Asymmetric Synthesis Utilizing Cascade Reactions

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MSc Chemistry

Molecular Sciences

Literature Thesis

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Asymmetric synthesis utilizing cascade reactions

Application of cascade reactions in total synthesis of complex natural compounds

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By Jurgen van Schaijk, 11958782

February 2021

12 EC

Primary examiner: Prof. Dr. Jan van Maarseveen

Secondary examiner: ---

Van ‘t Hoff Institute for Molecular Sciences

Synthetic Organic Chemistry

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

ABSTRACT

Total synthesis of natural products can usually become quite a lengthy series of synthetic steps. Although through this method the goal of the project can be reached, the issue is that the lengthy process is not only lengthy but also not atom economic. A partial solution to shorten these lengthy synthetic schemes and increase the atom economy, cascade reactions can be utilized. Cascade reactions, also known as domino or tandem reactions, is a chemical process consisting of at least two subsequent reactions where one transformation only occurs due to the previously formed chemical functionality. Isolation of intermediates is usually not observed, this is due to spontaneous nature of the sequence of reactions.

In this literature thesis we cover the different groups of cascade reactions and their applications in natural product synthesis. The cascade reactions can be categorized in the following groups: Nucleophilic-, electrophilic-, oganocatalytic-, pericyclic-, and radical cascades.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

LIST OF ABBREVIATIONS

AcOH acetic acid

AIBN azobisisobutyronitrile

Boc/Boc2O tert-Butoxycarbonyl/di-tert-butylcarbonate

DABCO 1,4-diazabicyclo[2.2. 2]octane

DCC N,N′-Dicyclohexylcarbodiimide

DCM dichloromethane

DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DIBAL diisobutylaluminium

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide

DPPA diphenylphosphoryl azide

KHMDS potassium bis(trimethylsilyl)amide

KI potassium iodide

LDA lithium diisopropylamide

MOM methoxymethyl

Phth phthalimide

PPA polyphosphoric acid

PTC phase-transfer catalysts

Py pyridine

TBAF tetra-n-butylamonium fluoride

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TEA triethyl amine

TFA trifluoroacetic acid

TfOH trifluoromethanesulfonic acid

THF tertrahydro furan

TMS tetrramethylsilane

TMSO trimethylsilyl ether

D2-He

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

CONTENTS

Abstract ...... 3

List of Abbreviations ...... 4

Introduction ...... 6

Early work in Cascade reactions ...... 8

Types of cascades ...... 9

Nuclephillic / electrophilic cascades ...... 9

Organocatalytic cascades ...... 10

Radical cascades ...... 11

Pericyclic cascades ...... 12

Goals of this thesis...... 14

Cascade reactions in asymmetric synthesis ...... 15

Chiral auxiliaries ...... 15

Cation-mediated cascade reactions ...... 15

Anion-mediate asymmetric cascade reactions ...... 23

Pericyclic cascades ...... 27

Radical cascades ...... 32

Conclusion and OUTLOOK ...... 36

Acknowledgements ...... 38

References ...... 39

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

INTRODUCTION

Development over the past decades in synthetic organic chemistry has influenced the field in fascinating ways. A considerable number of highly selective procedures have come to light which allow for the synthesis of complex molecules with excellent regio-, chemo-, diastereo-, and enantioselectivity.1 Amongst these is an incredible example for the synthesis of palytoxin, which contains 64 stereogenic centers and of which over 1019 different stereoisomers could exist.2 Despite such a great success, society’s image of chemistry has deteriorated, which could be explained by the increasing importance of environmental issues and the negative influence organic chemistry can have on the ecological balance.2

It is no longer only important what we can synthesize, but also how we go about it. Important issues in chemical production are the handling of chemical waste, the search for environmentally friendly/tolerable procedures, preservation of resources, and the increase of efficiency. Solution to these problems are not only important for the environmental concerns, but these also aid in the reduction of production costs.

FIGURE 1. STRUCTURE OF PALYTOXIN.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

Traditional procedures for the synthesis of compounds are usually conducted in a stepwise fashion, forming individual bonds one step at a time. A viable alternative to such a stepwise procedure would be the utilization of cascade type reactions. The utilization of cascade reactions grants organic chemists the ability to synthesize complex structures in one-pot reactions without the necessity to isolate intermediates. Chemical transformations with such an approach offer efficiency, economic benefits and relatively ecologically benign synthesis; a must for every organic chemist.3 The usefulness of cascade reactions is correlated by the number of bonds which are formed in a single sequence (called bond-forming efficiency), the increase in structural complexity, and whether it is suitable for general application.2 Cascade reactions can fall under the banner of “green chemistry”, this is due to the considerable savings involved when a single reaction step carries out several transformations.4 Consideration to follow the guidelines of “green chemistry” will become increasingly important in the future because both chemists and society in general will strive for increasingly more efficient and responsible methods for the management of natural resources.

In their review of cascade reactions (2006), Nicolaou et al. wrote: “Target-oriented synthesis provides the ultimate test of reaction design and applicability. The design of cascades to provide specific targeted molecules of considerable structural and stereochemical complexity poses a significant intellectual challenge and can be one of the most impressive activities in natural product synthesis. Cascade reactions therefore contribute immeasurably to both the science and art of total synthesis, bringing not only improved practical efficiency but also enhanced aesthetic appeal to synthetic planning. The recognition of these dual benefits is, of course, by no means an exclusively modern phenomenon. Indeed, cascade reactions (either as designed sequences or serendipitous discoveries) have attracted the attention of organic chemists since the formative years of total synthesis.”4

Tietze has defined a domino/cascade as reaction which involves two or more bond-forming transformations which take place under the same reaction conditions without adding additional reagents or catalysts, and in which the subsequent reactions only result as a consequence of the functionality formation derived from a previous transformation step. The quality and meaningfulness of a cascade reaction correlates strongly with the both the number of transformations that take place and the increase of the level of complexity in the molecule. Cascades can be performed as single-, two- and multicomponent reactions, therefore most (but not all) multicomponent reactions could be defined as a subgroup of cascade reactions. In the following sections the types of cascade reactions will be covered.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

