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].

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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.

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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 catalystscatalysts [ 16[16–18].–18]. Following Following this, this, bisoxazoline–copper(II) bisoxazoline–copper(II) complexes complexes and aand chiral a chiral bisphosphoramide catalyst in conjunction with SiCl4 were also shown to be effective in bisphosphoramide catalyst in conjunction with SiCl4 were also shown to be effective in mediating vinylogousmediating vinylogous Mukaiyama Mukaiyama aldol reactions aldol [ 19reactions–23]. The [19–23]. catalyst The systems catalyst mentioned systems mentioned thus far represent thus far enantioselectiverepresent enantioselective methods for methods simple aldol for simple reactions aldol extended reactions to vinylogous extended to Mukaiyama vinylogous aldol Mukaiyama reactions; thealdol catalytically reactions; the active catalytically species in active these species VMA reactionsin these VMA is a chiralreactions Lewis is a acid, chiral which Lewis mediates acid, which the reactionmediates by the electrophilic reaction by aldehyde electrophilic activation. aldehyde The first activation. catalyst systemThe first that catalyst was specifically system that designed was forspecifically use in the designed catalytic, for enantioselective, use in the catalytic, and vinylogous enantioselective, Mukaiyama and aldolvinylogous reaction Mukaiyama was a copper(II) aldol fluoridereaction/ wasTol-BINAP a copper(II) complex fluoride/Tol-BINAP in which the catalytically complex in active which species the catalytically was a bisphosphinyl active species copper(I) was a fluoridebisphosphinyl complex copper(I) [24–26]. fluoride complex [24–26]. Since the firstfirst pioneering reports of the Mukaiyama aldol reaction itself [27] [27] and the catalytic, enantioselective versionversion of of the the vinylogous vinylogous Mukaiyama Mukaiyama aldol aldol reaction reaction [16,17 [16,17],], the enantioselective the enantioselective VMA processVMA process has established has established itself as itself the goldas the standard gold stan fordard site-selective for site-selective construction construction of densely of adorneddensely δadorned-hydroxylated δ-hydroxylated a,β-unsaturated a,β-unsaturated carbonyl compoundscarbonyl compounds and related an polyketided related polyketide networks [networks1–3,5,7–9, 28[1–]. 3,5,7–9,28].In contrast to the Mukaiyama aldol reaction, its vinylogous extension, the so-called VMA reaction,In contrast involves to a regioselectivitythe Mukaiyama issue, aldol namely reaction,α-versus its vinylogousγ-addition. extension, In general, the metal so-called dienolates VMA favorreaction,α-alkylation involves a andregioselectivity silyl dienol issue, ethers namely favor γ-versus-alkylation -addition. products In (Schemegeneral, 4metal). Aluminum dienolates tris(2,6-diphenylphenoxide)favor -alkylation and silyl dienol (ATPH) ethers mediated favor -alkylation vinylogous products aldol reactions (Scheme are4). Aluminum exceptions tris(2,6- to this rule,diphenylphenoxide) because the α position (ATPH) is mediated deeply buried vinylogous in the aldol pocket reactions of the catalystare exceptions and therefore to this rule, is no because longer accessiblethe  position to electrophiles is deeply buried [29]. Thein the site pocket selectivity of the associated catalyst and with therefore metal dienolates is no longer can beaccessible overcome to byelectrophiles using their [29]. silyl The derivatives, site selectivity whose associated generation wi canth metal be controlled dienolates by can the be careful overcome choice by ofusing catalysts their (promoters)silyl derivatives, and additives. whose generation In this context, can be silyloxy controll dienesed by have the careful emerged choice as superb of catalysts surrogates (promoters) for metal dienolatesand additives. in the In vinylogousthis context, aldol silyloxy reaction. dienes have emerged as superb surrogates for metal dienolates in the vinylogous aldol reaction.

Scheme 4.4. The VMAR involves a regioselective issue,issue, namelynamely α-versus-versus γ-addition.-addition.

The didifferentﬀerent site selectivities of the metal dienolatesdienolates and the silyl dienol ethers can be explained by frontier molecular orbital electronelectron densitydensity calculationscalculations [[30].30]. For example, the HOMO coefficient and the electrophilic susceptibility value in (1-methoxy-1,3- butadienyloxy)trimethylsilane at C4 is significantly higher than at C2; a kinetic preference for the -

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For example, the HOMO coefficient and the electrophilic susceptibility value in (1-methoxy-1,3- butadienyloxy)trimethylsilaneMolecules 2019, 24, x FOR PEER REVIEW at C4 is significantly higher than at C2; a kinetic preference for4 of the 20 γ-addition product is therefore predicted. On the other hand, the lithium dienolate of methyl crotonate addition product is therefore predicted. On the other hand, the lithium dienolate of methyl crotonate displaysaddition aproduct larger HOMO is therefore coeffi predicted.cient and electrophilic On the other susceptibility hand, the lithium value dienol at C2 thanate of at methyl C4, rationalizing crotonate displays a larger HOMO coefficient and electrophilic susceptibility value at C2 than at C4, thedisplays observed a largerα-addition HOMO product coefficient (Scheme and5 )[electrophilic3]. These electronicsusceptibility effects value can beat alteredC2 than by at steric C4, rationalizing the observed -addition product (Scheme 5) [3]. These electronic effects can be altered interactionsrationalizing and the/or observed chelation. -addition product (Scheme 5) [3]. These electronic effects can be altered by steric interactions and/or chelation.

Scheme 5. Comparison of orbital coeﬃcients and electrophilic susceptibility of vinylogous silylketene Scheme 5. Comparison of orbital coefficients and electrophilic susceptibility of vinylogous silylketene acetals with metal dienolates. acetals with metal dienolates. Under typical conditions, most dienoxysilanes are unreactive toward aldehydes without Under typical conditions, most dienoxysilanes are unreactive toward aldehydes without activationUnder [31 typical–36]. Thus, conditions, catalysis ofmost the VMAdienoxysilanes reaction is crucialare unreactive and can proceed toward by aldehydes two fundamentally without activation [31–36]. Thus, catalysis of the VMA reaction is crucial and can proceed by two diactivationﬀerent mechanisms: [31–36]. Thus, (a) Aldehyde catalysis activationof the VM orA (b) reaction dienolate is activation crucial and (Scheme can6 ).proceed by two fundamentally different mechanisms: (a) Aldehyde activation or (b) dienolate activation (Scheme 6).

SchemeScheme 6.6. Aldehyde activation versusversus dienolate activation.activation. In the most common mode of aldehyde activation, a Lewis acid or Brønsted acid binds to the oxygen In the most common mode of aldehyde activation, a Lewis acid or Brønsted acid binds to the of the carbonyl group (see simple activation, Scheme7). Because a highly stereoselective outcome oxygen of the carbonyl group (see simple activation, Scheme 7). Because a highly stereoselective requires a high level of transition–structure organization, the binding mode plays an important outcome requires a high level of transition–structure organization, the binding mode plays an role in this process. In other words, to induce a large ∆∆G for competing transition structures, important role in this process. In other words, to induce a large G for competing transition diﬀerent catalysts use diﬀerent binding motifs. Conformational-biasing interactions, such as CH structures, different catalysts use different binding motifs. Conformational-biasing interactions, such hydrogen-bonding, π-stacking, or chelation, incorporated individually or in concert with the Lewis as CH hydrogen-bonding, -stacking, or chelation, incorporated individually or in concert with the acid/aldehyde complex, can contribute to high facial selectivity (Scheme7). Lewis acid/aldehyde complex, can contribute to high facial selectivity (Scheme 7). The following section summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the VMA reaction. The manuscript comprehensively condenses the last four years of research, covering the period 2016–2019. The discussion concentrates on enantioselective and/or diastereoselective variants that employ chiral ligand control. Purely substrate-controlled reactions leading to chiral adducts are also included. Reactions resulting in achiral products will not be discussed.

Scheme 7. Binding modes of the carbonyl group to the Lewis acid.

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addition product is therefore predicted. On the other hand, the lithium dienolate of methyl crotonate displays a larger HOMO coefficient and electrophilic susceptibility value at C2 than at C4, rationalizing the observed -addition product (Scheme 5) [3]. These electronic effects can be altered by steric interactions and/or chelation.

