Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool Α-Amino Acids for Natural Product Synthesis

molecules

Review Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis

Seung-Mann Paek 1, Myeonggyo Jeong 2, Jeyun Jo 2, Yu Mi Heo 1, Young Taek Han 3 and Hwayoung Yun 2,*

1 College of Pharmacy, Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju daero, Jinju 52828, Korea; [email protected] (S.-M.P.); [email protected] (Y.M.H.) 2 College of Pharmacy, Pusan National University, Busan 46241, Korea; [email protected] (M.J.); [email protected] (J.J.) 3 College of Pharmacy, Dankook University, Cheonan 31116, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-51-510-2810; Fax: +82-51-513-6754

Academic Editors: Carlo Siciliano and Constantinos M. Athanassopoulos Received: 15 June 2016; Accepted: 18 July 2016; Published: 21 July 2016

Abstract: Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review speciﬁcally examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of α-amino acid templates in natural product synthesis research and related areas.

Keywords: chiral pool; α-amino acid; natural product; total synthesis; asymmetric induction

1. Introduction The chiral pool approach is highly attractive in the asymmetric total synthesis of bioactive natural products with diverse and complex architectures [1,2]. This strategy is one of the best methods available to synthetic organic chemists for establishing pivotal stereocenters in optically active compounds [3–7]. The chiral pool is a versatile tool, comprising naturally occurring chiral molecules such as carbohydrates, amino acids, terpenes, alkaloids, and hydroxyacids [2,6]. They include enantiomerically enriched species that can be synthetically transformed into the desired target molecules. Chiral pool materials are also inexpensive and commercially available, making them adequate for use in accessing natural products and bioactive compounds [2]. The usage of the chiral pool in asymmetric synthesis can be classified in three general categories, as shown in Figure1: (a) chiral sources, used as building blocks containing built-in stereocenters for target molecules; (b) chiral devices, employed as useful tools for enantioselective catalysts and auxiliaries; and (c) chiral inducers, applied to the generation of new stereocenters in a substrate-controlled manner [1–7]. The chiral inducer strategy is a highly efficient method to exploit advantages of both the chiral source and device approach at the same time. The specific aim of this review is to present useful applications of enantiomerically enriched α-amino acids as substrate-controlled asymmetric inducers in natural product synthesis from 2011 to May 2016. Chirally pure α-amino acids are very useful materials due to diversity of functional group and ease of commercial use [7]. The α-amino acids described in this review are illustrated in Figure2. The use of amino acids as chiral sources and devices for asymmetric synthesis is not covered. Also, synthesis of acyclic or cyclic peptide natural products is not included.

Molecules 2016, 21, 951; doi:10.3390/molecules21070951 www.mdpi.com/journal/molecules Molecules 2016, 21, 951 2 of 13 Molecules 2016, 21, 951 2 of 13 Molecules 2016, 21, 951 2 of 13 Molecules 2016, 21, 951 2 of 13

FigureFigure 1.1. Three categoriescategories ofof chiralchiral poolpool useuse inin asymmetricasymmetric synthesis.synthesis. Figure 1. Three categories of chiral pool use in asymmetric synthesis. Figure 1. Three categories of chiral pool use in asymmetric synthesis.

Figure 2. Representative α‐amino acids. Figure 2. Representative αα‐-aminoamino acids. Figure 2. Representative α‐amino acids. 2. Chiral Pool: Proline 2. Chiral Pool: Proline 2. Chiral Pool: Proline 2. ChiralRecently, Pool: aProline wide range of natural and non‐natural product syntheses using proline as the chiral pool Recently, a wide range of natural and non‐natural product syntheses using proline as the chiral pool materialRecently, in a substrate a wide range‐controlled of natural manner and non-naturalhave been reported. product synthesesSuh et al. usingsynthesized proline polyhydroxylated as the chiral pool materialRecently, in a substrate a wide range‐controlled of natural manner and nonhave‐natural been reported. product synthesesSuh et al. usingsynthesized proline polyhydroxylated as the chiral pool materialindolizidine in a substrate-controlledalkaloids, 1‐deoxy‐6,8a manner‐di‐epi have‐castanospermine been reported. (4 Suh) and et 1 al.‐deoxy synthesized‐6‐epi‐castanospermine polyhydroxylated (7), materialindolizidine in a alkaloids,substrate‐ controlled1‐deoxy‐6,8a manner‐di‐epi have‐castanospermine been reported. (4 )Suh and et 1 ‐al.deoxy synthesized‐6‐epi‐castanospermine polyhydroxylated (7), indolizidinethat can act alkaloids,asalkaloids, selective 1-deoxy-6,8a-di- 1 ‐α‐deoxyglycosidase‐6,8a‐diepi ‐inhibitorsepi-castanospermine‐castanospermine [8,9]. L‐Proline (4) ( and4) and was 1-deoxy-6- 1 ‐utilizeddeoxyepi‐6 as-castanospermine‐epi a‐ platformcastanospermine to construct (7), that(7), that can act as selectiveα α‐glycosidase inhibitors [8,9]. L‐Proline was utilized as a platform to construct thatcanthe actindolizidinecan as act selective as selective skeleton,-glycosidase α‐glycosidase as shown inhibitors in inhibitors Scheme [8,9 ].1.[8,9]. L(-ProlineE) ‐LSilyl‐Proline enol was was utilizedether utilized 2, obtained as a as platform a platform from to L‐ construct prolineto construct via the a the indolizidine skeleton, as shown in Scheme 1. (E)‐Silyl enol ether 2, obtained from L‐proline via a indolizidineknown protocol skeleton, [10,11], as shown underwent in Scheme an 1aza.( E‐Claisen)-Silyl enol rearrangement ether 2, obtained to produce from L-proline the corresponding via a known theknown indolizidine protocol skeleton, [10,11], underwentas shown in an Scheme aza‐Claisen 1. (E)‐ Silylrearrangement enol ether 2 to, obtained produce from the Lcorresponding‐proline via a protocol9‐membered [10,11 lactam], underwent 3 in 66% an yield. aza-Claisen This transformation rearrangement was to produceimpressive the not corresponding only because 9-membered it created a known9‐membered protocol lactam [10,11], 3 in 66%underwent yield. This an transformationaza‐Claisen rearrangement was impressive to producenot only becausethe corresponding it created a lactamnew stereogenic3 in 66% yield. center This through transformation a 6‐membered was transition impressive state, not but only also because because it createdit afforded a new a cis stereogenic‐azoninone 9new‐membered stereogenic lactam center 3 inthrough 66% yield. a 6‐membered This transformation transition state, was but impressive also because not itonly afforded because a cis it‐azoninone created a centerframework through simultaneously. a 6-membered The transition final product state, 4 was but alsoafforded because after it subsequent afforded a transformations.cis-azoninone framework Similarly, newframework stereogenic simultaneously. center through The a final 6‐membered product 4 transition was afforded state, after but subsequentalso because transformations. it afforded a cis‐azoninone Similarly, simultaneously.(Z)‐silyl enol ether The 5 was ﬁnal converted product into4 was trans afforded‐azoninone after 6 under subsequent microwave transformations.‐assisted conditions. Similarly, It is framework(Z)‐silyl enol simultaneously. ether 5 was converted The final productinto trans 4 was‐azoninone afforded 6 after under subsequent microwave transformations.‐assisted conditions. Similarly, It is (noteworthyZ)-silyl enol that ether the5 synwas‐diol converted moiety intoof thetrans azoninone-azoninone skeleton6 under was microwave-assisted created via chiral communication conditions. It isof (noteworthyZ)‐silyl enol that ether the 5 synwas‐diol converted moiety ofinto the trans azoninone‐azoninone skeleton 6 under was microwavecreated via‐ assistedchiral communication conditions. It ofis noteworthythe L‐proline that that stereocenter the the synsyn‐diol-diol during moiety moiety aza of of‐ theClaisen the azoninone azoninone rearrangement skeleton skeleton was‐induced was created created ring via viaexpansion. chiral chiral communication communication The transition of the L‐proline stereocenter during aza‐Claisen rearrangement‐induced ring expansion. The transition ofstates the Lin-proline both these stereocenter conversions during made aza-Claisen it possibl rearrangement-inducede for the sole chiral center ring of expansion. amino acid The 1 transitionto induce thestates L‐proline in both stereocenter these conversions during made aza‐Claisen it possibl rearrangemente for the sole‐ inducedchiral center ring expansion.of amino acid The 1 transitionto induce statesadditional in both chirality these conversionsin cis or trans made azoninones it possible 3 and for 6. the sole chiral center of amino acid 1 to induce statesadditional in both chirality these conversionsin cis or trans made azoninones it possibl 3 ande for 6 .the sole chiral center of amino acid 1 to induce additional chirality in cis or trans azoninones 3 and 6.

Scheme 1. Total syntheses of castanospermines 4 and 7. Scheme 1. Total syntheses of castanospermines 4 and 7. SchemeScheme 1. TotalTotal syntheses of castanospermines 4 and 7.

