari Koskinen Received: 25 June 2019; Accepted: 19 August 2019; Published: 22 August 2019 Abstract: It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a β-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C–C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016–2019. Keywords: aldol reactions; Mukaiyama; natural product synthesis; stereoselectivity; vinylogy 1. Introduction Aldol reactions are among the most prominent and most frequently applied transformations in synthetic organic chemistry because they assemble the polyketide backbone of important biologically active compounds such as antibiotics and antitumor compounds. These reactions are valuable, not only because they generate new carbon-carbon bonds, but also because they create new stereogenic centers. The most frequently applied methods for aldol reactions often parallel the processes seen in the biosynthesis of polyketide natural products. In the biosynthesis, acetate or propionate units are added; subsequently, a series of further transformations (reductions, eliminations, and hydrogenations) are performed by large polyketide synthases to provide the substrate for the next aldol reaction. The laboratory synthesis mostly follows this modular approach by adding acetate and propionate fragments followed by reduction and oxidation steps, often coupled with extensive protecting group shuffling and additional chain-extension transformations, such as Horner–Wadsworth–Emmons (HWE) reactions (Scheme1). Even though a wide variety of polyketide structures can be accessed with established transformations, the use of vinylogous aldol reactions reduces the number of steps needed to access these structures. Therefore a substantial number of research groups have focused on these reactions to develop more efficient methods for the construction of larger polyketide segments in one step [1–5]. Molecules 2019, 24, 3040; doi:10.3390/molecules24173040 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 20 Molecules 2019, 24, x FOR PEER REVIEW 2 of 20 Molecules 2019, 24, 3040 2 of 19 Molecules 2019, 24, x FOR PEER REVIEW 2 of 20 Scheme 1. The vinylogous Mukaiyama aldol reaction (VMAR) is unique in its atom economy. SchemeScheme 1.1. TheThe vinylogousvinylogous MukaiyamaMukaiyama aldolaldol reactionreaction (VMAR)(VMAR) isis uniqueunique inin itsits atomatom economy.economy. AccordingScheme to1. The Fuson’s vinylogous principle Mukaiyama of vinylogy, aldol reaction an additional (VMAR) is adjacent unique in double its atom bond economy. extends the According to Fuson’s principle of vinylogy, an additional adjacent double bond extends the nucleophilicAccording character to Fuson’s of silyl principle enol ethers of vinylogy, [6]. Thus, thean additional vinylogous adjacent extension double of the Mukaiyamabond extends aldol the nucleophilicAccording character to Fuson’s of silyl principle enol ethers of vinylogy, [6]. Thus, anthe additional vinylogous adjacent extension double of the bond Mukaiyama extends aldol the reactionnucleophilic allows character the synthesis of silyl of enol larger ethers fragments [6]. Thus, while the incorporating vinylogous extension 1,5-relationships of the Mukaiyama and generating aldol reactionnucleophilic allows character the synthesis of silyl enol of ethers larger [6]. frag Thus,ments the vinylogouswhile incorporating extension of 1,5-relationshipsthe Mukaiyama aldol and tworeaction new stereocentersallows the andsynthesis one double of larger bond simultaneously.fragments while The incorporating vinylogous Mukaiyama 1,5-relationships aldol (VMA) and generatingreaction allows two new the stereocenters synthesis of and larger one double fragments bond simultaneously.while incorporating The vinylogous1,5-relationships Mukaiyama and reactiongenerating is of two great new interest stereocenters because and it provides one double rapid bond access simultaneously. to larger carbon The frameworksvinylogous Mukaiyama containing aldolgenerating (VMA) two reaction new stereocenters is of great interest and one because double it bondprovides simultaneously. rapid access Theto larger vinylogous carbon Mukaiyama frameworks aaldol double (VMA) bond reaction that is is available of great forinterest a wide because variety it provides of subsequent rapid transformationsaccess to larger carbon (dihydroxylation, frameworks containingaldol (VMA) a reactiondouble isbond of great that interest is available because for it provides a wide rapidvariety access of tosubsequent larger carbon transformations frameworks epoxidation,containing a cuprate double addition, bond that etc.) is [5 ,7available–12]. The for general a wide outcome variety of theof vinylogoussubsequent Mukaiyama transformations aldol (dihydroxylation,containing a double epoxidation, bond that cuprateis available addition, for a etc.)wide [5,7–12].variety ofThe subsequent general outcometransformations of the (VMA)(dihydroxylation, reaction is depictedepoxidation, in Scheme cuprate2. addition, etc.) [5,7–12]. The general outcome of the (dihydroxylation, epoxidation, cuprate addition, etc.) [5,7–12]. The general outcome of the vinylogousvinylogous MukaiyamaMukaiyama aldolaldol (VMA)(VMA) reactionreaction isis depicteddepicted inin SchemeScheme 2.2. vinylogous Mukaiyama aldol (VMA) reaction is depicted in Scheme 2. Scheme 2. The general outcome of the VMAR. SchemeScheme 2.2. TheThe generalgeneral outcomeoutcome ofof thethe VMAR.VMAR. Scheme 2. The general outcome of the VMAR. Not surprisingly, Prof. T. Mukaiyama, who first introduced the enoxysilane aldolization chemistry Not surprisingly, Prof. T. Mukaiyama, who first introduced the enoxysilane aldolization and developedNot surprisingly, it into a Prof. powerful T. Mukaiyama, transformation who tool, first was introduced among the the pioneers enoxysilane of the vinylogousaldolization chemistryNot surprisingly,and developed Prof. it intoT. Mukaiyama,a powerful tranwhosformation first introduced tool, was the am enoxongysilane the pioneers aldolization of the versionchemistrychemistry of his andand eponymous developeddeveloped reaction it into a (Scheme powerful3)[ 13trantran–15sformationsformation]. tool,tool, waswas amamongong the the pioneers pioneers of of the the vinylogous version of his eponymous reaction (Scheme 3) [13–15]. vinylogousvinylogous versionversion of his eponymous reaction (Scheme(Scheme 3)3) [13–15]. [13–15]. Scheme 3. The first example of the VMAR. SchemeScheme 3.3. TheThe firstfirstfirst exampleexample of of the the VMAR. VMAR. Molecules 2019, 24, 3040 3 of 19 Molecules 2019, 24, x FOR PEER REVIEW 3 of 20 For the reasons described above, the vinylogous Mukaiyama aldol reaction has become a strategically important and reliable transformation th thatat is increasingly employed in the asymmetric synthesis of complex molecules, particularlyparticularly polyketides.polyketides. For initiation of the VMA process, twotwo modesmodes ofof activationactivation havehave beenbeen employed:employed: Activation of the electrophile or activation of thethe nucleophilenucleophile (see(see below).below). In principle, three general methods are applied to dictate the stereochemicalstereochemical outcome of thisthis transformation:transformation: (1) Substrate control, wherein stereoinduction arises from existing stereocenters, (2) catalyst control, wherein an external agent functions as the stereo-controlling element, and (3) a combination of both methods. Because Because reagent- reagent- and substrate-controlled transformationstransformations remainremain dominant dominant in in polyketide polyketide synthesis, synthesis, the the invention invention of of a generala general catalyst catalyst system system to promote to promote catalytic, catalytic, enantioselective enantioselective VMA reactions VMA hasreactions become has a preeminent, become a overarchingpreeminent, goal.overarching goal. A brief chronologicalchronological synopsissynopsis of of the the catalytic, catalytic, enantioselective enantioselective VMA VMA reaction, reaction, making making no no claim claim of beingof being complete, complete, shows shows that that the the first first examples examples were were reported reported between between 1992–19951992–1995 usingusing boron-boron- and titanium(IV)-derived
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