EARLY WORK IN CASCADE REACTIONS

Arguably the first reported cascade reaction is in the total synthesis of tropinone by Robinson in 1917, it is considered a classic in total synthesis due to its simplicity and biomimetric approach. The synthesis is a good example of a biomimetric reaction or biogenetic reaction because the biosynthesis utilizes the same building blocks. The double mannich type reaction sequence/ cascade is initiated by the nucleophilic addition of methylamine to succinaldehyde, followed by the loss of water to generate the imine. Intramolecular addition of the imine to second aldehyde moiety concludes the first ring closure reaction. The enolate of acetone dicarboxylate performs an intermolecular mannich reaction onto the previously formed ring. Another enolate formation and imine formation followed by the loss of water forms the precursor for the second intramolecular Mannich reaction, acting as the second ring closure. Loss of both the carboxylic groups then completes the total synthesis of Tropinone.5

SCHEME 1. CASCADE REACTION TOWARDS THE TOTAL SYNTHESIS OF TROPINONE.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

TYPES OF CASCADES

NUCLEPHILLIC / ELECTROPHILIC CASCADES These types of cascades are constituted as such because the key step that initiates the cascade reaction is either a nucleophilic or electrophilic attack. Tetronasin is an acyltetronic acid polyether ionophore antibiotic, reported by ICI and Swiss Sandoz scientist in the early 1980’s.1 The natural compound is produced by Streptomyces longisporoflavus, it is of considerable commercial interest due to its biological activity as an antibiotic, antiparasitic and as a growth promoting agent in ruminants.2,3 The compounds unusual structure and properties have been made it the subject of extensive biosynthetic and synthetic studies.4,6 Tetronasin 1 posed as a significant synthetic challenge due to its characteristic twelve stereogenic centers, three different heterocyclic ring systems, two stereodefined alkenes and a triequatorially substituted cyclohexane unit (scheme 2).6

SCHEME 2. NUCLEOPHILLIC CASCADE REACTION IN THE SYNTHESIS OF TETRONASIN I.

Compound 2 is the precursor for the cascade reaction, it contains all the elements necessary to be able to undergo a metal mediated polyene cyclization. The secondary hydroxyl group is ideally placed to undergo a conjugate addition reaction to the acceptor dienic ester unit, through resonance this can result in the corresponding enolate 3 which then undergoes a secondary cyclization via a Michael addition to the terminal methyl acrylate moiety to generate the cyclohexyl ring of the natural product, this entire reaction

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis sequence is initiated with treatment of compound 1 with potassium hexamethyldisilazide in toluene at 0°C giving one single product.

ORGANOCATALYTIC CASCADES A subgroup of nucleophilic cascade reactions is also the organocatalyzed nucleophilic cascade reactions involving a nucleophile that is not incorporated into the product. A natural occurring compound, (+)-harziphilone, acts as an inhibitor of the binding interaction between the HIV-1 Rev protein and the Rev-responsive element (RRE) of viral mRNA The enantioselective total synthesis of (+)-harziphilone by J. Sorensen et. Al. was devised utilizing a heteroatom nucleophile that could act as an organocatalyst to induce the nucleophilic cascade reaction (scheme 3). To generate the oxacyclic ring of harziphilone, it was postulated that this could arise from a 6π-electrocyclization from compound 9. Containing several electrophilic sites and a high degree of unsaturation, it was perceived as challenging objective for synthesis. Therefore, interesting to explore whether this reactive species could be generated in situ from the doubly activated, polyunsaturated acyclic compound 5.6,7,8

SCHEME 3. ORGANOCATALYTIC CASCADE REACTION FOR THE TOTAL SYNTHETIS OF (+)-HARZIPHILONE.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

In this cascade reaction, DABCO acts as a nucleophile and adds to the unsubstituted enone system of 5, this affords the Baylis-Hillman-like zwitterion 6.From this intermediate, an intramolecular carbon- carbon bond formation and proton transfer potentially generates the zwitterion intermediate 7. A β- elimination reaction then returns the nucleophilic organocatalyst to the reaction medium to afford the favorably positioned diene 9, which enables the final 6π-electrocyclization to afford (+)-harziphilone. Another possibility for final oxacyclic ring formation could arise from zwitterion 8 via an intramolecular displacement of DABCO, also affording (+)-harziphilone.

RADICAL CASCADES In this type of cascade, the key step constitutes a radical reaction. Radical-based synthetic approaches are very suitable for cascade reactions due to their high reactivity and relatively unstable intermediates. One such impressive radical induced cascade reactions been used for the total synthesis of (-)-morphine (scheme 4), as reported by Parker and Fokas in 1992. Their synthetic approach of the morphine ring system was based on the cascade cyclization of an ortho allyloxy aryl radical intermediate.

SCHEME 4. RADICAL CASCADE REACTION OF (-)-MORPHINE BY FOKAS ET. AL.

In this reaction scheme, bromoaryl ether 10 was heated Bu3SnH and AIBN in benzene to 130°C, this formed the aryl radical 11 which then attacks the nearest and most substituted position of the double bond of the cyclohexene ring, thus forming the 5-membered furan ring of 12. This reaction also generated

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis a radical on the lesser substituted carbon of the double bond in the cyclohexene ring, which then attacks the β-carbon of the styrene double bond to form 13, elimination of the phenylthiol group of the styryl radical would give compound 14 in 30% yield. The final ring is formed through the deprotection of tosylamide RRR, forming a nitogen radical anion which reductively adds to the double bond, forming dihydroisocodeine. Several extra steps involving a Swern oxidation of dihydroisocodeine followed by a O- demethylation finally affored (-)-morphine.9-14

PERICYCLIC CASCADES Perhaps the most widely used and encountered type of cascade reactions is arguably the pericyclic reaction, this includes electrocyclizations, sigma tropic rearrangements and cycloadditions. Some of the previously discussed nucleophilic/electrophilic and radical type cascades did involve a pericyclic reaction, this section however is comprised solely of pericyclic reactions that embody the key step. The following example of pericyclic cascade reactions is focused on the synthesis of endiandric acid’s A-G, as reported by Nicolaou et al in 2009. This total synthesis utilizes two types of pericyclic reactions, twice an electrocyclization (8π e- and 6π e electrocyclization) and once a cycloaddition (Diels-Alder). 15,16,17,18