Molecules 2016, 21, 951 3 of 13 Molecules 2016, 21, 951 3 of 13 Molecules 2016, 21, 951 3 of 13 L AnotherAnother substrate-controlled substrate‐controlled chiral chiral inductioninduction application of of L‐proline-proline is is summarized summarized in inScheme Scheme 2. 2. Srihari et al. accomplished the stereoselective total synthesis of alkaloid (´)-allonorsecurinine (10)[12]. SrihariAnother et al. accomplished substrate‐controlled the stereoselective chiral induction total application synthesis of of alkaloid L‐proline (− )is‐allonorsecurinine summarized in Scheme (10) [12]. 2. To create the stereocenter in the lactone moiety of 10, precursor 8 was readily prepared from L-proline SrihariTo create et al.the accomplished stereocenter in the the stereoselective lactone moiety total of 10 synthesis, precursor of alkaloid 8 was readily (−)‐allonorsecurinine prepared from L (‐10proline) [12]. in three steps. The Grignard reaction of isopropenyl magnesium bromide with α-amidoketone 8 Toin threecreate steps. the stereocenter The Grignard in the reaction lactone moietyof isopropenyl of 10, precursor magnesium 8 was bromide readily prepared with α‐amidoketone from L‐proline 8 affordedinafforded three tertiary steps.tertiary The alcohol alcohol Grignard9 9in in high high reaction yield yield of andand isopropenyl withwith excellent magnesium facial facial selectivity, selectivity, bromide with with the theα‐ amidoketonepivotal pivotal tertiary tertiary 8 alcoholaffordedalcohol moiety moiety tertiary in in 9alcohol 9constructed constructed 9 in highvia via yieldSi Si-face‐face and additionaddition with excellent to the facialcarbonyl selectivity, group. group. Withwith With keythe key pivotalintermediate intermediate tertiary 9 9 inalcoholin hand, hand, subsequentmoiety subsequent in 9 constructed classical classical reactions,reactions, via Si‐face suchsuch addition asas AldolAldol to theand carbonyl Horner–Wittig Horner–Wittig group. reactions,With reactions, key intermediateprovided provided final ﬁnal 9 productinproduct hand,10 10,subsequent a, Euphorbiaceaea Euphorbiaceae classical alkaloid. alkaloid. reactions, such as Aldol and Horner–Wittig reactions, provided final product 10, a Euphorbiaceae alkaloid.

Scheme 2. Total synthesis of (−)‐allonorsecurinine (10). Scheme 2. Total synthesis of (´)-allonorsecurinine (10). Scheme 2. Total synthesis of (−)‐allonorsecurinine (10). Cycloaddition reactions have also been adapted for the proline‐derived total synthesis of natural Cycloaddition reactions have also been adapted for the proline-derived total synthesis of natural products.Cycloaddition Sarpong et reactions al. complete haved alsothe impressivebeen adapted syntheses for the ofproline ent‐citrinalin‐derived B total (15) synthesisand cyclopiamine of natural B products. Sarpong et al. completed the impressive syntheses of ent-citrinalin B (15) and cyclopiamine B (16) products.(16) as shown Sarpong in Scheme et al. complete 3 [13–15].d Ththee impressiveauthors utilized syntheses the chirality of ent‐citrinalin of D‐proline B (15 for) and the cyclopiamine stereoselective B as shown in Scheme3[ 13–15]. The authors utilized the chirality of D-proline for the stereoselective (construction16) as shown of in a Scheme cis‐fused 3 [13–15]. ring system The authors within utilizedfinal products the chirality 15 and of 16 D‐.proline Unsaturated for the cyanoamide stereoselective 12 constructionconstructionwas prepared of of a fromacis cis-fused‐ fusedD‐proline ringring insystem system 55% withinyield within over final ﬁnal sevenproducts products steps 15 15 andforand use16.16 Unsaturatedas. Unsaturateda dienophile cyanoamide cyanoamidein the key 12 12wasfacewas ‐selectiveprepared prepared Diels from from‐Alder DD‐proline-proline reaction. in in 55% When 55% yield yielddiene over over13 underwentseven seven steps steps cycloaddition for for use use as as a with adienophile dienophile 12 in the in presenceinthe the key key face-selectivefaceof Lewis‐selective acid Diels-Alder [16],Diels desired‐Alder reaction. reaction.product When 14When was diene dieneobtained13 13underwent underwent in 73% yield cycloaddition cycloaddition after a basic with workwith12 ‐12up.in in As thethe dienophile presencepresence of Lewisof12 Lewisprovided acid acid [16 ],a [16], convex desired desired face product environmentproduct14 was 14 was obtained in obtainedthe bicyclic in 73%in 73%ring yield yieldsystem, after after diene a basica basic 13 work-up. approached work‐up. As As the dienophile dienophile β‐face of12 provided12the provided unsaturated a convex a convex lactam face face environment ring environment selectively, in the establishingin the bicyclic bicyclic ring the ring system,two system, adjacent diene diene stereocenters13 13approached approached in tricyclic the theβ-face β‐ ketoneface of of the unsaturatedthe14 simultaneously. unsaturated lactam lactam ringSubsequent ring selectively, selectively, steps establishing transformed establishing the 14 theinto two two ent adjacent ‐adjacentcitrinalin stereocenters stereocenters B (15) and cyclopiamine in in tricyclic tricyclic ketone ketone B (16).14 simultaneously.14 simultaneously. Subsequent Subsequent steps steps transformed transformed14 14into intoent ent-citrinalin‐citrinalin B B (15 (15)) and and cyclopiamine cyclopiamine B ( 16).).

Scheme 3. Total syntheses of ent‐citrinalin B (15) and cyclopiamine B (16). SchemeScheme 3. 3.Total Totalsyntheses syntheses ofof entent-citrinalin‐citrinalin B ( (1515)) and and cyclopiamine cyclopiamine B B (16 (16).). Memory of chirality is a very special case. Recently, Kim et al. reported the first total synthesis of (−)‐penibruguieramineMemory of chirality A is( 22a very), employing special case. a biomimetic Recently, Kimapproach et al. reported (Scheme the 4) first[17,18]. total Acid synthesis 17 was of Memory of chirality is a very special case. Recently, Kim et al. reported the ﬁrst total synthesis (coupled−)‐penibruguieramine with L‐proline tA‐butyl (22), ester employing (18) in the a biomimeticpresence of DCC,approach providing (Scheme amide 4) [17,18].19, an intramolecular Acid 17 was of (´)-penibruguieramine A (22), employing a biomimetic approach (Scheme4)[ 17,18]. Acid 17 was coupledaldol reaction with L precursor,‐proline t‐butyl in 79% ester yield. (18) Exposurein the presence of 19 ofto DCC,sodium providing ethoxide amide enabled 19, anthe intramolecular pyrrolizidine coupled with L-proline t-butyl ester (18) in the presence of DCC, providing amide 19, an intramolecular aldolbackbone reaction and precursor,two additional in 79% stereogenic yield. Exposure centers of 1921 to besodium established ethoxide thro enabledugh memory the pyrrolizidine of chirality aldol reaction precursor, in 79% yield. Exposure of 19 to sodium ethoxide enabled the pyrrolizidine backboneand concomitant and two dynamic additional kinetic stereogenic resolution. centers When of 21 amide to be established19 was treated thro ughwith memory a base, ofits chirality central 21 backboneandchirality concomitant andshould two have additionaldynamic been kineticdeleted stereogenic resolution. by deprotonation. centers When of amide toHowever, be established19 was enolate treated through20 withcontained memorya base, a chiralits of central chirality axis, andchiralityresulting concomitant shouldin memory dynamichave ofbeen chirality kinetic deleted and resolution. by hamperingdeprotonation. When racemization. amideHowever,19 wasImpressively,enolate treated 20 contained with the adynamic base, a chiral its kinetic centralaxis, chiralityresultingresolution should in of memoryracemic have beenmethof chirality deletedine occurred, and by deprotonation.hampering creating an racemization. α‐chiral However, center Impressively, enolate in the 20amidecontained the moiety. dynamic a From chiral kinetic this axis, resultingresolutiontransformation, in of memory racemic bicyclic of meth amide chiralityine 21 occurred, was and obtained hampering creating in 77% an racemization. yield,α‐chiral with center 10% Impressively, ofin thethe corresponding amide the moiety. dynamic elimination From kinetic this resolutiontransformation,product. Following of racemic bicyclic an methine uneven amide 21tful occurred, was reduction obtained creating procedure, in 77% an yield,α-chiral (−)‐ penibruguieraminewith center 10% of in the the corresponding amide A was moiety. produced elimination From from this transformation,product.amide 21 Following in 86% bicyclic yield an (two amideuneven steps).21tfulwas reduction obtained procedure, in 77% yield, (−)‐penibruguieramine with 10% of the corresponding A was produced elimination from product.amide 21 Following in 86% yield anuneventful (two steps).reduction procedure, (´)-penibruguieramine A was produced from amide 21 in 86% yield (two steps).

Molecules 2016, 21, 951 4 of 13 Molecules 2016, 21, 951 4 of 13

Molecules 2016, 21, 951 4 of 13

SchemeScheme 4. 4.Total Total synthesis synthesis ofof penibruguieramine A A(22 ().22 ).