Scheme 5. Comparison of orbital coefficients and electrophilic susceptibility of vinylogous silylketene acetals with metal dienolates.

Under typical conditions, most dienoxysilanes are unreactive toward aldehydes without activation [31–36]. Thus, catalysis of the VMA reaction is crucial and can proceed by two fundamentally different mechanisms: (a) Aldehyde activation or (b) dienolate activation (Scheme 6).

Scheme 6. Aldehyde activation versus dienolate activation.

In the most common mode of aldehyde activation, a Lewis acid or Brønsted acid binds to the oxygen of the carbonyl group (see simple activation, Scheme 7). Because a highly stereoselective outcome requires a high level of transition–structure organization, the binding mode plays an important role in this process. In other words, to induce a large G for competing transition structures, different catalysts use different binding motifs. Conformational-biasing interactions, such Molecules 2019, 24, 3040 5 of 19 as CH hydrogen-bonding, -stacking, or chelation, incorporated individually or in concert with the Lewis acid/aldehyde complex, can contribute to high facial selectivity (Scheme 7).

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The following section summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the VMA reaction. The manuscript comprehensively condenses the last four years of research, covering the period 2016–2019. The discussion concentrates on enantioselective and/or diastereoselective variants that employ chiral ligand control. Purely substrate-controlledScheme reactions 7. Binding leading modes to chiral of the ad carbonyl ducts are group also to included. the Lewis Reactions acid. resulting in 2. Enantioselectiveachiral products will VMA not Reactionsbe discussed.

2.1.2. Formal Enantioselective Synthesis of VMA a CB2 Reactions Agonist Drug Candidate

2.1.The Formal isatin Synthesis core is of an a CB2 important Agonist heterocyclicDrug Candidate motif present in diverse natural and non-natural 2 productsThe with isatin biological core is andan important pharmaceutical heterocyclic activities. motif Tertiary present alcohol in diverseis natural the key and intermediate non-natural in the synthesisproducts of with a potential biological drug and candidate pharmaceutical (CB2 agonist) activities. for Tertiary reducing alcohol neuropathic 2 is the key and intermediate bone pain. in theIn synthesis this context, of a potential an asymmetric drug candidate vinylogous (CB2 Mukaiyama agonist) for redu aldolcing reaction neuropathic (VMAR) and protocol bone pain. enables access toIn a this CB2 context, agonist an building asymmetric block. vinylogous Thus, the Mukaiyama organocatalyzed aldol reaction VMA reaction (VMAR) of protocol (E)-(buta-1,3-dien- enables 1-yloxy)trimethylsilaneaccess to a CB2 agonist and building 1-(cyclopropylmethyl)-5-methylindoline-2,3-dione block. Thus, the organocatalyzed VMA reaction using of ( cinchonaE)-(buta-1,3- based thioureadien-1-yloxy)trimethylsilane catalyst 1 led to CB2 agonistand 1-(cyclopropylme precursor 2 inthyl)-5-methylindoline-2, good yield and excellent3-dione enantioselectivity using cinchona (94% ee)based (Scheme thiourea8)[ 37 catalyst]. It is noteworthy 1 led to CB2 thatagonist the precursor role of water 2 in good was crucialyield and for excellent this reaction. enantioselectivity In the absence of water(94% ee) almost (Scheme no conversion 8) [37]. It is occurred, noteworthy whereas that the the role presence of water of was 3 equiv crucial led for to this the VMARreaction. product In the in 75%absence yield. of water almost no conversion occurred, whereas the presence of 3 equiv led to the VMAR product in 75% yield.

Scheme 8. VMAR under bifunctional organocatalysis for medicinal chemistry scaﬀold construction.

Scheme 8. VMAR under bifunctional organocatalysis for medicinal chemistry scaffold construction. 2.2. Enantioselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans 2.2. Enantioselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans Substituted tetrahydrofurans are common structural motifs found in several natural products Substituted tetrahydrofurans are common structural motifs found in several natural products and biologically active compounds. Therefore, in recent years, many eﬀorts have been devoted to and biologically active compounds. Therefore, in recent years, many efforts have been devoted to the the development of stereoselective methods to generate multi-substituted tetrahydrofurans. Thus, development of stereoselective methods to generate multi-substituted tetrahydrofurans. Thus, a a chiral titanium BINOL catalyst generated in situ from Ti(Oi-Pr) and (R)-BINOL induced the VMAR chiral titanium−−BINOL catalyst generated in situ from Ti(Oi-Pr)4 and4 (R)-BINOL induced the VMAR of dienediolateof dienediolate3 and 3 and various various aldehydes aldehydes4 in 4 diethylin diethyl ether ether to furnishto furnish the the intermediate intermediate vinylogous vinylogous aldol product 5. That, in turn, was treated with BF OEt and a second equivalent of aldehydes 6 in ethyl aldol product 5. That, in turn, was treated with3• BF32•OEt2 and a second equivalent of aldehydes 6 in acetateethyl to acetate give rise to to give tetrahydrofurans rise to tetrahydrofurans7 with good 7 overall with good yield overall and good yield tomoderate and good enantioselectivity to moderate enantioselectivity (Scheme 9) [38]. It is noteworthy that this tandem reaction, a VMAR followed by a

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Molecules 2019, 24, x FOR PEER REVIEW 6 of 20 (Scheme9)[ 38]. It is noteworthy that this tandem reaction, a VMAR followed by a Lewis acid-mediated Lewis acid-mediated Prins-type cyclization with a second aldehyde, gave rise to 2,3,5-substituted Molecules 2019, 24, x FOR PEER REVIEW 6 of 20 Prins-typetetrahydrofurans cyclization by generating with a second three aldehyde,new σ-bonds gave and rise three to 2,3,5-substitutednew stereogenic centers tetrahydrofurans in a one-pot by generating three new σ-bonds and three new stereogenic centers in a one-pot process. process.Lewis acid-mediated Prins-type cyclization with a second aldehyde, gave rise to 2,3,5-substituted tetrahydrofurans by generating three new σ-bonds and three new stereogenic centers in a one-pot process.

Scheme 9. Synthesis of enantioenriched tetrahydrofurans using a chiral titanium BINOL catalyst. Scheme 9. Synthesis of enantioenriched tetrahydrofurans using a chiral titanium−BINOL− catalyst. 3. DiastereoselectiveScheme 9. Synthesis VMA of Reactions enantioenriched tetrahydrofurans using a chiral titanium−BINOL catalyst. 3. Diastereoselective VMA Reactions 3.1. Oxazaborolidinone3. Diastereoselective Catalysis VMA Reactions 3.1. Oxazaborolidinone Catalysis 3.1.1.3.1. Aetheramide Oxazaborolidinone A Catalysis 3.1.1. Aetheramide A The3.1.1. ﬁrstAetheramide total synthesis A of the highly potent anti-HIV natural product aetheramide A was accomplishedThe first using total the synthesis VMAR protocolof the highly utilizing potent oxazaborolidinone anti-HIV natural catalysis product as aaetheramide key step. The A reaction was The first total synthesis of the highly potent anti-HIV natural product aetheramide A was ofaccomplished silyl dienol ether using8 andthe vinylogousVMAR protocol aldehyde utilizing9 in oxazaborolidinone combination with oxazaborolidinonecatalysis as a key step. catalyst The 10 reactionaccomplished of silyl dienolusing theether VMAR 8 and protocol vinylogous utilizing aldehyde oxazaborolidinone 9 in combination catalysis with as oxazaborolidinone a key step. The gave the secondary alcohol 11 in 89% yield as a single diastereomer (Scheme 10)[39]. The observed catalystreaction 10 gaveof silyl the dienol secondary ether alcohol8 and vinylogous 11 in 89% aldehydeyield as a 9 single in combination diastereomer with (Scheme oxazaborolidinone 10) [39]. The diastereoselectivity and the absolute conﬁguration can be explained with a transition state depicted in observedcatalyst diastereoselectivity 10 gave the secondary and alcohol the absolute 11 in 89% configuration yield as a single can diastereomerbe explained (Scheme with a transition 10) [39]. The state Schemeobserved 10. Herein, diastereoselectivity the indole moiety and the shields absolute the configurationSi-face of the can aldehyde be explained leading with toa transition a Re-face state attack of depicted in Scheme 10. Herein, the indole moiety shields the Si-face of the aldehyde leading to a Re- the nucleophile.depicted in Scheme 10. Herein, the indole moiety shields the Si-face of the aldehyde leading to a Re- face attack of the nucleophile. face attack of the nucleophile. OTBS OTBS OH OTES OTBS 10 (1 eq), EtCN, OTBS OH OTES CHO 10 CO Me + CHO (1 eq), EtCN, CO Me2 Ph+ Ph –78 °C, 1 h Ph 33 26 2 OMeOMe –78 °C, 1 h 33 26 OTBSOTBS OTBSOTBS 88 9 9 11 11 (89%) (89%) singlesingle diastereomer diastereomer