For their total synthesis of the endiandric acids, they started from the polyunsaturated methylester 15, which contained the necessary geometrical aspects, was subjected to reductive conditions utilizing Lindlar’s catalyst producing the cis-disposed central olefinic bond. The intermediate spontaneously undergoes a 8π electrocyclization followed immediately by a 6π electrocyclization (all of these electrocyclizations are reversibe) giving a mixture of both endrianic acid A and D methylester. Upon heating it was observed that exclusively endriandric acid A methylester was produced, as Black et al. postulated, the reversible nature of the electrocyclization reactions allow for an 6π electrocyclic opening, a ring flip, and subsequent 6π electrocyclization to endriandric acid E, which can spontaneously and irreversibly undergo an intramolecular Diels-Alder cyclization to deliver endriandric acid A. To synthesize endiandric acids B and C, the exact same procedure was followed, only starting from polyunsaturated methylester 16.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 5. CASCADE REACTIONS TO A VARIETY OF ENDIANDRIC ACIDS.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

GOALS OF THIS THESIS

The organic transformations discussed in the previous section are used to illustrate early work of organic chemists in cascade reactions. Since the report of cascade reactions in organic synthesis, researchers have come a long way in discovering and utilizing these “multi-step” organic transformations for the asymmetric total synthesis of polycyclic natural products. Almost all asymmetric cascade reactions can be classified into the following categories: cation -mediated (electrophilic), anion-mediated (nucleophilic), pericyclic, radical. This thesis will present an overview of the achievements in total synthesis of natural products utilizing asymmetric cascade reactions and discuss the manners and methods utilized in these syntheses to allow for the asymmetric cascades and syntheses of all of the following natural products as well as potential modifications of reaction conditions and/or substrates to enhance the yield and/or selectivity of the cascade sequences. .

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

CASCADE REACTIONS IN ASYMMETRIC SYNTHESIS

CHIRAL AUXILIARIES

Chiral auxiliaries are stereo genic groups that are temporarily incorporated into a molecule with the purpose of controlling the stereochemical outcome of the synthesis, the chirality incorporated via the auxiliary can favor stereoselectivity of one or more subsequent reactions. The vast majority of biological and pharmaceutical molecules exist as one of two possible enantiomers, hence chemical synthesis of natural products and pharmaceutical compounds are designed to obtain these compounds in an enantiomerically pure form. Therefore chiral auxiliaries are one of many key strategies for chemists to selectively synthesize the desired stereoisomer of a compound. 19, 20, 21

CATION-MEDIATED CASCADE REACTIONS

Cationic sequences are one of the oldest types of cascade reactions known. The cascade is usually initiated by formation of a carbocation by elimination, addition, or by a positive particle. The cascade is then initiated by attack onto the carbocation by a nucleophile which then forms another cation, the reaction continues until the carbocation is trapped by a nucleophile or stabilized by elimination of a proton. 21

Many cationic cascade reactions towards natural products involve the formation of oxonium intermediates that undergo several transformations, amongst these is the isoprenoid Pinnatolide. Bohlmann et al. isolated the isoprenoid from the aerial parts of Athanasia species, either Athanasia pinnata or crithmifolia, which are flowering plants of the daisy family. Bohlmann determined its structure but did not give its absolute configuration of the stereocenter, in addition to this, neither the optical rotation nor CD spectrum are available. In 2012, Tietze et al. reported the first enantioselective total synthesis of (+)- (R)-Pinnatolide utilizing an asymmetric domino allylation reaction via an oxonium intermediate. Although there are several selective methods for both aryl and α,β-unsaturated alkyl ketones known, at the time Tietze’s method was the only procedure which provided high selectivities for the allylation of saturated alkyl ketones with the advantage of forming cyclic ethers from the obtained tertiary alcohols whilst utilizing a benzyl protecting group. 22

Starting from the commercially available methyl levulinate 17, this was treated with allytrimethylsilane in the presence of trimethylsilyl ether of (R)-phenylbenzylcarbinol (>99% ee) and a

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis catalytic amount triflic acid in DCM at -78°C afforded the homoallylic ether (R,R)-18, in 91% yield with a diastereoselectivity of 94:6. The mechanisms of this stereoselective cascade reaction proceeds via an oxenium ion intermediate 19 of the chiral auxiliary and the saturated ketone, this intermediate can then favorably be attacked by the allylsilane from the si-face. The transition state, showing the most favored stereochemical orientation, is exemplified as 20 in scheme 6. The selectivity of the reaction can be explained by the high steric demand of the phenylbenzyl group of the chiral auxiliary on the Re face of the reactive intermediate/transition state. The cascade is terminated by elimation of the silane side group adjacent to the carbocation which generates the allylic ester compound 22 in 91% yield with the dr of 94:1.

From homoallylic ether 22 towards the natural product, the next step is ozonolysis of the allylic moiety to the aldehyde. The homoallylic ether 22 is ozonolyized at -78°C in DCM/methanol (10:1) with triphenylphosphine as a peroxide scavenger, this reaction affords the diastereomeric mixture of aldehyde which is then reduced with NaBH4 afforded alcohol (R,R)-23 98% yield (dr 94:6).

Hydrogenolysis of alcohol 23 with catalytic amounts of palladium on charcoal in THF/methanol with 1 bar of H2 at 45°C afforded γ-lactone alcohol (R)-24 in quantitative yield and >99% ee. Mild oxidation of (R)-24 with Dess-Martin peiodinane in DCM at 0°C gave labile -lactone aldehyde 25, without any purification the crude was subsequently treated with dimethylvinyl Grignard reagent in THF at -60°C to afford allylic alcohol 26 in 40% yield over the two steps, giving an approximate 1:1 mixture of epimers. The final step of the reaction, DMP oxidation of the alcohol (5R)-26 in DCM at ambient temperature led to (+)- (R)-Pinnatoide in 90% yield.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 6. ASYMMETRIC TOTAL SYNTHESIS OF (+)-PINNATOLIDE