3. Chiral Pool: TryptophanScheme 4. Total synthesis of penibruguieramine A (22). 3. Chiral Pool: Tryptophan 3. ChiralTryptophan, Pool: Tryptophan an aromatic amino acid, has been used as a precursor in the total synthesis of Tryptophan,natural products an with aromatic indole amino‐derived acid, heterocyclic has been framework. used as a precursorThe indole inmoiety the total of tryptophan synthesis serves of natural productsas a Tryptophan,good with template indole-derived an for aromatic a copper heterocyclic ‐aminocatalyzed acid, asymmetric framework. has been arylation, used The as indole asa precursordepicted moiety in in Scheme ofthe tryptophan total 5 [19]. synthesis Reisman serves of as a goodnaturalet templateal. investigated products for with a copper-catalyzedand indole optimized‐derived these heterocyclic asymmetric reaction coframework.nditions. arylation, After The as in depictedandole extensive moiety in Scheme surveyof tryptophan 5of[ bidentate19]. serves Reisman as a good template for a copper‐catalyzed asymmetric arylation, as depicted in Scheme 5 [19]. Reisman et al.ligands investigated and electrophiles and optimized under (CuOTf) these reaction2 PhMe catalyst, conditions. cyclic Afterdipeptide an extensive23 in the presence survey of of L1 bidentate and et al. investigated and optimized these reaction conditions. After an extensive survey of bidentate [Ph2I]OTf afforded pyrroloindololine 24 in high yield and excellent diastereoselectivity, minimizing ligands and electrophiles under (CuOTf)2 PhMe catalyst, cyclic dipeptide 23 in the presence of L1 and ligandsthe undesired and electrophiles C‐2 arylated under product. (CuOTf) Two2 PhMe newly catalyst, created cyclic stereogenic dipeptide centers 23 in thewere presence induced of by L1 theand [Ph2I]OTf afforded pyrroloindololine 24 in high yield and excellent diastereoselectivity, minimizing the [Phchirality2I]OTf ofafforded tryptophan pyrroloindololine in a substrate‐ controlled24 in high manner.yield and excellent diastereoselectivity, minimizing undesiredthe undesired C-2 arylated C‐2 arylated product. product. Two newly Two newly created created stereogenic stereogenic centers centers were were induced induced by the by chirality the of tryptophanchirality of intryptophan a substrate-controlled in a substrate‐controlled manner. manner.

Scheme 5. Cu‐catalyzed arylation of cyclo‐(Trp‐Phe) 23.

This conversion strategy was applied directly to the total synthesis of (+)‐naseseazine A (28) and SchemeScheme 5. 5.Cu-catalyzed Cu‐catalyzed arylation of of cyclo cyclo-(Trp-Phe)‐(Trp‐Phe) 2323. . (+)‐naseseazine B (30) (Scheme 6) [20]. To construct the tetracyclic framework of 28, cyclic alanine‐ tryptophanThis conversion dimer 25 wasstrategy selected was as applied a chiral directly precursor. to theThe total pivotal synthesis arylation of of (+) diketopiperazine‐naseseazine A (2528 with) and (+)Thisadvanced‐naseseazine conversion electrophile B (30 strategy) 26(Scheme in the was presence 6) applied[20]. Toof (CuOTf)construct directly2 PhMe tothethe tetracyclic and total L2 provided synthesis framework desired of of (+)-naseseazine pyrroloindoline 28, cyclic alanine 27 A ‐ (28) andtryptophanin (+)-naseseazine moderate dimer yield. 25 Final Bwas (30 compoundselected) (Scheme as a28 chiral6 was)[ precursor.conveniently20]. To Th construct econstructed pivotal arylation the from tetracyclic tetracyclicof diketopiperazine intermediate framework 25 with 27 of 28, cyclicadvancedusing alanine-tryptophan a Larock electrophile indolization 26 in dimer the strategy presence25 was [21,22]. of selected(CuOTf) Additionally,2 PhMe as a chiraland another L2 precursor.provided natural desiredproduct, The pyrroloindoline pivotal (+)‐naseseazine arylation 27 of diketopiperazineinB, moderate was obtained yield.25 withstereoselectively Final advanced compound electrophilefrom 28 was cyclic conveniently proline26 in the‐tryptophan constructed presence precursor of from (CuOTf) tetracyclic 29,2 employingPhMe intermediate and aL2 similarprovided 27 desiredusingsynthetic pyrroloindoline a Larock sequence. indolization 27 in moderatestrategy [21,22]. yield. Additionally,Final compound another28 was natural conveniently product, (+) constructed‐naseseazine from tetracyclicB, wasInterestingly, intermediateobtained stereoselectively applying27 using this a methodology Larockfrom cyclic indolization proline to simple‐tryptophan strategy carboxamide [21 precursor,22 31]. afforded Additionally, 29, employing pyrroloindololine another a similar natural compound 32, possessing the opposite stereochemistry in the C‐2 and C‐3 positions. This discrepancy product,synthetic (+)-naseseazine sequence. B, was obtained stereoselectively from cyclic proline-tryptophan precursor 29, showsInterestingly, that amino applyingacids provide this methodologya tremendous toopport simpleunity carboxamide for the diastereosel 31 affordedective pyrroloindololine synthesis of the employing a similar synthetic sequence. compoundpyrroloindololine 32, possessing framework the opposite as shown stereochemistry in Scheme 7. in the C‐2 and C‐3 positions. This discrepancy Interestingly, applying this methodology to simple carboxamide 31 afforded pyrroloindololine showsTryptophan that amino wasacids also provide utilized a tremendous as a chiral pool opport reagentunity in for the the total diastereosel synthesisective of prenylated synthesis indole of the 32 compoundpyrroloindololinealkaloids ,(− possessing)‐brevicompanine framework the opposite asB (shown38) and stereochemistry in (+) Scheme‐aszonalenin 7. in (40 the) (Scheme C-2 and 8) C-3 [23]. positions. Carreira et This al. reported discrepancy showsa thathighlyTryptophan amino diastereoselective acids was providealso utilized and a tremendousregioselective as a chiral pool opportunity iridium reagent‐catalyzed in for the the total reverse diastereoselective synthesis prenylation of prenylated reaction. synthesis indole The of the pyrroloindololinealkaloidsreaction of(−) readily‐brevicompanine framework available as L ‐Btryptophan shown (38) and in (+) Scheme methyl‐aszonalenin 7ester. 33 (40 with) (Scheme tertiary 8) carbonate [23]. Carreira 34 in etthe al. presence reported aTryptophanof highly [{Ir(cod)Cl} diastereoselective was2] and also phosphoramidite utilized and regioselective as a chiralligand iridium pool35 [24] reagent‐catalyzed furnished in reverse the hexahydropyrrolo[2,3 total prenylation synthesis reaction. of‐b]indole prenylated The (−)‐exo‐36 in 58% yield. Initially, the exo/endo ratio of the prenylation was quite low (1.3:1). However, it indolereaction alkaloids of readily (´)-brevicompanine available L‐tryptophan B (38 methyl) and (+)-aszonalenin ester 33 with tertiary (40) carbonate (Scheme8 34)[ in23 the]. Carreira presence et al. was improved to >20:1 by extensive optimization of base, ligand, and reaction temperature. Importantly, reportedof [{Ir(cod)Cl} a highly2 diastereoselective] and phosphoramidite and regioselective ligand 35 [24] iridium-catalyzed furnished hexahydropyrrolo[2,3 reverse prenylation‐b]indole reaction. the installation of two vicinal stereogenic centers was controlled by the chirality of tryptophan. After The( reaction−)‐exo‐36 ofin 58% readily yield. available Initially, theL-tryptophan exo/endo ratio methylof the prenylation ester 33 withwas qu tertiaryite low (1.3:1). carbonate However,34 in it the this successful result, (−)‐brevicompanine B (38) [25], a plant growth regulator, was finally obtained was improved to >20:1 by extensive optimization of base, ligand, and reaction temperature. Importantly, presence of [{Ir(cod)Cl}2] and phosphoramidite ligand 35 [24] furnished hexahydropyrrolo[2,3-b]indole (´)-exo-the installation36 in 58% yield.of two Initially,vicinal stereogenic the exo/endo centersratio was of controlled the prenylation by the waschirality quite of lowtryptophan. (1.3:1). However,After this successful result, (−)‐brevicompanine B (38) [25], a plant growth regulator, was finally obtained it was improved to >20:1 by extensive optimization of base, ligand, and reaction temperature.