HNHN RR HOHO H H HH N N O O OO OO OO OO MeOMeO OO OO B BB B PhPh N OO N N N NN Ts Ts 1010 Ts Ts NHNH MeMe

OO OO rationalerationale for for the the stereochemicalstereochemical outcome of the VMAR 33 26 OMe outcome of the VMAR 33 26 OMe OH OH aetheramide A aetheramide A Scheme 10. VMAR using oxazaborolidinone catalysis as a key step in the total synthesis of

aetheramide A. Molecules 2019, 24, x FOR PEER REVIEW 7 of 20

Molecules 2019, 24, 3040 7 of 19 Scheme 10. VMAR using oxazaborolidinone catalysis as a key step in the total synthesis of aetheramide A. 3.1.2. Nannocystin Ax 3.1.2. Nannocystin Ax Nannocystin Ax is a cytotoxic 21-membered depsipeptide which was isolated from the Nannocystin Ax is a cytotoxic 21-membered depsipeptide which was isolated from the myxobacterial genus Nannocystis sp. In the second total synthesis of Nannocystin Ax, a vinylogous myxobacterial genus Nannocystis sp. In the second total synthesis of Nannocystin Ax, a vinylogous Horner Wadsworth Emmons reaction (HWE) and a vinylogous Mukaiyama aldol reaction (VMAR) Horner−Wadsworth−Emmons reaction (HWE) and a vinylogous Mukaiyama aldol reaction (VMAR) were used as the key steps for the construction of the polyketide fragment. Thus, aldehyde 13, were used as the key steps for the construction of the polyketide fragment. Thus, aldehyde 13, TES- TES-ketene acetal 12, and the oxazaborolidinone Lewis acid 10 generated in situ from NTs-L-tryptophan ketene acetal 12, and the oxazaborolidinone Lewis acid 10 generated in situ from NTs-L-tryptophan and dichlorophenylborane were combined in a VMAR. Coordination between the aldehyde and the and dichlorophenylborane were combined in a VMAR. Coordination between the aldehyde and the chiral Lewis acid leads to an attack from the less hindered re face of the aldehyde, giving preference to chiral Lewis acid leads to an attack from the less hindered re face of the aldehyde, giving preference the R-conﬁgured hydroxy group at C5. Alcohol 14 was obtained in good yield but unfortunately with to the R-configured hydroxy group at C5. Alcohol 14 was obtained in good yield but unfortunately only moderate diastereoselectivity for the desired product (Scheme 11)[40]. with only moderate diastereoselectivity for the desired product (Scheme 11) [40].

Scheme 11. VMAR using oxazaborolidinone catalysis as a key step in the total synthesis of Scheme 11. VMAR using oxazaborolidinone catalysis as a key step in the total synthesis of nannocystin Ax. nannocystin Ax. 3.2. The Kobayashi Protocol 3.2. The Kobayashi Protocol In 2004, a vinylogous extension of the Evans’ aldol strategy, the so-called Kobayashi protocol, was investigated.In 2004, a vinylogous The highly extension diastereoselective of the Evans’ VMA aldol reaction strategy, using Evans’the so-called auxiliary-based Kobayashi vinylketene protocol, wassilyl Ninvestigated.,O-acetals provided The highly an eﬃ cientdiastereoselective and hitherto unprecedentedlyVMA reaction highusing degree Evans’ of remoteauxiliary-based [1,7- and 1,6,7-]vinylketene asymmetric silyl N induction,O-acetals [ 41provided]. an efficient and hitherto unprecedentedly high degree of remote [1,7- and 1,6,7-] asymmetric induction [41]. 3.2.1. Nannocystin A 3.2.1. Nannocystin A Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anti-cancer properties. In 2016Nannocystin two total syntheses A is a 21-membered of nannocystin cyclodepsipeptide A were described showing featuring remarkable a very similar anti-cancer VMAR properties. according Into the2016 Kobayashi two total protocol syntheses [41]. Theof nannocystin independent A and were contemporaneous described featuring development a very of similar VMAR adductsVMAR 17aaccordingand 17b todemonstrates the Kobayashi the protocol extreme [41]. viability The independent and sustainability and contemporaneous of this process (Scheme development 12)[42,43 of]. VMARIn a parallel adducts eﬀort, 17a nannocystin and 17b demonstrates A was constructed the extreme from essentially viability and the samesustainability fragment of18 this. process

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Molecules(Scheme2019 12), 24 [42,43]., 3040 In a parallel effort, nannocystin A was constructed from essentially the 8same of 19 fragment 18.

Scheme 12. VMAR as a key step in the total synthesis of nannocystin A according to the Scheme 12. VMAR as a key step in the total synthesis of nannocystin A according to the Kobayashi Kobayashi protocol. protocol. 3.2.2. Nannocystin Ax 3.2.2. Nannocystin Ax The first total synthesis of nannocystin Ax features an extension of the Kobayashi protocol, namely a syn-selectiveThe first total VMAR synthesis using acetals of nannocystin mediated byAx BF featOEtures an(Scheme extension 13)[ 44of]. the This Kobayashi reaction originallyprotocol, 3• 2 wasnamely developed a syn-selective in 2013 byVMAR Hosokawa using etacetals al. [45 mediated]. Thus, the by aldol BF3•OEt reaction2 (Scheme of acetal 13)19 [44].and This vinylketene reaction silyloriginallyN,O-acetal was developedent-15a under in 2013 the action by Hosokawa of BF OEt et al.directly [45]. Thus, afforded the thealdol methyl reaction ether of20 acetalwith 14:119 and dr 3• 2 invinylketene 88% yield. silyl The N advantage,O-acetal ofent this-15a VMAR under isthe the action direct of formation BF3•OEt2 of directly a methoxy afforded group, the a methyl feature oftenether required20 with 14:1 in bioactive dr in 88% natural yield. The products; advantage this streamlinesof this VMAR natural is theproduct direct formation synthesis. of a methoxy group, a feature often required in bioactive natural products; this streamlines natural product synthesis. 3.2.3. Maltepolide C Structurally, maltepolide C is a 20-membered cytotoxic macrolide connected to a side chain through an E-double bond. The macrolactone core of the molecule contains seven stereocenters, one E,E-diene unit, one highly substituted Z-olefin, one substituted E-olefin in conjugation with the lactone carbonyl, and a highly substituted THF moiety. From this structural information and previous studies [46], it was recognized that a Kobayashi VMAR could establish the C1–C7 fragment 23 of the bioactive molecule. Accordingly, treatment of N,O-silyl ketene acetal 21 and iodo acrylate 16 with TiCl4 provided the desired hydroxyl imide 22 with the exclusive formation of one diastereomer in 75% yield (Scheme 14)[47].

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TBSO O OMe O O OMe N BF •OEt , CH Cl , I N O + 3 2 2 2 51O I OMe –78 °C to –60 °C

ent-15a 19 20 (88%) dr 14:1

Cl HO

Cl O O N HO H NH NMe 1 O O O

5 OMe

nannocystin Ax Scheme 13. VMAR as a key step in the ﬁrst total synthesis of nannocystin Ax according to a modiﬁed MoleculesScheme 2019, 2413., x VMAR FOR PEER as a REVIEW key step in the first total synthesis of nannocystin Ax according to a modified10 of 20 KobayashiKobayashi protocol.protocol.