In 2019, Takaya et. al. reported the shortest asymmetric total synthesis of (-)-lycopedine as well as the first total asymmetric total synthesis of flabelliformine via a cascade cyclization reaction involving the generation of an oxonium species which initiates the domino cascade reaction. The synthesis is initiated by preparation of the linear cascade cyclization substrate 35. Commercially available crotonamide 27 is subjected to Hosomi-Sakurai allylation to generate 28 in high yield and diastereoselectivity (87%, dr 22.3 : 1), the stereochemistry of the methyl-substituent at the C15 position is the same as in (-)-lycopodine. Compound 28 was converted to thioester 29 by treatment with lithium thiolate which resulted in the successful removal of the Evan’s oxazolidinone moiety in 88% yield. Thioester was then coupled to iodine

30 in the presence of zinc and 5 mol% of PdCl2(PPh3)2 giving allylic ketone 31 in good yield (88%). In tandem, the thioester of crotonic acid 32 was prepared and then immediately subjected to Fukuyama coupling

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis with iodine 33 to give enone 34 in 86% yield. The obtained ketone 31 and enone 34 were introduced to a second-generation Hoveyda-Grubbs catalysts to undergo olefin cross metathesis to give the desired linear substrate 35. 23, 24

SCHEME 7. SYNTHESIS OF CASCADE SUBSTRATE FOR LYCOPODINE ALKALKOID.

With the linear cascade cyclization substrate 35 in hand, it was treated with methane sulfonic acid in methanol at 40°C to obtain the desired compound 37a in 11% yield and its diastereomeric isomer in 28% yield. Treatment of the substrate 35 with methanesulfonic acid deprotected the bis Boc-protected amine side group as well as the TBDPS protected alcohol side group, generating a free amine side group and a cyclic oxenium side group, compounds 36a. The cascade reaction involves the nucleophilic attack of the aminic moiety on the allylic position of the enone moiety which simultaneously forms three new cyclic systems, forming compounds 37a and 37b in 11% and 28% yield, respectively.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 8. CASCADE REACTION IN THE SYNTHESIS OF (-)-LYCOPODINE.

From tetracyclic intermediate 37a, the total synthesis of both (-)-lycopodine and flabelliformine is completed by treatment of 37a with HBR in AcOH at room temperature to give ammonium bromide salt 38, this was treated with NaOH to initiate pyrrolidine ring formation and completing the total synthesis, giving (-)-lycopodine in 80% yield from the last step. From this point, α-hydroxilation of (-)-lycopodine on the ketonic position gave flabelliformine in 46% yield over the final step, thus completing the shortest ever asymmetric total synthesis of both (-)-lycopedine and flabelliformine. The selectivity of this synthesis can be attributed towards the formation of the most stable conformations of the intermediates that are initially formed during the cascade reaction, the formation and orientation here of perfectly position the reactive sites for the subsequent transformation, thus allowing for the formations of the four newly generated cyclic systems in a single step. In this total synthesis, a possible modification which would involve the installation of a chiral auxiliary (perhaps a ethyl 1-(4-methoxyphenyl substituent) onto the amine moiety as opposed to it having two Boc-groups could potentially significantly slow down the formation of 36b and therefore inversely increase the formation of 36a, and therefore improve the yield of 37a, making this cascade considerably more selective and efficient.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 9. FINAL STEPS TOWARDS THE ASYMMETRIC TOTAL SYNTHESIS OF (-)-LYCOPODINE AND FLABELLIFORMINE.

Iminium ion mediated cascade reactions are often employed to form heterocyclic rings in total synthesis, Pandey et. al. (2018) reported the asymmetric total synthesis of aspidosperma alkaloids vincadifformine and ervinceine. Their asymmetric total synthesis of these alkaloids is enabled by their iminium ion-enamine cascade reaction that in one step generates two new rings, two new stereogenic enters, and three new sigma bonds. Although a great deal of synthetic efforts have been reported regarding the synthesis of aspidosperma alkaloids, both racemic and enantioselective, most of these have relied on a synthetic procedure that proceed by an intramolecular Diels-Alder type cycloaddition reaction. 25, 26

The synthesis was initiated by preparation of the cascade reaction precursors, both 45 and 47. Compound 39 was prepared from commercially available 2-chloronicotnic acid and (S)-prolinol, followed by functional group transformation to give 39. From here, 39 was subjected to Birch reduction-alkylation using allylic bromide which gave 40 in 46% yield as a single diastereomer after single crystallisation in dichloromethane-n-pentane. The great diastereoselectivity of this reaction is caused by the involvement of the rigid molecular structure of the enolate intermediate where the proline stereocenters preferentially direct the alkylation from the β-face. Compound 40 was then treated with CH3COOH:THF:H2O (1:1:8) at room temperature to selectively break the ether bond, giving 41 in 89% yield. This was then subjected to methanolysis with copper (II) triflate in methanol to obtain 42 in 87% yield and with excellent enantioselectivity (>99%). The terminal olefinic functionality of 42 was reduced by one carbon atom via sequential oxidative cleavage with OsO4/NaIO4, dithioacetalization (with (1,3-propanedithiol, BF3·OEt2,

CH2Cl2) of the resulting aldehyde which is then immediately subjected to reductive desulfurization (Raney

Nickel, H2, EtOH, reflux) to afford 43 in 53% yield over three steps. Compound 43 as reduced under Luche’s conditions which was immediately followed by tosylation of the generated alcoholic moiety to produce 44 in 73% yield. Finally, N-Boc protection followed by reduction of de amide with DIBAL-H resulted in the

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis corresponding hemiaminal, which was subsequently treated with TFA in DCM to afford chiral imine 45 in 83% yield over three steps (>99%ee).

SCHEME 10. SYNTHESIS OF CASCADE SUBSTRATE IN THE TOTAL SYNTHESIS OF (+)=VINCADIFFORMINE.

Indoleic compound 47 was synthesized from commercially available 3-(2-chloroethyl)-1H-indole (46). Initial treatment of 3-(2-chloroethyl)-1H-indole with tert-butyl hypochlorite in the presence of TEA generates chloro-substituted C3 indolenine, subsequent treatment with BF3·OEt2 generates the C2 alkylated indole with ethanol. Addition of the ketene induces nucleophilic attack of the ketene onto the C2 position of the indole, simultaneously expelling the ethoxy substituent, providing substrate 47 in 61% yield.