Importantly, the installation of two vicinal stereogenic centers was controlled by the chirality of tryptophan. After this successful result, (´)-brevicompanine B (38)[25], a plant growth regulator, Molecules 2016, 21, 951 5 of 13

Molecules 2016, 21, 951 5 of 13 Molecules 2016, 21, 951 5 of 13 was ﬁnally obtained from iterative amidations in good yield. The total synthesis of another alkaloid, fromMolecules iterative 2016, 21 amidations, 951 in good yield. The total synthesis of another alkaloid, (+)‐aszonalenin5 of ( 1340 ) (+)-aszonaleninfrom[26], aiterative substance (40 amidations)[ P26 inhibitor], a substance in goodfor the yield. P human inhibitor The neurokinintotal for synthesis the human‐1 receptor, of another neurokinin-1 was alkaloid, efficiently receptor, (+)‐ aszonalenincompleted was efﬁciently from (40) [26], a substance P inhibitor for the human neurokinin‐1 receptor, was efficiently completed from completedDfrom‐tryptophan iterative from D methyl amidations-tryptophan ester in 39 methylgood via a yield.similar ester The synthetic39 totalvia asynthesissimilar procedure. of synthetic another procedure.alkaloid, (+)‐aszonalenin (40) D[26],‐tryptophan a substance methyl P inhibitor ester 39 forvia thea similar human synthetic neurokinin procedure.‐1 receptor, was efficiently completed from D‐tryptophan methyl ester 39 via a similar synthetic procedure.

Scheme 6. Total synthesis of (+)‐naseseazines A and B. SchemeScheme 6. 6.Total Total synthesis synthesis ofof (+)-naseseazines(+)‐naseseazines A Aand and B. B. Scheme 6. Total synthesis of (+)‐naseseazines A and B.

Scheme 7. Diastereoselective cyclization for pyrroloindoline skeleton. SchemeScheme 7. 7.Diastereoselective Diastereoselective cyclizationcyclization for for pyrroloindoline pyrroloindoline skeleton. skeleton. Scheme 7. Diastereoselective cyclization for pyrroloindoline skeleton.

Scheme 8. Total syntheses of (−)‐brevicompanine B (38) and (+)‐aszonalenin (40). SchemeScheme 8.8. TotalTotal synthesessyntheses of (−)‐brevicompanine BB ((3838)) andand (+) (+)‐‐aszonaleninaszonalenin ( 40(40).). Scheme 8. Total syntheses of (´)-brevicompanine B (38) and (+)-aszonalenin (40).

Molecules 2016, 21, 951 6 of 13

Molecules 2016, 21, 951 6 of 13 A more recent example of tryptophan-templated chiral pool synthesis is illustrated in Scheme9. Baran et al.A more accomplished recent example the totalof tryptophan syntheses‐templated of verruculogen chiral pool (45 synthesis) and fumitremorgin is illustrated in Scheme A (46), 9. which bothMoleculesBaran contain et 2016 al. a , uniqueaccomplished21, 951 eight-membered the total syntheses endoperoxide of verruculogen [27–29 (45].) and Diastereoselective fumitremorgin A Pictet-Spengler(46), which6 of 13 both contain a unique eight‐membered endoperoxide [27–29]. Diastereoselective Pictet‐Spengler cyclization of 42, prepared from N-Boc-L-tryptophan methyl ester (41), with TBDPS-protected cyclizationA more of recent 42, preparedexample of from tryptophan N‐Boc‐‐Ltemplated‐tryptophan chiral methyl pool synthesisester (41 ),is illustratedwith TBDPS in ‐Schemeprotected 9. peroxy-aldehyde 43 gave tricycle 44. Although the facial selectivity was relatively low (2:1), major Baranperoxy et‐aldehyde al. accomplished 43 gave thetricycle tota l44 syntheses. Although of verruculogenthe facial selectivity (45) and was fumitremorgin relatively low A (2:1),(46), whichmajor diastereomerbothdiastereomer contain44 was a44 unique was effectively effectively eight exploited‐membered exploited to endoperoxide ﬁnishto finish the the total to[27–29].tal syntheses. syntheses. Diastereoselective The The chirality chirality ofPictet of tryptophan tryptophan‐Spengler from the chiralcyclizationfrom poolthe chiral wasof 42 criticalpool, prepared was for critical creating from for N creating the‐Boc new‐L‐tryptophan the stereocenter new stereocenter methyl in the ester indolein the (41 indole system.), with system. TBDPS The pivotal The‐protected pivotal methoxy groupperoxymethoxy in precursor‐aldehyde group in42 43precursorwas gave introduced tricycle 42 was 44 introduced. by Although Ir-catalyzed by the Ir‐catalyzed facial borylation selectivity borylation and was Chan-Lam and relatively Chan‐Lam couplinglow coupling (2:1), [major30 [30].]. diastereomer 44 was effectively exploited to finish the total syntheses. The chirality of tryptophan from the chiral pool was critical for creating the new stereocenter in the indole system. The pivotal methoxy group in precursor 42 was introduced by Ir‐catalyzed borylation and Chan‐Lam coupling [30].

SchemeScheme 9. Total9. Total syntheses syntheses of of verruculogen verruculogen ( (4545) )and and fumitremorgin fumitremorgin A ( A46). (46 ).

4. Chiral Pool: Tyrosine 4. Chiral Pool: Tyrosine Scheme 9. Total syntheses of verruculogen (45) and fumitremorgin A (46). Various natural product syntheses have started from chiral pool reagent tyrosine, which can be Various natural product syntheses have started from chiral pool reagent tyrosine, which can 4.transformed Chiral Pool: into Tyrosine enantiomerically pure intermediates. Tokuyama et al. reported the total synthesis of be transformeddimeric alkaloid into (−) enantiomerically‐acetylaranotin 49 in 2012 pure (Scheme intermediates. 10) [31,32]. Alkaloid Tokuyama 49 features et al. a dihydrooxepine reported the total synthesisbackboneVarious of dimeric synthesized natural alkaloid product from α (´ ,β‐syntheses)-acetylaranotinunsaturated have ketone started49 48in from by 2012 olefin chiral (Scheme isomerization, pool reagent 10)[31 Wharton ,tyrosine,32]. Alkaloid rearrangement, which 49canfeatures be a dihydrooxepinetransformedBaeyer‐Villiger into backboneoxidation, enantiomerically and synthesized further pure steps. intermediates. from Theα tota,β-unsaturated l Tokuyamasynthesis commenced et ketoneal. reported48 withby the theoleﬁn total preparation synthesis isomerization, of Whartondimericenone rearrangement, 48 alkaloid via oxidative (−)‐acetylaranotin Baeyer-Villigerdearomatization 49 in 2012 oxidation,of N ‐(SchemeCbz‐L‐tyrosine and 10) further[31,32]. (47) Alkaloidand steps. subsequent The 49 features total conjugate synthesis a dihydrooxepine addition commenced of backbone synthesized from α,β‐unsaturated ketone 48 by olefin isomerization, Wharton rearrangement, withthe the transition preparation state amino of enone moiety.48 Thisvia remarkable oxidative reaction dearomatization was previously of Ndeveloped-Cbz-L-tyrosine and described (47) and Baeyer‐Villiger oxidation, and further steps. The total synthesis commenced with the preparation of subsequentby Wipf conjugateet al. [33]. After addition oxidative of the dearomatization transition state of the amino phenol moiety. moiety in This 47, two remarkable transition reactionstates, T1 was enoneand T2 48, for via concomitant oxidative dearomatization conjugate addition of areN‐Cbz possible.‐L‐tyrosine T1 was (47 more) and stable, subsequent due to conjugatehaving less addition A1,3‐strain of previously developed and described by Wipf et al. [33]. After oxidative dearomatization of the phenol the(H andtransition carbonyl state oxygen), amino moiety.resulting This in 48remarkable being obtained reaction exclusively was previously as the developedmajor diastereomer. and described This moiety in 47, two transition states, T and T , for concomitant conjugate addition are possible. T was byhigh Wipf facial et selectivityal. [33]. After further oxidative demonstrates de1 aromatization 2the superiority of the phenol of amino moiety acids in as 47 chiral, two inducers.transition states, T1 1,3 moreand stable, T2, for due concomitant to having conjugate less A addition-strain are (H possible. and carbonyl T1 was more oxygen), stable, resulting due to having in 48 lessbeing A1,3‐strain obtained exclusively(H and ascarbonyl the major oxygen), diastereomer. resulting in This 48 being high facialobtained selectivity exclusively further as the demonstrates major diastereomer. the superiority This of aminohigh acidsfacial selectivity as chiral inducers.further demonstrates the superiority of amino acids as chiral inducers.

Scheme 10. Total synthesis of (−)‐acetylaranotin (49).

Alkene asymmetric dihydroxylation is another example of tyrosine utilized as a chiral template. The stereoselective synthesisScheme of py rrolidinone10. Total synthesis alkaloid of ( −rigidiuscula)‐acetylaranotinmide (49 A). was completed by Krishna Scheme 10. Total synthesis of (´)-acetylaranotin (49).