3.2.3. Maltepolide C Structurally, maltepolide C is a 20-membered cytotoxic macrolide connected to a side chain through an E-double bond. The macrolactone core of the molecule contains seven stereocenters, one E,E-diene unit, one highly substituted Z-olefin, one substituted E-olefin in conjugation with the lactone carbonyl, and a highly substituted THF moiety. From this structural information and previous studies [46], it was recognized that a Kobayashi VMAR could establish the C1–C7 fragment 23 of the bioactive molecule. Accordingly, treatment of N,O-silyl ketene acetal 21 and iodo acrylate 16 with TiCl4 provided the desired hydroxyl imide 22 with the exclusive formation of one diastereomer in 75% yield (Scheme 14) [47].

Scheme 14. First total synthesis of maltepolide C using Kobayashi’s VMAR protocol as a key step. Scheme 14. First total synthesis of maltepolide C using Kobayashi’s VMAR protocol as a key step. 3.2.4. (+)-Methynolide 3.2.4. (+)-Methynolide (+)-Methynolide is an aglycone of the 12-membered macrolidic antibiotic methymycin and has been(+)-Methynolide a key target molecule is an aglycone over the of past the four 12-membered decades. Inmacrolidic the highly antibiotic convergent methymycin total synthesis and has of been a key target molecule over the past four decades. In the highly convergent total synthesis of (+)- methynolide, the C1–C7 fragment was prepared by a Kobayashi VMAR protocol using a vinyl ketene silyl N,O-acetal and a -oxyaldehyde (Scheme 15) [48]. It is known that -oxyaldehydes are challenging substrates in Kobayashi VMARs, probably due to the -elimination of an oxygen- containing functional group, and/or chelation that results in the deactivation of the Lewis acid [49,50]. For this purpose, exploratory studies have identified -oxyaldehyde 24c (Scheme 15, entry 10) as an ideal candidate for this pivotal transformation, resulting in both excellent yield and diastereoselectivity. The desired anti-aldol product 25c could be obtained in 90% yield on a gramscale using 2.0 equivalent of aldehyde 24c in toluene in the presence of catalytic amounts of H2O [51].

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(+)-methynolide, the C1–C7 fragment was prepared by a Kobayashi VMAR protocol using a vinyl ketene silyl N,O-acetal and a β-oxyaldehyde (Scheme 15)[48]. It is known that β-oxyaldehydes are challenging substrates in Kobayashi VMARs, probably due to the β-elimination of an oxygen-containing functionalMolecules 2019 group,, 24, x and FOR/ orPEER chelation REVIEW that results in the deactivation of the Lewis acid [49,50]. 11 of 20

SchemeScheme 15. 15.Total Total synthesis synthesis of of ( +(+)-methynolide)-methynolide using a a Kobayashi Kobayashi VMAR. VMAR.

3.2.5.For Lagunamide this purpose, A exploratory studies have identified β-oxyaldehyde 24c (Scheme 15, entry 10) as an ideal candidate for this pivotal transformation, resulting in both excellent yield and diastereoselectivity. Lagunamide A not only possesses excellent anti-malarial properties, but it also has unique, The desired anti-aldol product 25c could be obtained in 90% yield on a gramscale using 2.0 equivalent highly cytotoxic properties against leukemia cell lines and against colon cancer. The therapeutic of aldehyde 24c in toluene in the presence of catalytic amounts of H O[51]. potential of lagunamide A coupled with its relative scarceness in 2nature has garnered significant 3.2.5.interest Lagunamide from a number A of research laboratories. In a recent approach, two iterative Kobayashi VMARs have been applied in order to selectively install three contiguous stereocenters at C37, C38, andLagunamide C39 of the Asouthern not only polyketide possesses (C27–C45) excellent anti-malarial segment of lagunamide properties, butA. The it also first has VMAR unique, [50,52] highly cytotoxicestablished properties the anti-aldol against motif leukemia at C38–C39 cell lines and and the against second colon VMAR cancer. [50] introduced The therapeutic the stereocenter potential of lagunamideat C37 (Scheme A coupled 16). By with adopting its relative a known scarceness protocol in [52], nature the first has garneredVMAR yielded significant 96% of interest anti-alcohol from a number28 in an of excellent research diastereomeric laboratories. Inratio a recent (>98:2). approach, The second two VMAR, iterative employing Kobayashi aldehyde VMARs 29 and have chiral been appliedvinylketene in order silyl to N selectively,O-acetal ent install-15a, was three more contiguous challenging, stereocenters however. Initially, at C37, the C38, VMAR and conducted C39 of the southernin the conventional polyketide (C27–C45) CH2Cl2 medium segment provided of lagunamide a low yield A. (30%) The first of alcohol VMAR product [50,52] established30 albeit with the anti-aldolgood diastereoselectivity motif at C38–C39 (91:9). and the However, second VMAR when toluene [50] introduced containing the 10 stereocenter mol% of water at C37was (Schemeapplied as 16 ). Bya adopting medium and a known the reaction protocol was [ 52conducted], the first for VMAR 72 h the yieldedyield increased 96% of modestly anti-alcohol to 48%28 within an the excellent same diastereomericdiastereoselectivity ratio (> (91:9)98:2). instead The second (see entry VMAR, 2 in employingthe table included aldehyde in 29Schemeand chiral16). The vinylketene exact role silylof N,Othe-acetal presenceent-15a of ,water was more during challenging, the Kobayashi however. VMAR Initially, is unknown, the VMAR but the conducted rate enhancement in the conventional effect of H2O was demonstrated in previous studies [51]. CH2Cl2 medium provided a low yield (30%) of alcohol product 30 albeit with good diastereoselectivity (91:9). However, when toluene containing 10 mol% of water was applied as a medium and the reaction was conducted for 72 h the yield increased modestly to 48% with the same diastereoselectivity (91:9) instead (see entry 2 in the table included in Scheme 16). The exact role of the presence of water during

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the Kobayashi VMAR is unknown, but the rate enhancement eﬀect of H2O was demonstrated in previousMolecules studies 2019, 24, x [51 FOR]. PEER REVIEW 12 of 20

SchemeScheme 16. 16.Synthesis Synthesis of theof C27–C45the C27–C45 segment segment of lagunamide of lagunamide A using A using two iterative two iterative Kobayashi Kobayashi VMARs. VMARs. 3.2.6. Amphidinolide N 3.2.6.Amphidinolide Amphidinolide N N is an extremely potent cytotoxic macrolide that was ﬁrst isolated from a culturedAmphidinolideAmphidinium N sp. is(Y-5) an extremely strain in 1994.potent Due cytotoxic to its challengingmacrolide that structure was first and isolated extraordinarily from a potentcultured cytotoxicity, Amphidinium amphidinolide sp. (Y-5) strain N is in a 1994. highly Due attractive to its challenging target for structure total synthesis. and extraordinarily Consequently, a convergentpotent cytotoxicity, synthesis amphidinolide of the C1–C13 N segmentis a highly of attr amphidinolideactive target for N total was reportedsynthesis. using Consequently, a Kobayashi a VMARconvergent as a key synthesis step (Scheme of the 17 C1–C)[5313]. Forsegment that, theof amphidinolide VMAR of acetaldehyde N was reported32 with using the dienol a Kobayashi silyl ether 31 VMARdelivered as aδ -hydroxy-key step (Schemeα-methyl- 17)α ,[53].β-unsaturated For that, the imide VMAR33 [of54 acetaldehyde] in 91% yield 32 as with a single the dienol diastereomer silyl (drether> 20:1). 31 delivered -hydroxy--methyl-,-unsaturated imide 33 [54] in 91% yield as a single diastereomer (dr > 20:1).

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Scheme 17. Convergent synthesis of the C1–C13 segment of amphidinolide N using Kobayashi VMAR as a key step.