With the cascade substrates in hand, both 45 and 47 were combined and treated with KI in DMF which initiated the cascade reaction. Sn2 of 45 onto the ethyl side group of the indole generates the reactive species that will undergo the cascade sequence. Upon formation of iminium ion 48, this initiates the spirocyclization to give the tetracyclic intermediates 49a and 49b, now due to the close proximity of the nucleophilic carbon center of enamine 49a to the electrophilic iodometylene group, it can be transformed to (+)-vincadiformine with a 35% yield. The low yield is arguably caused by the simultaneous

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis formation of 49b, which potentially could undergo Curtin-Hamett equilibration to still give rise to 49a and thus (+)-vincadiformine but could also decompose to some other compound, in-situ decomposition of 47 could also be add to. The selectivity in this synthesis of (+)-vincadifformine can be attributed to the utilization of the chiral substrate 45. The low yield could perhaps be improved by the utilization of a chiral phosphoric acid or phosphonate. Lowering the temperature of the reaction could allow more time for a chiral phosphonate or phosphoric acid to coordinate and then prevent the formation of 49b, then presumably increasing the yield and efficiency of this reaction. Utilization of phosphoric acids and phosphonates in the spirocyclization of indoles has previously been reported by Xia et. al.47

SCHEME 11. CASCADE REACTION IN THE TOTAL SYNTHESIS OF (+)-VINCADIFFORMINE.

The cascade reactions of this chapter showed a variety of cationic/electrophile-mediated reaction sequences that allowed for the asymmetric syntehses of one heterocycle for (+)-pinnatolide, three new cyclic systems for (+)-vincadifformine, and four new cyclic systems for (-)-lycopodeine. These cascades employed the formation of both oxonium and iminium ion species as key intermediates that allow for subsequent organic transformations. This shows the range of the number of cyclic systems that could be generated in a single transformational step, not to mention the number of new chiral centers generated during these same reactions. Within the synthesis of (-)-lycopedeine, utilization of a chiral auxiliary on the amine functional group could potentially significantly affect the selectivity of the generated intermediates,

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis if this could be controlled, the reaction conditions could be somewhat modified to increase the yield and also the efficiency of this total synthesis. Another potential modification of these cascade reactions could be applied to the total synthesis of (+)-vincadifformine, as mentioned, the utilization of a chiral phosphoric acid or phosphonate which could ligate in situ to reactive intermediate to favor the continuation of the cascade for only one of the in situ generated enantiomers and thus increasing both the yield and selectivity of the cascade reaction.

ANION-MEDIATE ASYMMETRIC CASCADE REACTIONS

The largest family of cascade reactions are anion-mediated cascade reactions, here an anion or nucleophile is generated by simple deprotonation, which then reacts with an electrophile, in turn generating another anionic functionality, the cascade ends when the anionic functionality is captured by a proton or by elimination of an X- group. A great deal of anionic cascade reactions involve Michael- initiated or -terminated processes to generate cyclic structures.21

In 2015 Tomioka et al. reported a short synthesis of (+)-β-lycorane via an asymmetric conjugate addition/ Michael cascade reaction. Their synthetic strategy starts from the asymmetric conjugate addition of aryllithium 50 to nona-2,7-dienedioate 51, which is mediated by a chiral ligand (scheme 12). The generated lithium enolate 52 subsequently undergoes an intramolecular Michael reaction which afforded the trisubstituted cyclohexane 53 with three contiguous stereogenic centres in 68% yield and an ee of 99%. The diastereoselectivity of the cascade reaction is induced by the preferential intramolecular Michael reaction with conformer 52a as opposed to conformer 52b due to the absence of 1,3-diaxial repulsion of the alkenoate moiety that is observed in conformer 52b. Compound 53 is subsequently treated with HCl in ethanol to give the protodesilylated half ester 54 in 98% yield. This is then subjected to Curtius rearrangement with diphenylphosphoryl azide and followed by Bischler-Napieralsky type cyclization with polyphosphoric acid to give lactam 55 in 70% yield. Final treatment of lactam 55 with borane-dimethyl sulfide complex and refluxing in THF induced three sequential transformations, initially reduction of the lactam, lactam formation of the generated amine and the proximate ester, then final reduction of this lactam to directly give (+)-β-lycorane in 70% yield over the final step. The asymmetric anionic cascade mediated synthesis of (+)-β-lycorane was completed in 5 steps from the dieneoate species. Although the yield and selectivity of this cascade reaction is good 27, 28, 29, 30

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 12. ASSYMETRIC CASCADE REACTION OF (+)-Β-LYCORANE.

Han et. Al., in 2019, reported the enantioselective total synthesis of (+)-tronocarpine which was enabled by an asymmetric cascade reaction. Starting from the commercially available tryptamine, several manipulations provided the substrate 56 for the Michael/Aldol cascade reaction. To achieve the asymmetric reaction cascade reaction they proposed the use cinchona bases as chiral phase-transfer catalysts (PTCs) and is essential for the asymmetric reaction due to its bifunctional ion-pairing/H-bonding interaction activity. The cascade reaction of 56 with acrolein proceeded under basic conditions with aqeoous KOH in Et2O/CHCl3, 57 was obtained in 67% yield with 93% ee. The Phth group was removed and the amine was immediately methoxycarbonyl protected, the alcoholic moiety was oxidized to the ketone with Dess-Martin periodinane to produce 58 in 50% yield over 3 steps. Treatment of 58 with Raney Nickel initiated a tandem process which involved reduction of the cyanogroup and concomitant intramolecular hemiamidation with the carbamate to form the seven-membered hemiaminal 59. 30, 31, 32 It could be interesting to modify compound 51 to a nitroalkene, which could reduce additional steps in this reaction.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 13. CASCADE SEQUENCE AND TOTAL SYNTHESIS OF TRONOCARPINE.