Alkene asymmetric dihydroxylation is another example of tyrosine utilized as a chiral template. AlkeneThe stereoselective asymmetric synthesis dihydroxylation of pyrrolidinone is another alkaloid example rigidiuscula of tyrosinemide A was utilized completed as a chiralby Krishna template. Thestereoselective synthesis of pyrrolidinone alkaloid rigidiusculamide A was completed by Molecules 2016, 21, 951 7 of 13

Molecules 2016, 21, 951 7 of 13 Krishna et al. (Scheme 11) [34,35]. To incorporate the syn-diol moiety in 53, they dihydroxylated 51 etMolecules al. (Scheme 2016, 21 ,11) 951 [34,35]. To incorporate the syn‐diol moiety in 53, they dihydroxylated 51 using7 of the 13 using the Upjohn method (OsO4/NMO) [36]. This transformation afforded desired diol 52 as a Upjohn method (OsO4/NMO) [36]. This transformation afforded desired diol 52 as a single diastereomer single diastereomer in 69% yield. The chirality of γ-lactam 52 was thought to be responsible for the inet 69%al. (Scheme yield. The 11) chirality[34,35]. Toof γ‐incorporatelactam 52 wasthe synthought‐diol moietyto be responsible in 53, they for dihydroxylated the enantiomerically 51 using pure the α enantiomericallytyrosineUpjohn method‐induced pure(OsO α‐facial4 tyrosine-induced/NMO) selectivity. [36]. This Finally, transformation-facial the O selectivity.‐benzyl afforded group Finally,desired in 52 diolwas the 52 Odeprotected -benzylas a single group diastereomerto afford in 52 thewas deprotectedoriginallyin 69% yield. toproposed affordThe chirality thestructure originally of γ‐ oflactam rigidiusculamide proposed 52 was thought structure A. toUnfortunately, be of responsible rigidiusculamide the for experimental the enantiomerically A. Unfortunately, data was pure not the experimentalidenticaltyrosine‐ inducedto data that wasof α‐ thefacial not authentic identicalselectivity. natural to Finally, that product of the [35].O authentic‐benzyl group natural in 52 product was deprotected [35]. to afford the originally proposed structure of rigidiusculamide A. Unfortunately, the experimental data was not identical to that of the authentic natural product [35].

Scheme 11. Total synthesis of rigidiusculamide A (53). Scheme 11. Total synthesis of rigidiusculamide A (53). 5. Chiral Pool: Serine Scheme 11. Total synthesis of rigidiusculamide A (53). 5. Chiral Pool: Serine 5. ChiralSerine, Pool: containing Serine a hydroxymethyl group, has also been used as the powerful chiral pool reagent inSerine, the synthesis containing of complex a hydroxymethyl target molecules. group, A has part alsoicularly been impressive used as the example, powerful the chiral enantioselective pool reagent in the synthesissynthesisSerine, of containing complex(−)‐α‐kainic target a acidhydroxymethyl molecules. (60), in which A group, particularly Zhou has and also impressiveLi beenet al. used present example, as the a unique powerful the enantioselectiveSmI chiral2‐catalyzed pool reagent [3 synthesis + 2] of (´intramolecularin)- theα-kainic synthesis acid cycloaddition of (60 complex), in which target reaction Zhou molecules. and with Li excellent et A al. part present icularlydiastereoselectivity, a unique impressive SmI2 example, -catalyzedis summarized the [3 enantioselective + 2]in intramolecularScheme 12 cycloaddition[37,38].synthesis The of reactionkey (−)‐α‐ precursor,kainic with acid excellentcyclopropane (60), in diastereoselectivity, which 56, wasZhou synthesized and Li et is al. summarized from present D‐serine a uniquein methylScheme SmI ester2‐ 12catalyzed HCl[37, 38(55] ).[3 using The + 2] key precursor,conventionalintramolecular cyclopropane protocols. cycloaddition56 When, was reaction synthesizedcyclopropane with excellent from56 wasD diastereoselectivity,-serine treated methyl with samarium ester is HClsummarized diiodide, (55) using inketyl Scheme conventional radical 12 protocols.57[37,38]. was The Wheninitially key cyclopropane precursor,formed. Rapid cyclopropane56 cleavagewas treated 56 of, wasthe with cyclsynthesizedopropyl samarium fromring diiodide, Dand‐serine subsequent methyl ketyl radical ester cycloaddition HCl57 (was55) using initiallywas formed.observed,conventional Rapid which protocols. cleavage afforded When of desired the cyclopropane cyclopropyl bicyclic ketone 56 ring was 59 and treatedin good subsequent with yield. samarium It was cycloaddition hypothesized diiodide, ketyl was that radical observed, ketyl 57 was initially formed. Rapid cleavage of the cyclopropyl ring and subsequent cycloaddition was whichradical afforded 57 spontaneously desired bicyclic transformed ketone into59 enolatein good radical yield. 58 It. This was newly hypothesized created chiral that center ketyl favored radical 57 observed, which afforded desired bicyclic ketone 59 in good yield. It was hypothesized that ketyl spontaneously2,3‐trans stereoselectivity transformed over into 2,3 enolate‐cis via radicalfacial control58. This from newly the sole created chiral chiralcenter centerfrom the favored chiral amino 2,3-trans acid.radical With 57 spontaneouslykey intermediate transformed 59 in hand, into the enolate asymmetric radical synthesis 58. This ofnewly kainoid created 60 was chiral accomplished center favored via stereoselectivity over 2,3-cis via facial control from the sole chiral center from the chiral amino acid. a2,3 high‐trans‐yielding stereoselectivity sequence. over 2,3‐cis via facial control from the sole chiral center from the chiral amino Withacid. key With intermediate key intermediate59 in hand,59 in hand, the asymmetric the asymmetric synthesis synthesis of of kainoid kainoid60 60was was accomplished via via a high-yieldinga high‐yielding sequence. sequence.

Scheme 12. Total synthesis of (−)‐α‐kainic acid (60).

Scheme 12. Total synthesis of (−)‐α‐kainic acid (60). The synthesis of isoScheme‐haouamine 12. Total B is synthesis another ofexample (´)-α-kainic (Scheme acid (13)60). [39,40]. Structurally, this alkaloid, 64, consists of an indeno‐tetrahydropyridine core fused to a highly distinctive 11‐membered p‐cyclophaneThe synthesis ring. Traunerof iso‐haouamine et al. investigated B is another a substrate example‐controlled (Scheme oxidative13) [39,40]. phenol Structurally, coupling this to establishalkaloid,The synthesis 64the, consists indeno of iso-haouamine‐oftetrahydropyridine an indeno‐tetrahydropyridine B is ring. another Coupling example core precursor fused (Scheme to a enonehighly 13 )[ 62distinctive39 was,40 ].readily Structurally, 11‐membered prepared this alkaloid,fromp‐cyclophane N64‐Boc, consists protected ring. of Trauner an L‐ indeno-tetrahydropyridineserine et al.(61 ).investigated With desired a substrate intermediate core‐ fusedcontrolled 62 to prepared, a highlyoxidative distinctivecarbonyl phenol activation coupling 11-membered byto p-cyclophanetriflicestablish anhydride the ring. indeno and Trauner ‐concomitanttetrahydropyridine et al. investigated 1,4‐addition ring. ofCoupling a the substrate-controlled electron precursor‐rich aromatic enone oxidative 62ring was produced phenolreadily enolprepared coupling ether to establish from N the‐Boc indeno-tetrahydropyridine protected L‐serine (61). With ring. desired Coupling intermediate precursor 62 enone prepared,62 was carbonyl readily activation prepared by from triflic anhydride and concomitant 1,4‐addition of the electron‐rich aromatic ring produced enol ether

Molecules 2016, 21, 951 8 of 13

N-Boc protected L-serine (61). With desired intermediate 62 prepared, carbonyl activation by triﬂic Molecules 2016, 21, 951 8 of 13 anhydride and concomitant 1,4-addition of the electron-rich aromatic ring produced enol ether 63 in moderate63Molecules in moderate 2016 yield., 21, During 951yield. During the crucial the crucial addition addition process, process, the syn the-substituted syn‐substituted cyclopentane cyclopentane skeleton skeleton8 of 13 was constructedwas constructed without without racemization. racemization. The new The quaternary new quaternary stereogenic stereogenic center center in 63 was in 63 ultimately was ultimately derived 63 in moderate yield. During the crucial addition process, the syn‐substituted cyclopentane skeleton fromderived the chiral from poolthe chiral stereocenter pool stereocenter in 62. in 62. was constructed without racemization. The new quaternary stereogenic center in 63 was ultimately derived from the chiral pool stereocenter in 62.