3.2.7.Scheme Tabtoxinine- 17.17. ConvergentConvergentβ-Lactam synthesis synthesis(TβL) of of the the C1–C13 C1–C13 segment segme ofnt amphidinolide of amphidinolide N using N Kobayashiusing Kobayashi VMAR VMARas a key as step. a key step. Tabtoxinine-β-lactam (TβL) is a potent inhibitor of glutamine synthetase. Therefore, TβL is 3.2.7. Tabtoxinine-β-Lactam (TβL) expected3.2.7. Tabtoxinine- to be a selectiveβ-Lactam pesticide (TβL) and many synthetic studies on TβL have been reported, recently cumulatingTabtoxinine- in a stereoseβ-lactamlective (TβL) synthesis is a potent of inhibitorTβL by a ofremote glutamine asymmetric synthetase. induction. Therefore, The pivotal TβL is Tabtoxinine-β-lactam (TβL) is a potent inhibitor of glutamine synthetase. Therefore, TβL is Kobayashiexpected to VMAR be a selective process pesticideis depicted and in many Scheme synthetic 18 [55]. studies on TβL have been reported, recently expected to be a selective pesticide and many synthetic studies on TβL have been reported, recently cumulatingHere, careful in a stereoselective tuning of the chiral synthesis auxiliary of Tβ L(R by2), the a remote silyl ether asymmetric group (R induction.1), and the TheLewis pivotal acid cumulating in a stereoselective synthesis of TβL by a remote asymmetric induction. The pivotal affordedKobayashi tertiary VMAR alcohol process 36 is in depicted excellent in Schemeyield and 18 [selectivity55]. (see entry 5 in the table included in Kobayashi VMAR process is depicted in Scheme 18 [55]. Scheme 18). Here, careful tuning of the chiral auxiliary (R2), the silyl ether group (R1), and the Lewis acid O afforded tertiaryOR1 alcohol 36 in excellent yield and selectivity (see entry 5 in the table included in O PMBN O O Scheme 18). O N PMBN Lewis acid (x eq), O + O N OR1 CH Cl , –78°, time OH O O 2 2 PMBN O O R2 O 2 R2 PMBN Lewis acid (x eq), 2 R N O + N R OH O 34 35CH2Cl2, –78°, time 36 2 O 2 R R2 R R2 R1 R2 Lewis acid x Time (h) yield (%) dr 34O 35 36 PMBN TBDPS H TiCl4 — — (95) 1:2

CO2H RTBDPS1 RMe2 LewisSnCl4 acid —x Time— (h) yield(94) (%) 5:1dr O OH TBDPS H TiClSnCl4 — — (95)(94) 10:11:2 PMBN NH2 4 TBS Ph SnCl — — (95) >20:1 tabtoxinine- -lactamCO (T 2L)H TBDPS Me SnCl4 — — (94) 5:1 TBDPS Ph SnCl 3 12 (97) >20:1 OH TBDPS H SnCl4 — — (94) 10:1 NH2 TBS Ph SnCl — — (95) >20:1 tabtoxinine-Scheme 18. -lactamTotalTotal synthesis (T L) of tabtoxinine- β-lactam-lactam (T (Tβ4L)L) using using the the Kobayashi Kobayashi VMAR VMAR protocol. TBDPS Ph SnCl4 3 12 (97) >20:1 3.2.8.Here, Fidaxomicin careful tuning of the chiral auxiliary (R2), the silyl ether group (R1), and the Lewis acid aﬀordedScheme tertiary 18. alcoholTotal synthesis36 in excellentof tabtoxinine- yieldβ-lactam and selectivity (TβL) using (see the entryKobayashi 5 in VMAR the table protocol. included in SchemeFidaxomicin, 18). also known as tiacumicin B and lipiarmycin A3, constitutes a macrolide antibiotic 3.2.8.used forFidaxomicin the treatment of Clostridium difficile infections (CDI), which are considered to be responsible for a significant number of hospital-acquired infections, resulting in over 29000 deaths each year in Fidaxomicin, also known as tiacumicin B and lipiarmycin A3, constitutes a macrolide antibiotic used for the treatment of Clostridium difficile infections (CDI), which are considered to be responsible for a significant number of hospital-acquired infections, resulting in over 29000 deaths each year in

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3.2.8. Fidaxomicin Fidaxomicin, also known as tiacumicin B and lipiarmycin A3, constitutes a macrolide antibiotic used for the treatment of Clostridium difficile infections (CDI), which are considered to be responsible Moleculesfor a significant 2019, 24, x number FOR PEER of REVIEW hospital-acquired infections, resulting in over 29000 deaths each year14 in of the 20 US. While vancomycin and metronidazole are generally prescribed for this condition as a first-line thetreatment, US. While the introductionvancomycin ofand fidaxomicin metronidazole in the are USA generally and the prescribed EU in 2011 for provided this condition a new therapeutic as a first- lineoption. treatment, Due to increasedthe introduction demand, of the fidaxomicin commercial in macrolide the USA antibiotic and the fidaxomicinEU in 2011 veryprovided recently a new was therapeuticsynthesized option. in a highly Dueconvergent to increased manner demand, using the acommercial Kobayashi macrolid VMAR ase aantibiotic key step. fidaxomicin very recentlyInterestingly, was synthesized the described in a highly VMAR convergent protocol manner requires using a more a Kobayashi sophisticated VMAR procedural as a key approach. step. Interestingly, the described VMAR protocol requires a more sophisticated procedural approach. In the first generation synthesis of 38 (entry 1, Scheme 19)[56], a premixed solution of TiCl4 and In the first generation synthesis of 38 (entry 1, Scheme 19) [56], a premixed solution of TiCl4 and aldehyde 16 at –78 ◦C was treated with vinylketene silyl-N,O-acetal 37, and added in one portion aldehyde 16 at –78 °C was treated with vinylketene silyl-N,O-acetal 37, and added in one portion at at –78 ◦C. In the second generation synthesis and after extensive experimentation, it was found that –78aminal °C. 37In doesthe second not need generation to be added synthesis in one and portion, after extensive instead it experimentation, can be delivered it by was syringe found pump that aminal 37 does not need to be added in one portion, instead it can be delivered by syringe pump at – at –78 ◦C over a period of 20 min to cleanly obtain the desired product in high yield and excellent 78diastereoselectivity °C over a period (entry of 20 2, min Scheme to cleanly 19)[57 ].obtain It is noteworthy the desired that product for the in transformation high yield and of excellent38 to the diastereoselectivityaglycone of fidaxomicin (entry the 2, stereochemistryScheme 19) [57]. at It C11is noteworthy had to beinverted that for the by atransformation Mitsunobu reaction. of 38 to the aglycone of fidaxomicin the stereochemistry at C11 had to be inverted by a Mitsunobu reaction.

Scheme 19. TotalTotal synthesis of fidaxomicin ﬁdaxomicin using the Kobayashi VMAR protocol.

3.2.9. PF1163B Recently, aa concise concise total total synthesis synthesis of PF1163B of PF1163 wasB achieved was achieved (Scheme 20(Scheme)[58]. For20) this, [58]. Hosokawa’s For this, Hosokawa´sextension [59 extension] of the Kobayashi [59] of the Kobayashi VMAR of VMAR ketene of silyl keteneN,O silyl-acetal N,O15a-acetal, mediated 15a, mediated by excess by excess TiCl4 (4TiCl equivalent),4 (4 equivalent), proceeded proceede withd with saturated saturated aldehyde aldehyde39 39to to give give adduct adduct40 40in in moderate moderate yieldyield with moderate stereoselectivity. The The Birch Birch reduction reduction of of α,,β-unsaturated-unsaturated imide imide 4040,, possessing possessing the the R configured,conﬁgured, lessless hindered hindered isopropyl isopropyl side side chain, chain, gave thegave reduction the reduction product 41productwith the 41S conﬁgurationwith the S configurationat C10 in good at stereoselectivity C10 in good (6:1)stereoselectivity by employing (6 2-isopropylbenzimidazole:1) by employing 2-isopropylbenzimidazole as a bulky proton source. as a bulkyOf proton note, source. in the described VMAR protocol, two separate stereogenic centers in PF1163B, C10, and C13Of note, respectively, in the described were constructed VMAR protocol, with one two chiral sepa synthon.rate stereogenic This demonstrates centers in aPF1163B, short sequence C10, and to prepareC13 respectively, medium-size were derivatives. constructed with one chiral synthon. This demonstrates a short sequence to prepare medium-size derivatives.