Subsequent oxidation of 59 delivered lactam 60 in 53% yield over two steps. Next was the direct α,β-oxidative dehydrogenation utilizing a modified process as reported by Diao and Stahl, Treatment of

60 with Pd(OAc)2, Cu(OAc)2, O2, and DMSO at 60°C produced α,β-unsaturated ketone 61 in 77% yield. Iodination of 61 provided α-iodinated enone 62 in 99.2% ee. Sonogashira cross-coupling with ethynyltrimethylsilane provided alkyne 63. Removal of the CO2Me protecting group on the amide proceeded under initial treatment with CeCl3, i-PrOH in THF, followed by treatment with NaBH4 to give the free 7-membered lactam 64 in 75% yield. Deoxygenation of Lactam proceeded efficiently through a two-step procedure which involved the formation xanthate followed by Barton-McCombie radical deoxygenation to deliver 65 in 60% yield over the two steps. This was then treated with LiEt3BH to selective reduce the indolyl-lactam to hemiaminal 66 as a single diastereoisomer. Desilylation of

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis hemiaminal was realized with treatment of TBAF to afford alkyne 67 in 88% yield. To finalize the synthesis of tronocarpine, alkyne HESt was subjected to mercury-catalyzed alkyne hyrdration and acid- promoted concomitant inversion of the β-OH to the thermodynamically more stable α-OH center completed the asymmetric total synthesis of tronocarpine. The utlizization of a cinchona derived phase- transfer catalysts does have a significant effect on the stereoselectivity of the cascade reaction that forms the important skeletal structure of (+)-tronocarpine, it is however important to be aware of the availability and human/environmental toxicity of chemicals such as acrolein. It is of course difficult to realize a suitable alternative. The cascade sequence from 56 to 57 utilizes a Michael/aldol reaction, perhaps the propenal moiety could already be substituted on the primary aminic position of tryptamine. The potential reactive species could be an tethered amide with an unsaturated propenal functionality on the -position of the amide. If this species is feasible, this might allow this reaction to become an intramolecular Michael/aldol reaction which includes a lactamization, meaning that two new cyclic systems would be created as well as two new chiral centers. . This would also require that the nitrile not be previously installed in 56. Furthermore it would likely still be necessary to utilize the cinchona derived phase transfer catalyst to facilitate the asymmetric cascade sequence.

The anionic cascade sequences for the syntheses of (+)-β-lycorane of this chapter proceded via an asymmetric conjugate addition reaction as opposed to the Michael/Aldol reaction utilized in the total synthesis of (+)-tronocarpine. Some of the selectivity of the selectivity of the these cascade reactions can be attributed to the utilization of a chiral ligand and utliziation of a cinchona type PTC, respectively.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

PERICYCLIC CASCADES

Pericyclic cascade reactions are possibly the most encountered type of cascade reaction, these pericyclic reactions include cycloadditions, electrocyclizations and sigmatropic rearrangements. The combination of 8π-6π electrocyclization cascade sequences with a cycloadditions has been implicated in the biosynthesis of a variety of natural products, amongst these are the previously discussed endriandric acid alkaloids. The biosynthesis for these alkaloids involves the conrotatory 8π electrocyclization to yield a cycloocatriene illustrated in scheme 5, this intermediate subsequently undergoes disrotatory 6π electrocyclization to generate a bycyclic system consisting of hexadiene group adjacent to trans substituted cyclobutene group. As seen in scheme 5, this then undergoes a formal Diels-Alder reaction to generate endiandric acid C. additionally, other alkaloids such as kingianin A undergoes a similar sequence of electocyclizations and Diels-Alder to form a significantly different end product. 33, 34

Trauner et al. reported the bioinspired synthesis of (-)-PF-1018 by combining a cascade sequence of an 8π electrocyclization followed by an immediate Diels-Alder reaction. The success of their cascade reaction can be attributed to the substitution pattern of the starting polyene substrate. The total synthesis began by the asymmetric addition of the Brown’s chiral allyl borane 69 to aldehyde 68 which gave the MOM protected diol 70 in 60% yield and 96% ee. This was then subjected to olefin cross-metatheses with methyl acrylate and subsequently immediately converted to the silyl ether 71 in 59% yield over two steps. This unsaturated ester was subjected to cross-coupling with the alkenyl stannane under Stille-Liebeskind conditions.

The cross coupling product 73 initially underwent 8π-electrocyclization to generate intermediate 74, this subsequently underwent a [4+2] Diels-Alder reaction to 75. This pericyclic cascade sequence generated three new cyclic systems in a single step. This reflects the strong torquoselectivity (rottional directionality of the conrotatory cyclization) which is attributed to the specific helical arrangement of cyclizing tetraene. It is also interesting that this reaction avoids the competing 6-electrocyclization which is partly due to the tortsional strain that is possibly caused by the methyl and enoate side chain in the necessary planar arrangement of the 8-membred ring. The group utilized some DFT calculations to determine what allows for the selectivity of the reaction, what they concluded from these calculations are that both the MOM and silyl ether groups are responsible for the formation of 75 as the only product of this cascade sequence.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 14. SUBSTRATE SYNTHESIS AND PERICYCLIC CASCADE REACTION OF (-)-PF-1018

From here, the cascade product 75 was treated with TBAF to cleave the silyl ether to give the corresponding secondary alcohol 76, this was then converted to its benzyl xanthate derivative 77. The benzyl xanthate group was subjected to Barton-McCombie deoxygenation to give the MOM ether compound 78. The MOM ether was cleaved under modified Fujioka conditions and was then immediately oxidized to ketone 79 with Dess-Martin periodinane. The ketone in 79 was converted to the enol triflate, which was then subjected to Negishi coupling, this installed the olefinic double bond. Subsequent reduction pf the methyl ester with DIBAL gave primary alcohol 80 in 56% yield over three steps. The final steps in the total synthesis involve the oxidation of the primary alcohol to the unstable aldehyde with DMP, this was then immediately condensed with the tetramic acid phosphonate 81, this gave (-)-PF-1018 and its Isomer in a 3.5:1 mixture and a 47% yield over the two steps. 35, 36, 37, 38

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

SCHEME 15. COMPLETION OF TOTAL SYNTHESIS OF (-)-PF-108 BY TRAUNER ET. AL.