SchemeScheme 13. 13. TotalTotal synthesissynthesis of iso iso-haouamine‐haouamine B B (64 (64).). Scheme 13. Total synthesis of iso‐haouamine B (64). More recently, Ciufolini et al. described the total synthesis of (+)‐erysotramidine (70) using an L L‐serineMore recently,derivative Ciufolini (Scheme et 14) al. described[41,42]. Advanced the total synthesisoxazoline of 67 (+)-erysotramidine, prepared from L‐serine (70) using methyl an ester-serine More recently, Ciufolini et al. described the total synthesis of (+)‐erysotramidine (70) using an derivative(66) via DCC (Scheme coupling 14) [41 and,42]. Burgess Advanced reagent oxazoline‐induced67, cyclization prepared from [43],L was-serine converted methyl into ester enone (66) via 68 DCCas L‐serine derivative (Scheme 14) [41,42]. Advanced oxazoline 67, prepared from L‐serine methyl ester couplinga precursor and Burgessfor stereoselective reagent-induced Michael cyclization cyclization. [43 Exposure], was converted of electronically into enone deficient68 as aenone precursor 68 in for (66) via DCC coupling and Burgess reagent‐induced cyclization [43], was converted into enone 68 as stereoselectiveCH2Cl2 to TsOH Michael resulted cyclization. in the desired Exposure tetracyclic of electronically core of 69 deﬁcientas a single enone diastereomer68 in CH in2Cl excellent2 to TsOH a precursor for stereoselective Michael cyclization. Exposure of electronically deficient enone 68 in resultedyield. Although in the desired the serine tetracyclic hydroxyl core group of 69 ascould a single approach diastereomer the two reactive in excellent Michael yield. acceptors, Although the the CH2Cl2 to TsOH resulted in the desired tetracyclic core of 69 as a single diastereomer in excellent serineformation hydroxyl of desired group product could approach 69 was favored. the two The reactive high Michaeldiastereos acceptors,electivity thewas formation assumed to of result desired yield. Although the serine hydroxyl group could approach the two reactive Michael acceptors, the productfrom the69 wasminimization favored. Theof unwanted high diastereoselectivity nonbonding interactions was assumed between to resultthe methyl from ester the minimization group and formation of desired product 69 was favored. The high diastereoselectivity was assumed to result ofacylamido unwanted group nonbonding [44,45]. interactionsThe pseudoaxial between conformation the methyl of the ester methyl group ester and group acylamido resulted group from [44 the,45 ]. from the minimization of unwanted nonbonding interactions between the methyl ester group and chirality of serine. After this chiral communication, (+)‐erysotramidine (70) was synthesized from key Theacylamido pseudoaxial groupconformation [44,45]. The ofpseudoaxial the methyl conformation ester group resulted of the methyl from the ester chirality group ofresulted serine. fromAfter the this synthetic intermediate 69 using further manipulations. chiralchirality communication, of serine. After (+)-erysotramidine this chiral communication, (70) was (+) synthesized‐erysotramidine from (70 key) was synthetic synthesized intermediate from key 69 usingsynthetic further intermediate manipulations. 69 using further manipulations.

Scheme 14. Total synthesis of (+)‐erysotramidine (70). Scheme 14. Total synthesis of (+)‐erysotramidine (70). 6. Chiral Pool: Alanine Scheme 14. Total synthesis of (+)-erysotramidine (70). 6. ChiralThe stereocenterPool: Alanine in alanine, a simple chiral pool reagent, has also provided good opportunities for 6. Chiral Pool: Alanine chiral induction. Gouault et al. accomplished the asymmetric total synthesis of dendrobate alkaloid The stereocenter in alanine, a simple chiral pool reagent, has also provided good opportunities for (+)The‐241D stereocenter (74) and isosolenopsin in alanine, a ( simple76) (Scheme chiral 15) pool [46–48]. reagent, Structurally has also provided, these alkaloids good opportunities consist of chiral induction. Gouault et al. accomplished the asymmetric total synthesis of dendrobate alkaloid cis‐2,6‐dialkylpiperidine. Vinylogous lactams 72 and 73, which were used as chiral precursors, were for(+) chiral‐241D induction. (74) and isosolenopsin Gouault et al.(76) accomplished(Scheme 15) [46–48]. the asymmetric Structurally total, these synthesis alkaloids of consist dendrobate of cis‐2,6‐dialkylpiperidine. Vinylogous lactams 72 and 73, which were used as chiral precursors, were

Molecules 2016, 21, 951 9 of 13 alkaloid (+)-241D (74) and isosolenopsin (76) (Scheme 15)[46–48]. Structurally, these alkaloids consist of Moleculescis-2,6-dialkylpiperidine. 2016, 21, 951 Vinylogous lactams 72 and 73, which were used as chiral precursors,9 of 13 wereMolecules readily 2016, prepared21, 951 from N-Boc protected D-alanine 71 [49]. The catalytic hydrogenation9 of 13 of readily prepared from N‐Boc protected D‐alanine 71 [49]. The catalytic hydrogenation of Boc‐deprotected Boc-deprotected amine 73 ﬁnally gave the target molecule, (+)-241D (74), via stereoselective reduction amine 73 finally gave the target molecule, (+)‐241D (74), via stereoselective reduction of both the alkene ofreadily both the prepared alkene from and N‐ ketone.Boc protected In addition, D‐alanine 71 key [49]. intermediate The catalytic 75hydrogenation, which was of transformedBoc‐deprotected into andamine ketone. 73 finally In gaveaddition, the target key intermediatemolecule, (+) ‐241D75, which (74), viawas stereoselective transformed reduction into enantiopure of both the alkaloid alkene enantiopure alkaloid isosolenopsin (76), was obtained by hydrogenation under similar conditions. The isosolenopsinand ketone. In (76 addition,), was obtained key intermediate by hydrogenation 75, which under was similar transformed conditions. into Theenantiopure newly generated alkaloid newly generated stereogenic centers in 74 and 75 were affected by the chirality of D-alanine. The total stereogenicisosolenopsin centers (76), wasin 74 obtained and 75 wereby hydrogenation affected by the under chirality similar of conditions.D‐alanine. TheThe totalnewly synthesis generated of synthesis of isosolenopsin (76) was completed using deoxygenation and Boc-deprotection steps. isosolenopsinstereogenic centers (76) was in 74completed and 75 wereusing affected deoxygenation by the chiralityand Boc ‐deprotectionof D‐alanine. steps.The total synthesis of isosolenopsin (76) was completed using deoxygenation and Boc‐deprotection steps.

SchemeScheme 15. 15.Total Total syntheses syntheses ofof (+)-241D(+)‐241D ( (7474)) and and isosolenopsin isosolenopsin (76 (76). ). Scheme 15. Total syntheses of (+)‐241D (74) and isosolenopsin (76). 7. Chiral Pool: Threonine 7. Chiral Pool: Threonine 7. Chiralα‐Amino Pool: acid Threonine threonine is a special chiral pool reagent, containing an extra stereocenter. Recently, α-Amino acid threonine is a special chiral pool reagent, containing an extra stereocenter. Recently, Seebergerα‐Amino et al. acid published threonine the is total a special synthesis chiral of pool protected reagent, legionaminic containing an acid extra 80 stereocenter.from D‐threonine Recently, as a Seeberger et al. published the total synthesis of protected legionaminic acid 80 from D-threonine as startingSeeberger material et al. published (Scheme 16)the [50,51].total synt Conventionalhesis of protected protection legionaminic of chiral acid pool 80 reagent from D 77‐threonine, followed as by a a starting material (Scheme 16)[50,51]. Conventional protection of chiral pool reagent 77, followed DIBALstarting‐H material reduction, (Scheme provided 16) [50,51]. chiral Conventionalaldehyde 78 inprotection high yield of chiral[52]. Withpool reagentthreoninal 77, followed78 in hand, by by DIBAL-H reduction, provided chiral aldehyde 78 in high yield [52]. With threoninal 78 in hand, treatmentDIBAL‐H withreduction, 2‐lithiofuran provided resulted chiral aldehydein desired 78 alcohol in high 79 .yield Although [52]. Withthe organometallic threoninal 78 inaddition hand, treatment with 2-lithiofuran resulted in desired alcohol 79. Although the organometallic addition reactiontreatment could with produce 2‐lithiofuran a diastereomeric resulted in mixture, desired thealcohol desired 79 .syn Although‐configured the alcohol,organometallic 79, was obtainedaddition syn 79 reactionwithreaction a could5:1 could ratio produce produceand in 80% a a diastereomeric diastereomeric isolated yield. mixture, mixture,This ster eoselectivity the desired syn was‐-conﬁguredconfigured caused by alcohol,the alcohol, chirality 79, was ,of was threonine obtained obtained withaminowith a a 5:1 5:1acid ratioratio via and Cram in in 80%‐ 80%chelation isolated isolated control yield. yield. This of thester This eoselectivitynucleophilic stereoselectivity was addition caused was [53]. by caused the The chirality newly by the of generated threonine chirality of threoninestereogenicamino acid amino centervia acid Cram served via‐ Cram-chelationchelation as a key control stereocenter control of the in of nucleophilicC the‐6 within nucleophilic legionamic addition addition acid[53]. [ 53(81The].). The newly newly generated generated stereogenicstereogenic center center served served as as a a key key stereocenter stereocenter inin C-6C‐6 within legionamic acid acid (81 (81).).