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SchemeScheme 20.20. Total synthesissynthesis ofof PF1163BPF1163B employingemploying Hosokawa´sHosokawa´s synsyn-selective-selective KobayashiKobayashi VMAR. VMAR. 3.2.10. Stoloniferol B 3.2.10. Stoloniferol B Stoloniferol B, isolated from Penicillium stoloniferum QY2-10, is a common core structure of citrinin Stoloniferol B, isolated from Penicillium stoloniferum QY2-10, is a common core structure of derivatives. However, the total synthesis of stoloniferol B had never been reported. The ﬁrst total citrinin derivatives. However, the total synthesis of stoloniferol B had never been reported. The first synthesis of stoloniferol B was presented using a Kobayashi VMAR. The synthesis started with the total synthesis of stoloniferol B was presented using a Kobayashi VMAR. The synthesis started with vinylogous Mukaiyama aldol reaction between 21 and paraldehyde 42 (Scheme 21)[60]. The reaction the vinylogous Mukaiyama aldol reaction between 21 and paraldehyde 42 (Scheme 21) [60]. The proceeded in high yield (82%) with excellent diastereoselectivity (>20:1) to give anti adduct 43. reaction proceeded in high yield (82%) with excellent diastereoselectivity (>20:1) to give anti adduct 43.

SchemeScheme 21.21. FirstFirst totaltotal synthesissynthesis ofof stoloniferolstoloniferol BB viavia aa KobayashiKobayashi VMAR.VMAR.

3.2.11. C1–C17 Segment of Bafilomycin N

Because bafilomycin A1 is a well-known anti-tumor agent inhibiting v-ATPase at picomolar concentration, its congener bafilomycin N is also expected to be an attractive target for antitumor

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3.2.11. C1–C17 Segment of Baﬁlomycin N

Because bafilomycin A1 is a well-known anti-tumor agent inhibiting v-ATPase at picomolar concentration,Molecules 2019, 24, its x FOR congener PEER REVIEW bafilomycin N is also expected to be an attractive target for antitumor16 of 20 drugs. Although total synthesis of bafilomycin A1 has been achieved, synthetic studies on the new congenerdrugs. Although bafilomycin total N synthesis are unreported. of bafilomycin Very recently, A1 has thebeen first achieved, total synthesis synthetic of studies the C1–C17 on the segment new ofcongener bafilomycin bafilomycin N was presentedN are unreported. using an Veryanti recent- (C3–C11)ly, the andfirst total a syn synthesis- (C12–C17) of the selective C1–C17 Kobayashi segment VMARof bafilomycin (Scheme N 22 was)[61 presented]. Strikingly, using the an two anti fragments- (C3–C11) 45andand a syn47-were (C12–C17) constructed selective with Kobayashi the same chiralVMAR synthon. (Scheme Thus, 22) [61]. aldehyde Strikingly,44 was the subjected two fragments to the vinylogous45 and 47 were Mukaiyama constructed aldol with reaction the same with thechiral use synthon. of ent-21 Thus,to give aldehydeanti adduct 44 was45 (C3–C11). subjected to The the rate vinylogous enhancement Mukaiyama effect of aldol H2O reaction in the VMAR with wasthe demonstrateduse of ent-21 to in give previous anti adduct studies 45 [(C3–C11).51]. The synthesisThe rate enhancement of C12–C17 segmenteffect of H472Ostarted in the fromVMAR the synwas-selective demonstrated Kobayashi in previous VMAR between studies vinylketene[51]. The synthesis silyl N, Oof-acetal C12–C17ent- 21segmentand chloral 47 started46. The from reaction the proceededsyn-selective smoothly Kobayashi to aff VMARord syn betweenadduct 47 vinylketenein excellent silyl diastereoselectivity N,O-acetal ent-21 (> 20:1)and [chloral59,62]. 46. The reaction proceeded smoothly to afford syn adduct 47 in excellent diastereoselectivity (>20:1) [59,62].

Scheme 22. Synthesis of the C1–C17 segment of bafilomycin N via Kobayashi VMARs. Scheme 22. Synthesis of the C1–C17 segment of bafilomycin N via Kobayashi VMARs. 3.2.12. C3–C21 Segment of Aflastatin A 3.2.12. C3–C21 Segment of Aflastatin A Aflastatin A remains an attractive and challenging target molecule because the complexity and large sizeAflastatin of this A compound remains an require attractive efficient and methodologieschallenging target and molecule adequate because strategies the to complexity achieve its and total synthesis.large size Theof this very compound recent synthesis require ofefficient the C3–C21 methodologies segment ofand aflastatin adequate A strategies involves twoto achieve Kobayashi its VMAtotal reactionssynthesis. as The key very steps recent (Scheme synthesis 23)[63 ].of It th ise noteworthy C3–C21 segment to mention, of aflastatin the two A fragments involves49 twoand entKobayashi-43 were constructedVMA reactions with as the key same steps chiral (Scheme synthon. 23) [63]. The It known is noteworthy VMAR betweento mention,N,O -acetalthe two21 andfragments methacrolein 49 and (ent48)-43 has were always constructed been a cumbersomewith the same process, chiral synthon. because The under known standard VMAR conditions between N,O-acetal 21 and methacrolein (48) has always been a cumbersome process, because under standard (1.0 equivalent of TiCl4 in CH2Cl2, 2.0 equivalent of 48), the aldol adduct 49 is only formed in low yield conditions (1.0 equivalent of TiCl4 in CH2Cl2, 2.0 equivalent of 48), the aldol adduct 49 is only formed (23%) [64], presumably as a result of polymerization of 48. During an extensive survey of reaction in low yield (23%) [64], presumably as a result of polymerization of 48. During an extensive survey conditions, the authors improved the yield of 49 to 65% with greater than 20:1 diastereoselectivity by of reaction conditions, the authors improved the yield of 49 to 65% with greater than 20:1 using toluene as the solvent and 4.0 equivalent of 48 [64]. In the very recent version of this Kobayashi diastereoselectivity by using toluene as the solvent and 4.0 equivalent of 48 [64]. In the very recent VMAR a yield of 76% was achieved (Scheme 23)[63]. The second Kobayashi VMAR was also developed version of this Kobayashi VMAR a yield of 76% was achieved (Scheme 23) [63]. The second Kobayashi VMAR was also developed earlier [60], and herein repeated as the enantiomeric process with nearly the same yield (80%) and diastereoselectivity (18:1) affording ent-43 [63].

Molecules 2019, 24, 3040 16 of 19 earlier [60], and herein repeated as the enantiomeric process with nearly the same yield (80%) and diastereoselectivity (18:1) aﬀording ent-43 [63]. Molecules 2019, 24, x FOR PEER REVIEW 17 of 20

SchemeScheme 23. 23. SynthesisSynthesis of of the the C3–C21 C3–C21 segment segment of of aflastatin aﬂastatin A A via via Kobayashi Kobayashi VMARs. VMARs.

4.4. Conclusions Conclusions TheThe efficient eﬃcient synthesis synthesis of of complex complex natural natural products products is is often often a a hurdle hurdle that that has has to to be be overcome overcome beforebefore issues issues of of chemical chemical biolog biologyy can can be be addressed. addressed. On On that that background, background, the the vinylogous vinylogous Mukaiyama Mukaiyama aldolaldol reaction reaction has has become become one one of of the the pivotal pivotal transfor transformationsmations to to gain gain rapid rapid acce accessss to to natural natural products. products. OverOver the years,years, aa variety variety of of di ﬀdifferenterent enantioselective enantioselective and and diastereoselective diastereoselective transformations transformations have havebeen been demonstrated demonstrated that allowthat allow the synthesisthe synthesis of all of structural all structural motifs motifs found found in natural in natural products products and andpolyketides polyketides in particular. in particular. Besides Besides the improvement the improvement of existing of methods, existing one methods, can expect one elaboration can expect of elaborationsubsequent transformationsof subsequent transfor in ordermations to further in functionalizeorder to further the structural functionalize motifs the which structural are generated motifs whichby the are vinylogous generated Mukaiyama by the vinylogous aldol reaction. Mukaiyama aldol reaction.

AuthorAuthor Contributions: Conceptualization, M.C.;M.C.; writing—original writing—original draft draft preparation, preparation, M.C.; M.C.; writing—review writing—review and andediting, editing, M.C.; M.C.; supervision, supervision, M.K.; M.K.; funding funding acquisition, acquisition, M.K. M.K.