In 2013, Liu et. al. reported the total synthesis of Bolivianine via an intramolecular Hetero Diels- Alder cascade approach. Their total synthesis starts from the commercially available (+)-verbeneone which was subjected to Michael addition using the vinyl magnesiumbromide with copper iodide to generate 83 in 86% yield. This was then followed by cyclobutane opening by addition of Zn(OAc)2 and BF3·EtO2 in Ac2O which generated the enolacetate 84. This was then directly transformed to the 1,3-dioxolane 85 in the presence of acid. Allylic oxidations and subsequent Luche reduction afforded compound 86 in 71% yield. Next was the metal catalysed cyclopropanation via an allylic carbenoid intermediate 87 that which then gives 88 in 65% yield as the only diastereomer. This approached produces an active metal carbene species from the palladium catalyst and the sodium salt. The synthesis then continued by deprotection of the dioxalane to produce the corresponding ketone 89. Compound 89 was treated with the functionalized pyruvate which was immediately followed by acid catalyzed furan formation to yield 90 in 95% yield. Subsequent protection to the silyl ether by initial reduction of the furan species with DIBAL and then treatment with TBSCl yielding 91 in 87% yield over 2 steps. Treatment with DDQ and subsequent

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis deprotection yielded onoseriolide 92 in 46% yield over the last two steps, which is one of the substrates necessary for the hetero Diels-Alder reaction.39, 40

SCHEME 16. SYNTHESIS OF ONOSERIOLIDE SUBSTRATE FOR PERICYCLIC CASCADE REACTION.

Onoseriolide and β-E-ocimine were dissolved in toluene and heated to 150°C in a sealed tube which initiated the cascade reaction to deliver bolivianine in 52% yield as a single isomer. This one-pot Diels-Alder/intramolecular hetero Diels-Alder cascade reaction shows endo selective cycloaddition of the diene on the bottom face of the onoseriolide scaffold. Tis cascade sequence underwent two consecutive pericyclic transformations, generated three rings systems, four new C-C bonds and five stereogenic centers with excellent selectivity’s. Although the initial first Diels-Alder cyclization reaction requires elevated temperatures and the aldehyde moiety to activate the dieneophile, the second intramolecular hetero Diels-Alder reaction process was found to occur spontaneously t room temperature. The success of this

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis reaction is particularly interesting due to the difficulty of the first cycloaddition reaction. However, it would be interesting to explore the utilization of catalytic processes with chiral Lewis acid catalysts to enhance the reactivity and selectivity of Diels-Alder reactions to further improve on the notion of utilizing cascade sequences for the total synthesis of natural products as reported by Corey et. al. 48

SCHEME 17, CASCADE REACTION AND COMPLETETION OF (-)-BOLIVIANINE BY LIU ET. AL.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

RADICAL CASCADES

In the last several decades, the organic chemistry community has witnessed the increased utilization of radical type reactions in the total syntheses of complex natural products. Complex and stereochemically rich terpenoids have proven to be ideal candidates for the utilization of such radical cyclization reactions. In this chapter we review the total syntheses of a variety of natural products that utilize radical cascade cyclization’s as the key step in these syntheses. Many of these natural products are arguably some of the most synthetically challenging products which are created by synthetic chemists.

Micalazio et. al. reported in 2016 their asymmetric approach of the total synthesis of (-)-jiadifenin utilizing an intramolecular cascade cyclization reaction. The total synthesis started by regioselective addition of organometallic reagent from 97 to chiral epoxide 96. The formed homoallylic alcohol 98 was converted to enyne 99 by a sequence of desilylation, epoxide formation, and then nucleophilic addition of propynyl lithium. Hydrindane was generated by exposure of stannyl-substituted TMS acetylene in combination with Ti(Oi-Pr)4, n-BuLi which was followed by the addition of lithium alkoxide of enyne, resulting in compound 100 with a yield of 73% with a ds of >20:1. Treatment of hydrindane with TBAF removed the TMS group which was then followed by silylation of the secondary alcohol group. Selenophenyl methyl ester 101 was retrieved by tin-lithium exchange of 100 followed by carboxylation and esterification with PhSeCH2Cl, the ester was obtained in 85% yield as a single stereoisomer. Selenphenyl ester derivative 101 contained an adjacent ene species, which was selectively mono hydrolysed on the -position next to the ester with osmium tetroxide, producing 102 in 85% yield.41, 42, 43

The radical cascade reaction was initiated by heating selenophenyl methyl ester 102 in the presence of Bu3SnH and AIBN, this resulted in the formation of two cyclized products, which both contained the newly formed sterically congested quaternary center in a combined yield of 80%. Formation of 105 was expected whilst the ethyl ester 106 was not expected, it was rationalized that this product was formed from radical 104 followed by stereoselective 5-exo trig cyclization. Both products 105 and 106 in the radical cascade reaction were then converted to the tetracyclic bis-lactone 107 by a relatively simple sequence of functional group transformations. Desilylation of the tetracyclic bis-lactone 107 with TBAF, followed by sequential oxidation produced enone 108. Removal of the tertiary TMS-ether with was followed by -hydroxylation via a process involving epimerization delivered product 109. Jones oxidation followed by methanolysis successfully delivered the natural product of (-)-jiadifenin. Although this total synthesis is a prime example of how the reactivity of radicals chemistry can be controlled within total

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis synthesis, perhaps there is room within this synthesis to further develop this cascade sequence to allow for several additional intramolecular cyclization’s.

SCHEME 18. RADICAL CASCADE CYCLIZATION IN THE TOTAL SYNTHESIS OF (-)-JIADIFENIN BY MICALAZIO ET. AL.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

In 2016, Overman et. al reported the total synthesis of (-)-chromodorolide B, this natural compound is produced in the marine nudibranches of the Chromodoris genus. Their total synthesis of this natural compound involves an interesting intermolecular radical addition/cyclization/ fragmentation cascade reaction as their key step. Their reported total synthesis starts from the enantioenriched enedione 111, A five step series of transformations was utilized to obtain the trans-hydrindanone cyclopropane 112 in 67% yield over these steps. Reductive cleavage of the cyclopropane was achieved by hydrogenation with Adam’s catalysts, followed by treatment with PCC oxidation of the ketone to generate 113 in 88% yield in two steps. Conversion of ketone 113 to the vinyl iodide proceeded easily by utilization of Barton’s two-step hydrazone iodination procedure, giving 114 in 84% yield. Coupling of vinyl iodide with aldehyde 115 proceeded via Nozaki-Hiyama-Kishi coupling, utilization of the sulfonamide ligand 116 proved crucial in achieving the desired diastereoselectivity (>20:1 dr), the yield of 117 was 66%. 44, 45, 46