Scheme 16. De novo synthesis of orthogonally protected legionaminic acid 80. SchemeScheme 16. 16.De De novo novosynthesis synthesis ofof orthogonallyorthogonally protected protected legionaminic legionaminic acid acid 8080. . 8. Conclusions 8. Conclusions 8. ConclusionsNaturally occurring chiral pool α‐amino acids provide synthetic chemists with a powerful tool for theNaturally incorporation occurring of pivotal chiral stereocenterspool α‐amino in acids optically provide active synthetic natural chemistsproducts. with Until a now,powerful α‐amino tool Naturally occurring chiral pool α-amino acids provide synthetic chemists with a powerful tool acidsfor the have incorporation been exploited of pivotal for use stereocenters not only as in chiral optically sources active and natural devices, products. but also Until as chiral now, inducersα‐amino for the incorporation of pivotal stereocenters in optically active natural products. Until now, α-amino inacids strategies have been for exploitedthe synthesis for use of notcomplex only astarget chiral mo sourceslecules. and In devices,this review, but alsomany as applicationschiral inducers of acidsα‐in aminostrategies have beenacids for exploited as the chiral synthesis forinducers use of not complex in only a substrate as target chiral ‐mocontrolled sourceslecules. and Inmanner devices, this review, were but also specificallymany as chiralapplications discussed. inducers of in Toα‐amino establish acids challenging as chiral stereocenters inducers in ina naturalsubstrate product‐controlled architectures, manner thewere chirality specifically of α‐amino discussed. acids wasTo establish applied challengingto a remarkable stereocenters variety of in reactions, natural product such as architectures, rearrangement, the cy chiralityclization, of cycloaddition,α‐amino acids was applied to a remarkable variety of reactions, such as rearrangement, cyclization, cycloaddition,

Molecules 2016, 21, 951 10 of 13 strategies for the synthesis of complex target molecules. In this review, many applications of α-amino acids as chiral inducers in a substrate-controlled manner were speciﬁcally discussed. To establish challenging stereocenters in natural product architectures, the chirality of α-amino acids was applied to a remarkable variety of reactions, such as rearrangement, cyclization, cycloaddition, nucleophilic addition to carbonyls, and hydrogenation. To conclude, attempts at utilizing α-amino acids as chiral inducers for the creation of new stereogenic centers will continue.

Acknowledgments: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A1A02036681). Conﬂicts of Interest: The authors declare no conﬂict of interest.

Abbreviations The following abbreviations are used in this manuscript: Ac Acetyl Ala Alanine BBN Borabicyclo[3.3.1]nonane Bn Benzyl Boc t-Butoxycarbonyl Bu Butyl Cbz Benzyloxycarbonyl cod 1,5-Cyclooctadiene DCE 1,1-Dichloroethane DCC N,N'-Dicyclohexylcarbodiimide DIBAL-H Diisobutylaluminum hydride DMAP N,N-4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DTBP 2,6-Di-tert-butylpyridine Et Ethyl Fmoc 9-Fluorenylmethoxycarbonyl HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate KHMDS Potassium bis(trimethylsilyl)amide LDA Lithium diisopropylamide Leu Leucine LHMDS Lithium bis(trimethylsilyl)amide Me Methyl Mes Mesityl MS Molecular sieves MW Microwave NMO N-Methylmorpholine N-oxide Phe Phenylalanine TBAI Tetra-n-butylammonium iodide TBDPS t-Butyldiphenylsilyl TBS t-Butyldimethylsilyl Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran TIPS Triisopropylsilyl Trp Tryptophan Ts p-toluenesulfonyl

References

1. Casiraghi, G.; Zanardi, F. Stereoselective Approaches to Bioactive Carbohydrates and Alkaloids-With a Focus on Recent Syntheses Drawing from the Chiral Pool. Chem. Rev. 1995, 95, 1677–1716. [CrossRef] 2. Rouf, A.; Taneja, S.C. Synthesis of Single-enantiomer Bioactive Molecules: A Brief Overview. Chirality 2014, 26, 63–78. [CrossRef][PubMed] 3. Blaser, H.-U. The Chiral Pool as a Source of Enantioselective Catalysts and Auxiliaries. Chem. Rev. 1992, 92, 835–852. [CrossRef] 4. Nugent, W.A.; RajanBabu, T.V.; Burk, M.J. Beyond Nature’s Chiral Pool: Enantioselective Catalysis in Industry. Science 1993, 259, 479–483. [CrossRef][PubMed] Molecules 2016, 21, 951 11 of 13

5. Goti, A.; Cicchi, S.; Cordero, F.M.; Fedi, V.; Brandi, A. A Straightforward Route to Enantiopure Pyrrolizidines and Indolizidines by Cycloaddition to Pyrroline N-Oxides Derived from the Chiral Pool. Molecules 1999, 4, 1–12. [CrossRef] 6. Haleema, S.; Vavan Sasi, P.; Ibnusaud, I.; Polavarapu, P.L.; Kagan, H.B. Enantiomerically pure compounds related to chiral hydroxy acids derived from renewable resources. RSC Adv. 2012, 2, 9257–9285. [CrossRef] 7. Singh, P.; Samanta, K.; Das, S.K.; Panda, G. Amino acid chirons: a tool for asymmetric synthesis of heterocycles. Org. Biomol. Chem. 2014, 12, 6297–6339. [CrossRef][PubMed] 8. Yun, H.; Kim, J.; Sim, J.; Lee, S.; Han, Y.T.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. Asymmetric Syntheses of 1-Deoxy-6,8a-di-epi-castanospermine and 1-Deoxy-6-epi-castanospermine. J. Org. Chem. 2012, 77, 5389–5393. [CrossRef][PubMed] 9. Winchester, B.G.; Cenci di Bello, I.; Richardson, A.C.; Nash, R.J.; Fellows, L.E.; Ramsden, N.G.; Fleet, G. The structural basis of the inhibition of human glycosidases by castanospermine analogues. Biochem. J. 1990, 269, 227–231. [CrossRef][PubMed] 10. Paek, S.-M.; Kim, N.-J.; Shin, D.; Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. A Concise Total Synthesis of (+)-Tetrabenazine and (+)-α-Dihydrotetrabenazine. Chem. Eur. J. 2010, 16, 4623–4628. [CrossRef] [PubMed] 11. Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Use of 1,8-Diazabicyclo[5.4.0]undec-7-ene in Preparation of Trimethylsilyl Enol Ethers and Trimethylsilylacetylenes. Bull. Chem. Soc. Jpn. 1981, 54, 3229–3230. [CrossRef] 12. Reddy, A.S.; Srihari, P. A facile approach to the synthesis of securinega alkaloids: stereoselective total synthesis of (´)-allonorsecurinine. Tetrahedron Lett. 2012, 53, 5926–5928. [CrossRef] 13. Mercado-Marin, E.V.; Garcia-Reynaga, P.; Romminger, S.; Pimenta, E.F.; Romney, D.K.; Lodewyk, M.W.; Williams, D.E.; Andersen, R.J.; Miller, S.J.; Tantillo, D.J.; et al. Total synthesis and isolation of citrinalin and cyclopiamine congeners. Nature 2014, 509, 318–324. [CrossRef][PubMed] 14. Bond, R.F.; Boeyens, J.C.A.; Holzapfel, C.W.; Steyn, P.S. Cyclopiamines A and B, novel oxindole metabolites of Penicillium cyclopium westling. J. Chem. Soc. Perkin Trans. 1 1979, 1751–1761. [CrossRef] 15. Pimenta, E.F.; Vita-Marques, A.M.; Tininis, A.; Seleghim, M.H.R.; Sette, L.D.; Veloso, K.; Ferreira, A.G.; Williams, D.E.; Patrick, B.O.; Dalisay, D.S.; Andersen, R.J.; Berlinck, R.G.S. Use of Experimental Design for the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species. J. Nat. Prod. 2010, 73, 1821–1832. [CrossRef][PubMed] 16. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H. Synthetic approach towards tetrodotoxin. I. Diels-Alder reaction of α-oximinoethylbenzoquinones with butadiene. Tetrahedron Lett. 1970, 11, 5127–5128. [CrossRef] 17. Kim, J.H.; Lee, S.; Kim, S. Biomimetic Total Synthesis of (´)-Penibruguieramine A Using Memory of Chirality and Dynamic Kinetic Resolution. Angew. Chem. Int. Ed. 2015, 54, 10875–10878. [CrossRef][PubMed] 18. Zhou, Z.-F.; Kurtán, T.; Yang, X.-H.; Mándi, A.; Geng, M.-Y.; Ye, B.-P.; Taglialatela-Scafati, O.; Guo, Y.-W. Penibruguieramine A, a Novel Pyrrolizidine Alkaloid from the Endophytic Fungus Penicillium sp. GD6 Associated with Chinese Mangrove Bruguiera gymnorrhiza. Org. Lett. 2014, 16, 1390–1393. [CrossRef] [PubMed] 19. Kieffer, M.E.; Chuang, K.V.; Reisman, S.E. Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B. J. Am. Chem. Soc. 2013, 135, 5557–5560. [CrossRef] [PubMed] 20. Raju, R.; Piggott, A.M.; Conte, M.; Aalbersberg, W.G.L.; Feussner, K.; Capon, R.J. Naseseazines A and B: A New Dimeric Diketopiperazine Framework from a Marine-Derived Actinomycete, Streptomyces sp. Org. Lett. 2009, 11, 1390–1393. [CrossRef][PubMed] 21. Larock, R.C.; Yum, E.K. Synthesis of Indoles via Palladium-Catalyzed Heteroannulation of Internal Alkynes. J. Am. Chem. Soc. 1991, 113, 6690–6692. [CrossRef] 22. Garfunkle, J.; Kimball, F.S.; Trzupek, J.D.; Takizawa, S.; Shimamura, H.; Tomishima, M.; Boger, D.L. Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I. J. Am. Chem. Soc. 2009, 131, 16036–16038. [CrossRef][PubMed] 23. Ruchti, J.; Carreira, E.M. Ir-Catalyzed Reverse Prenylation of 3-Substituted Indoles: Total Synthesis of (+)-Aszonalenin and (´)-Brevicompanine B. J. Am. Chem. Soc. 2014, 136, 16756–16759. [CrossRef][PubMed] 24. Diebolt, O.; Tricas, H.; Freixa, Z.; van Leeuwen, P.W.N.M. Strong π-Acceptor Ligands in Rhodium-Catalyzed Hydroformylation of Ethene and 1-Octene: Operando Catalysis. ACS Catal. 2013, 3, 128–137. [CrossRef] Molecules 2016, 21, 951 12 of 13