Funding:Funding: ThisThis research research received received no no external external funding. funding. Conﬂicts of Interest: The authors declare no conﬂict of interest. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Cordes, M.H.; Kalesse, M. The Asymmetric Vinylogous Mukaiyama Aldol Reaction. Org. React. 2019, 98, 173–174. 2. Kalesse, M. Recent Advances in Vinylogous Aldol Reactions and Their Applications in the Syntheses of Natural Products. Top. Curr. Chem. 2005, 244, 43–76.

Molecules 2019, 24, 3040 17 of 19

3. Denmark, S.E.; Heemstra, J.R., Jr.; Beutner, G.L. Catalytic, Enantioselective, Vinylogous Aldol Reactions. Angew. Chem. Int. Ed. 2005, 44, 4682–4698. [CrossRef][PubMed] 4. Soriente, A.; DeRosa, M.; Villano, R.; Scettri, A. Recent Advances in Asymmetric Aldol Reaction of Masked Acetoacetic Esters Promoted by Ti(IV) / BINOL: A New Methodology, Non-Linear Eﬀects and Autoinduction. Curr. Org. Chem. 2004, 8, 993–1007. [CrossRef] 5. Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. The Vinylogous Aldol Reaction: A Valuable, Yet Understated Carbon Carbon Bond-Forming Maneuver. Chem. Rev. 2000, 100, 1929–1972. [CrossRef] − [PubMed] 6. Fuson, R.C. The Principle of Vinylogy. Chem. Rev. 1935, 16, 1–27. [CrossRef] 7. Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress. Chem. Rev. 2011, 111, 3076–3154. [CrossRef][PubMed] 8. Kan, S.B.J.; Ng, K.K.H.; Paterson, I. The Impact of the Mukaiyama Aldol Reaction in Total Synthesis. Angew. Chem. Int. Ed. 2013, 52, 9097–9108. [CrossRef][PubMed] 9. Kalesse, M.; Cordes, M.; Symkenberg, G.; Lu, H.-H. The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis. Nat. Prod. Rep. 2014, 31, 563–594. [CrossRef][PubMed] 10. Frías, M.; Cie´slik,W.; Fraile, A.; Rosado-Abón, A.; Garrido-Castro, A.F.; Yuste, F.; Alemán, J. Development and Application of Asymmetric Organocatalytic Mukaiyama and Vinylogous Mukaiyama-Type Reactions. Chem. Eur. J. 2018, 24, 10906–10933. [CrossRef][PubMed] 11. Hosokawa, S. Recent development of vinylogous Mukaiyama aldol reactions. Tetrahedron Lett. 2018, 59, 77–88. [CrossRef] 12. Hosokawa, S. Remote Asymmetric Induction Reactions using a E,E-Vinylketene Silyl N,O-Acetal and the Wide Range Stereocontrol Strategy for the Synthesis of Polypropionates. Acc. Chem. Res. 2018, 51, 1301–1314. [CrossRef][PubMed] 13. Mukaiyama, T.; Ishida, A. A Convenient Method for the Preparation of δ-alkoxy-α,β-unsaturated Aldehydes by Reaction of Acetals with 1-trimethylsiloxy-1,3-butadiene. Chem. Lett. 1975, 4, 319–322. [CrossRef] 14. Ishida, A.; Mukaiyama, T. New Method for the Preparation of Polyenals from δ-alkoxy-α,β-unsaturated Aldehydes. Chem. Lett. 1975, 4, 1167–1170. [CrossRef] 15. Ishida, A.; Mukaiyama, T. A New Method for the Preparation of δ-Alkoxy-α,β-unsaturated Aldehydes and Polyenals. Bull. Chem. Soc. Jpn. 1977, 50, 1161–1168. [CrossRef] 16. Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Use of 1, 3-Dioxin-4-ones and Related Compounds in Synthesis. XLIV. Asymmetric Aldol Reaction of 4-Trimethylsiloxy-6-methylene-1, 3-dioxines: Use of Tartaric Acid-Derived (Acyloxy)borane Complex as the Catalyst. Chem. Pharm. Bull. 1994, 42, 839–845. [CrossRef] 17. Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. An Eﬃcient Asymmetric Aldol Reaction of 4-Trimethylsiloxy- 6-methylene-1,3-dioxines by Chiral Binaphthol-Titanium Complex Catalysis. Heterocycles 1995, 41, 1435–1444. 18. Singer, R.A.; Carreira, E.M. Catalytic, Enantioselective Dienolate Additions to Aldehydes: Preparation of Optically Active Acetoacetate Aldol Adducts. J. Am. Chem. Soc. 1995, 117, 12360–12361. [CrossRef] 19. Evans, D.A.; Kozlowski, M.C.; Murry, J.A.; Burgey, C.S.; Campos, K.R.; Connell, B.T.; Staples, R.J. C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of Catalytic Enantioselective Aldol Additions of Enolsilanes to (Benzyloxy)acetaldehyde. J. Am. Chem. Soc. 1999, 121, 669–685. [CrossRef] 20. Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of the Catalytic Enantioselective Aldol Additions of Enolsilanes to Pyruvate Esters. J. Am. Chem. Soc. 1999, 121, 686–699. [CrossRef] 21. Denmark, S.E.; Beutner, G.L. Lewis Base Activation of Lewis Acids. Vinylogous Aldol Reactions. J. Am. Chem. Soc. 2003, 125, 7800–7801. [CrossRef][PubMed] 22. Denmark, S.E.; Beutner, G.L.; Wynn, T.; Eastgate, M.D. Lewis Base Activation of Lewis Acids: Catalytic, Enantioselective Addition of Silyl Ketene Acetals to Aldehydes. J. Am. Chem. Soc. 2005, 127, 3774–3789. [CrossRef][PubMed] 23. Denmark, S.E.; Heemstra, J.R., Jr. Lewis Base Activation of Lewis Acids: Catalytic, Enantioselective Vinylogous Aldol Addition Reactions. J. Org. Chem. 2007, 72, 5668–5688. [CrossRef] Molecules 2019, 24, 3040 18 of 19