The methyl ester was initially hydrolized under basic conditions and subsequently coupled to N- hydroxyphthalimide with DCC. Subsequent chlorination of the secondary allylic alcohol initiated allylic rearrangement to give the activated ester 118 in 43% yield over three steps, which was the substrate for the key radical cascade reaction. The radical cascade reaction was initiated by Photoinduced fragmentation of the N-acyloxyphthalimide moiety, mediated by the ruthenium catalyst this generated the hindered tertiary radical species 119, this diastereoselectively added to the chiral butanolide fragment. This radical addition resulted into the α-carbonyl-stabilized radical 120 which subsequently underwent a non-diastereoselective intramolecular 5-exo-trig radical cyclization onto the alkene moiety of the system, this produced both 121a and 121b in 37 and 28% yield, respectively. The minor product was subjected to DIBAL to convert this to the lactol, which was immediately acetylated in situ, giving the corresponding alcohol 122. The key stereocenter which connects both the cyclic systems together was obtained by heterogeneous catalysis reduction of the double bond, giving 123 in 58% yield over the last three steps. Next was the two step oxidation of the primary alcohol to a carboxylic acid, giving 124, this was then treated with acid to give lactol 125. The final step of this total synthesis envolved acetylation of the secondary and tertiary alcohols to afford (-)-chromodorolide B in 49% yield over the last steps. It is impressive that synthetic chemists have utilized radical cascade sequences to obtain complex natural products. It could be noted that the second reaction in the cascade sequence is the bottle-neck in obtaining a decent amount of the right diastereoisomer, as shown in scheme 19. Possibly the utilization of a chiral di- amine ligand such as (R)-(i Pr)-Pybox could potentially influence the selectivity of the transition metal mediated radical cascade sequence. Furthermore it is quite impressive that such complexity was able to

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis be obtained in a single cascade sequence with radical chemistry whilst minimizing alternative radical reactions.

SCHEME 19. TOTAL SYNTHESIS OF (-)-CHROMODROLIDE B BY OVERMAN ET.AL. IN 2016 UTILIZING A RADICAL CASCADE SEQUENCE.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

CONCLUSION AND OUTLOOK

The described work in this literature thesis give strong testament to the power of asymmetric cascade reactions which is based on the use of chiral auxiliaries of enantioenriched substrates. The utilization of these different types of cascade reactions, allow synthetic chemists to rapidly assemble complex frameworks of a great variety of alkaloid families. Strategic design and development of new asymmetric cascade reactions is regarded as a great intellectual challenge for organic chemists. The enormous benefits associated with cascade reactions have motivated chemists to continue to develop and exploit these in organic synthesis. Within this literature thesis the preparation of cascade substrates has also ben included because the strategic planning of these cascade sequences are far from trivial and play a vital role in the success of these reactions.

The discussed cation-mediated/electrophilic cascade sequences in the total syntheses of (-)- lycopedine and (+)-vincadifformine utilized inspiring cascade reactions that involved the several new bond formations via cationic intermediates. Although these total syntheses were successful and the cascade sequences had a key role, these did cascade sequences did yield diastereomers and it would be of great interest to further explore the utilization of chiral auxiliaries (for (-)-lycopedine) as well as the use of chiral phosphonates during these cascade sequences to prevent the formation of other intermediates, with the sole purpose of increasing the yield and efficiency of these reactions.

Anionic/nucleophile-mediated cascade sequences have been thoroughly explored and are generally composed of sequences involving Michael-type reactions. The cascade sequences that were vital in the total syntheses for (-)-β-lycorane and (+)-tronocarpine utilized a conjugate addition/Michael cascade and a phase transfer catalysts mediates Michael/Aldol cascade reaction, respectively. Although creating the desired stereochemical orientations of functional groups, having a nitroalkene substituent could work as a better Michael acceptor and potentially reduce the total number of steps in this reaction and already have the nitrogen atom in the system. The very first step in the reported total synthesis of (+)-tronocarpine by Han is the Michael/Aldol cascade reaction, utilizing a PTC and acrolein as the Michael acceptor. Although this reaction provides a good yield and good ee, perhaps prospering planning and redesigning the cascade substrate, this could be transformed to an intramolecular Michael/Aldol cascade reaction without actually having to use acrolein due to it’s toxicity concerns and that it is not commercially available anymore in Europe.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

The pericyclic reactions discussed in this literature thesis have shown the it’s power to create complex products via electrocyclic components, such as in the biomimetic synthesis of (-)-PF-1018, here Trauner et. al. showed an 8π electrocyclization followed by a formal [4+2] Diels-Alder reaction. The protecting groups in this reaction were strategically placed and completely avoided the formation of any other competing side reactions. The Diels/Alder intramolecular Hetero Diels-Alder cascade sequence in the total synthesis of (-)-bolivianine by Lu et. al. was an impressive feat in itself, here it could be argued that the high temperatures necessary in order to activate the dienophile could be a drawback, here it would be interesting to utilize a chiral lewis acid to both lower the reaction temperature and increase the reaction efficiency, thus making it more attractive to apply in other total syntheses of other natural products.

Although synthetic radical research of the past has determined many “commandments” which described the modes of basic reactivity and cyclization mechanisms of free radicals, modern day synthetic chemists have searched for more readily available functional groups as radical initiators to develop improved methods and merge this chemistry with other areas of chemistry. The syntheses by Micalazio et. al. of (-)jiadefin and Overman’s synthesis of (-)-chromodrolide B showed how far the field of radical chemistry has come in controlling the incredible reactivity of radical species in the application of natural product total synthesis, much more is left to learn within this field and the future shows much promise for what it could become.

Although there are relatively few examples of the utilization of cascade reaction in the total synthesis of complex natural products, development in this field has shown great promise of what could be achieved in the application of these methods and the importance of strategic planning in this field of chemistry. In order to encourage this state of the art chemistry it is of utmost importance to share the increasingly precise understanding of the mechanisms and kinetics of organic transformations.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

ACKNOWLEDGEMENTS

I would like to offer my gratefulness to prof. dr. Jan Maarseveen for giving me the opportunity to conduct literature research on this subject, which further developed my interest in these complex cascade reactions. The subject covered many different types of reactions and a variety of natural products with a great range in their structures, of course suggesting that their syntheses are also significantly different.

Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

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Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

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Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis

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