25. Kusano, M.; Sotoma, G.; Koshino, H.; Uzawa, J.; Chijimatsu, M.; Fujioka, S.; Kawano, T.; Kimura, Y. Brevicompanines A and B: New plant growth regulators produced by the fungus, Penicillium brevicompactum. J. Chem. Soc. Perkin Trans. 1 1998, 1, 2823–2826. [CrossRef] 26. Kimura, Y.; Hamasaki, T.; Nakajima, H.; Isogai, A. Structure of aszonalenin, a new metabolite of aspergillus zonatus. Tetrahedron Lett. 1982, 23, 225–228. [CrossRef] 27. Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L.R.; Phil, S.B. Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation. J. Am. Chem. Soc. 2015, 137, 10160–10163. [CrossRef][PubMed] 28. Cole, R.J.; Kirksey, J.W.; Moore, J.H.; Blankenship, B.R.; Diener, U.L.; Davis, N.D. Tremorgenic Toxin from Penicillium verruculosum. Appl. Microbiol. 1972, 24, 248–250. [PubMed] 29. Yamazaki, M.; Suzuki, S.; Miyaki, K. Tremorgenic Toxins from Aspergillus fumigatus FRES. Chem. Pharm. Bull. 1971, 19, 1739–1740. [CrossRef][PubMed] 30. Shade, R.E.; Hyde, A.M.; Olsen, J.-C.; Merlic, C.A. Copper-Promoted Coupling of Vinyl Boronates and Alcohols: A Mild Synthesis of Allyl Vinyl Ethers. J. Am. Chem. Soc. 2010, 132, 1202–1203. [CrossRef] [PubMed] 31. Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama, H. Total Synthesis of (´)-Acetylaranotin. Angew. Chem. Int. Ed. 2012, 51, 13062–13065. [CrossRef][PubMed] 32. Nagarajan, R.; Huckstep, L.L.; Lively, D.H.; DeLong, D.C.; Marsh, M.M.; Neuss, N. Aranotin and Related Metabolites from Avachniofus Aureus I. Determination of Structure. J. Am. Chem. Soc. 1968, 90, 2980–2982. [CrossRef] 33. Wipf, P.; Kim, Y.; Goldstein, D.M. Asymmetric Total Synthesis of the Stemona Alkaloid (´)-Stenine. J. Am. Chem. Soc. 1995, 117, 11106–11112. [CrossRef] 34. Krishna, P.R.; Reddy, B.K. Total Synthesis of a Pyrrolidin-2-one with the Structure Proposed for the Alkaloid Rigidiusculamide A. Helv. Chim. Acta 2013, 96, 1564–1570. [CrossRef] 35. Li, J.; Liu, S.; Niu, S.; Zhuang, W.; Che, Y. Pyrrolidinones from the Ascomycete Fungus Albonectria rigidiuscula. J. Nat. Prod. 2009, 72, 2184–2187. [CrossRef][PubMed]

36. Vanrheenen, V.; Kelly, R.C.; Cha, D.Y. An improved catalytic OsO4 oxidation of oleﬁn to cis-1,2-glycols using tertiary amine oxides as the oxidant. Tetrahedron Lett. 1976, 17, 1973–1976. [CrossRef] 37. Luo, Z.; Zhou, B.; Li, Y. Total Synthesis of (´)-(α)-Kainic Acid via a Diastereoselective Intramolecular [3 + 2] Cycloaddition Reaction of an Aryl Cyclopropyl Ketone with an Alkyne. Org. Lett. 2012, 14, 2540–2543. [CrossRef][PubMed] 38. Murakami, S.; Takemoto, T.; Shimizu, Z. The effective principle of Digenea simplex Aq. I. Separation of the effective fraction by liquid chromatography. J. Pharm. Soc. Jpn. 1953, 73, 1026–1028. 39. Matveenko, M.; Liang, G.; Lauterwasser, E.M.W.; Zubía, E.; Trauner, D. A Total Synthesis Prompts the Structure Revision of Haouamine B. J. Am. Chem. Soc. 2012, 134, 9291–9295. [CrossRef][PubMed] 40. Garrido, L.; Zubía, E.; Ortega, M.J.; Salvá, J. Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum. J. Org. Chem. 2003, 68, 293–299. [CrossRef][PubMed] 41. Paladino, M.; Zaifman, J.; Ciufolini, M.A. Total Synthesis of (+)-3-Demethoxyerythratidinone and (+)-Erysotramidine via the Oxidative Amidation of a Phenol. Org. Lett. 2015, 17, 3422–3425. [CrossRef] [PubMed] 42. Ito, K.; Furukawa, H.; Haruna, M. Studies on the Erythrina Alkaloids. VII. Alkaloids of Erythrina arborescens ROXB. (2). Structures of New Alkaloids, Erysotramidine, Erytharbine and 11-Hydroxyerysotrine. Yakugaku Zasshi 1973, 93, 1617–1621. [PubMed] 43. Wipf, P.; Miller, C.P. A New Synthesis of Highly Functionalized Oxazoles. J. Org. Chem. 1993, 58, 3604–3606. [CrossRef] 44. Chow, Y.L.; Colòn, C.J.; Tan, J.N.S. A(1,3) interaction and conformational energy of axial-axial 1,3-dimethyl interaction. Can. J. Chem. 1968, 46, 2821–2825. [CrossRef] 45. Lunazzi, L.; Macciantelli, D.; Tassi, D.; Dondoni, A. Conformational studies by dynamic nuclear magnetic resonance. Part 17. Stereodynamic processes in hindered piperidyl-amides and -amidines. J. Chem. Soc. Perkin Trans. 2 1980, 717–723. [CrossRef] 46. Gouault, N.; Le Roch, M.; de Campos Pinto, G.; David, M. Total synthesis of dendrobate alkaloid (+)-241D, isosolenopsin and isosolenopsin A: application of a gold-catalyzed cyclization. Org. Biomol. Chem. 2012, 10, 5541–5546. [CrossRef][PubMed] Molecules 2016, 21, 951 13 of 13

47. Edwards, M.W.; Daly, J.W.; Myers, C.W. Alkaloids from a Panamanian Poison Frog, Dendrobates speciosus: Identification of Pumiliotoxin-A and Allo-pumiliotoxin Class Alkaloids, 3,5-Disubstituted Indolizidines, 5-Substituted 8-Methylindolizidines, and a 2-Methyl-6-nonyl-4-hydroxypiperidine. J. Nat. Prod. 1988, 51, 1188–1197. [CrossRef][PubMed] 48. Leclercq, S.; Daloze, D.; Braekman, J.C. Synthesis of the Fire Ant Alkaloids, Solenopsins. A Review. Org. Prep. Proced. Int. 1996, 28, 499–543. [CrossRef] 49. Gouault, N.; le Roch, M.; Cheignon, A.; Uriac, P.; David, M. Enantiospecific Synthesis of Pyridinones as Versatile Intermediates toward Asymmetric Piperidines. Org. Lett. 2011, 13, 4371–4373. [CrossRef][PubMed] 50. Matthies, S.; Stallforth, P.; Seeberger, P.H. Total Synthesis of Legionaminic Acid as Basis for Serological Studies. J. Am. Chem. Soc. 2015, 137, 2848–2851. [CrossRef][PubMed] 51. Zunk, M.; Kiefel, M.J. The occurrence and biological significance of the α-keto-sugars pseudaminic acid and legionaminic acid within pathogenic bacteria. RSC Adv. 2014, 4, 3413–3421. [CrossRef] 52. Liang, X.; Lee, C.-J.; Chen, X.; Chung, H.S.; Zeng, D.; Raetz, C.R.H.; Li, Y.; Zhou, P.; Toone, E.J. Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem. 2011, 19, 852–860. [CrossRef][PubMed] 53. Szechner, B.; Achmatowicz, O.; Galdecki, Z.; Fruziński,A. Synthesis and absolute configuration of four diastereoisomeric 1-(2-furyl)-2-aminobutane-1,3-diols. Tetrahedron 1994, 50, 7611–7624. [CrossRef]

© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).