24. Kruger, J.; Carreira, E.M. Apparent Catalytic Generation of Chiral Metal Enolates: Enantioselective Dienolate Additions to Aldehydes Mediated by Tol-BINAP Cu(II) Fluoride Complexes. J. Am. Chem. Soc. 1998, 120, • 837–838. [CrossRef] 25. Pagenkopf, B.L.; Krüger, J.; Stojanovic, A.; Carreira, E.M. Mechanistic Insights into Cu-Catalyzed Asymmetric Aldol Reactions: Chemical and Spectroscopic Evidence for a Metalloenolate Intermediate. Angew. Chem. Int. Ed. 1998, 37, 3124–3126. [CrossRef] 26. Bluet, G.; Bazan-Tejeda, B.; Campagne, J.-M. Catalytic Asymmetric Access to α,β Unsaturated δ-Lactones through a Vinylogous Aldol Reaction: Application to the Total Synthesis of the Prelog-Djerassi Lactone. Org. Lett. 2001, 3, 3807–3810. [CrossRef] 27. Corey, E.J.; Cywin, C.L.; Roper, T.D. Enantioselective Mukaiyama-aldol and aldol-dihydropyrone annulation reactions catalyzed by a tryptophan-derived oxazaborolidine. Tetrahedron Lett. 1992, 33, 6907–6910. [CrossRef] 28. Brodmann, T.; Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Highly Stereoselective Aldol Reactions in the Total Syntheses of Complex Natural Products. Synlett 2009, 2, 174–192. 29. Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. Conceptually New Directed Aldol Condensation Using Aluminum Tris(2,6-diphenylphenoxide). J. Am. Chem. Soc. 1998, 120, 813–814. [CrossRef] 30. Fukui, K.; Yonezawa, T.; Nagata, C.; Shingu, H. Molecular Orbital Theory of Orientation in Aromatic, Heteroaromatic, and Other Conjugated Molecules. J. Chem. Phys. 1954, 22, 1433–1442. [CrossRef] 31. Denmark, S.E.; Fan, Y. Catalytic, Enantioselective Aldol Additions to Ketones. J. Am. Chem. Soc. 2002, 124, 4233–4235. [CrossRef] 32. Myers, A.G.; Widdowson, K.L. A silicon-directed aldol condensation. Synthesis of enantiomerically pure anti aldols. J. Am. Chem. Soc. 1990, 112, 9672–9674. [CrossRef] 33. Denmark, S.E.; Griedel, B.D.; Coe, D.M.; Schnute, M.E. Chemistry of Enoxysilacyclobutanes: Highly Selective Uncatalyzed Aldol Additions. J. Am. Chem. Soc. 1994, 116, 7026–7043. [CrossRef] 34. Myers, A.G.; Kephart, S.E.; Chen, H. Silicon-directed aldol reactions. Rate acceleration by small rings. J. Am. Chem. Soc. 1992, 114, 7922–7923. [CrossRef] 35. Myers, A.G.; Widdowson, K.L.; Kukkola, P.J. Silicon-directed aldol condensation. Evidence for a pseudorotational mechanism. J. Am. Chem. Soc. 1992, 114, 2765–2767. [CrossRef] 36. Denmark, S.E.; Lee, W. Investigations on Transition-State Geometry in the Lewis Acid- (Mukaiyama) and Fluoride-Promoted Aldol Reactions. J. Org. Chem. 1994, 59, 707–709. [CrossRef] 37. Laina-Martín, V.; Humbrías-Martín, J.; Fernández-Salas, J.A.; Alemán, J. Asymmetric vinylogous Mukaiyama aldol reaction of isatins under bifunctional organocatalysis: Enantioselective synthesis of substituted 3-hydroxy-2-oxindoles. Chem. Commun. 2018, 54, 2781–2784. [CrossRef][PubMed] 38. Hoﬀmeyer, P.; Schneider, C. Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans Initiated by a Titanium–BINOLate-Catalyzed Vinylogous Aldol Reaction. J. Org. Chem. 2019, 84, 1079–1084. [CrossRef] [PubMed] 39. Gerstmann, L.; Kalesse, M. Total Synthesis of Aetheramide A. Chem. Eur. J. 2016, 22, 11210. [CrossRef] [PubMed] 40. Poock, C.; Kalesse, M. Total Synthesis of Nannocystin Ax. Org. Lett. 2017, 19, 4536–4539. [CrossRef] 41. Shirokawa, S.-I.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki, A.; Hosokawa, S.; Kobayashi, S. Remote Asymmetric Induction with Vinylketene Silyl N,O-Acetal. J. Am. Chem. Soc. 2004, 126, 13604–13605. [CrossRef][PubMed] 42. Yang, Z.; Xu, X.; Yang, C.-H.; Tian, Y.; Chen, X.; Lian, L.; Pan, W.; Su, X.; Zhang, W.; Chen, Y. Total Synthesis of Nannocystin A. Org. Lett. 2016, 18, 5768–5770. [CrossRef] 43. Liao, L.; Zhou, J.; Xu, Z.; Ye, T. Concise Total Synthesis of Nannocystin A. Angew. Chem. Int. Ed. 2016, 55, 13263–13266. [CrossRef][PubMed] 44. Zhang, Y.-H.; Liu, R.; Liu, B. Total synthesis of nannocystin Ax. Chem. Commun. 2017, 53, 5549–5552. [CrossRef][PubMed] 45. Tsukada, H.; Mukaeda, Y.; Hosokawa, S. syn-Selective Kobayashi Aldol Reaction Using Acetals. Org. Lett. 2013, 15, 678–681. [CrossRef][PubMed] 46. Hoecker, J.; Gademann, K. Enantioselective Total Syntheses and Absolute Conﬁguration of JBIR-02 and Mer-A2026B. Org. Lett. 2013, 15, 670–673. [CrossRef] 47. Rao, K.N.; Kanakaraju, M.; Kunwar, A.C.; Ghosh, S. Total Synthesis of the Proposed Structure of Maltepolide C. Org. Lett. 2016, 18, 4092–4095. [CrossRef][PubMed] Molecules 2019, 24, 3040 19 of 19

48. Suzuki, T.; Fujimura, M.; Fujita, K.; Kobayashi, S. Total synthesis of (+)-methynolide using a Ti-mediated aldol reaction of a lactyl-bearing oxazolidin-2-one, and a vinylogous Mukaiyama aldol reaction. Tetrahedron 2017, 73, 3652–3659. [CrossRef] 49. Jürjens, G.; Kirschning, A. Synthesis of a Cytotoxic Ansamycin Hybrid. Org. Lett. 2014, 16, 3000–3003. [CrossRef] 50. Banasik, B.A.; Wang, L.; Kanner, A.; Bergdahl, B.M. Further insight into the asymmetric vinylogous Mukaiyama aldol reaction (VMAR); application to the synthesis of the C27–C45 segment of lagunamide A. Tetrahedron 2016, 72, 2481–2490. [CrossRef] 51. Yamaoka, M.; Nakazaki, A.; Kobayashi, S. Rate enhancement by water in a TiCl4-mediated stereoselective vinylogous Mukaiyama aldol reaction. Tetrahedron Lett. 2010, 51, 287–289. [CrossRef] 52. Hosokawa, S.; Matsushita, K.; Tokimatsu, S.; Toriumi, T.; Suzuki, Y.; Tatsuta, K. The first total synthesis and structural determination of epi-cochlioquinone A. Tetrahedron Lett. 2010, 51, 5532–5536. [CrossRef] 53. Toyoshima, A.; Sasaki, M. Toward a total synthesis of amphidinolide N: Convergent synthesis of the C1–C13 segment. Tetrahedron Lett. 2016, 57, 3532–3534. [CrossRef] 54. Nagasawa, T.; Kuwahara, S. Formal Total Synthesis of Lactimidomycin. Org. Lett. 2013, 15, 3002–3005. [CrossRef] 55. Ejima, H.; Wakita, F.; Imamura, R.; Kato, T.; Hosokawa, S. Stereoselective Synthesis of Tabtoxinine-β-lactam by Using the Vinylogous Mukaiyama Aldol Reaction with Acetate-Type Vinylketene Silyl N,O-Acetal and α-Keto-β-lactam. Org. Lett. 2017, 19, 2530–2532. [CrossRef] 56. Miyatake-Ondozabal, H.; Kaufmann, E.; Gademann, K. Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B, Lipiarmycin A3). Angew. Chem. Int. Ed. 2015, 54, 1933–1936. [CrossRef] 57. Hattori, H.; Kaufmann, E.; Miyatake-Ondozabal, H.; Berg, R.; Gademann, K. Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3). J. Org. Chem. 2018, 83, 7180–7205. [CrossRef][PubMed] 58. Sengupta, A.; Hosokawa, S. Total Synthesis of PF1163B. Synlett 2019, 30, 709–712. 59. Mukaeda, Y.; Kato, T.; Hosokawa, S. Syn-Selective Kobayashi Aldol Reaction Using the E,E-Vinylketene Silyl N,O-Acetal. Org. Lett. 2012, 14, 5298–5301. [CrossRef] 60. Ohashi, T.; Hosokawa, S. Total Syntheses of Stoloniferol B and Penicitol A, and Structural Revision of Fusaraisochromanone. Org. Lett. 2018, 20, 3021–3024. [CrossRef] 61. Sato, H.; Hosokawa, S. Synthesis of the C1–C17 Segment of Bafilomycin N. Synlett 2019, 30, 577–580. 62. Shinoyama, M.; Shirokawa, S.-I.; Nakazaki, A.; Kobayashi, S. A Switch of Facial Selectivities Using α-Heteroatom-Substituted Aldehydes in the Vinylogous Mukaiyama Aldol Reaction. Org. Lett. 2009, 11, 1277–1280. [CrossRef][PubMed] 63. Murakoshi, S.; Hosokawa, S. Synthesis of C3–C21 Segment of Aflastatin A Using Remote Asymmetric Induction Reactions. Org. Lett. 2019, 21, 758–761. [CrossRef][PubMed] 64. Matsui, R.; Seto, K.; Sato, Y.; Suzuki, T.; Nakazaki, A.; Kobayashi, S. Convergent Total Synthesis of (+)-TMC-151C by a Vinylogous Mukaiyama Aldol Reaction and Ring-Closing Metathesis. Angew. Chem. Int. Ed. 2011, 50, 680–683. [CrossRef][PubMed]

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