Total synthesis of (−)-α-cyclopiazonic acid: a study in perseverance

Chapter 1

Total synthesis of (
)-a-cyclopiazonic acid: a study in perseverance Oleksandr Zhurakovskyi,a Michael A. Shawb and Varinder K. Aggarwal* School of Chemistry, University of Bristol, Bristol, United Kingdom *Corresponding author. email: [email protected]

Chapter Outline Preface 1 1. Introduction 2 2. Aziridinations and epoxidations using chiral sulfur ylides 5 3. Aziridine cycloadditions and related reactions 9 4. Synthesis of building blocks 10 4.1 Indole building block 10 4.2 Synthesis of the sulfonium salts 13

5. Initial Cyclization and formal synthesis of a-CPA 6. Racemic synthesis of a-CPA via ester isoxazole 7. Enantioselective synthesis of a-CPA using bromoisoxazole 8. Conclusion Acknowledgments References

16 19 24 31 31 31

This chapter is dedicated to the memory of Gilbert Stork, whose creativity, insight, intuition, humor, humility, and humanity were just some of his abiding qualities.

Preface Synthesis is tough. Planned routes rarely succumb to practical execution without significant modification because issues such as functional group a. Present address: Pharmaron UK, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom. b. Present address: Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Strategies and Tactics in Organic Synthesis. https://doi.org/10.1016/B978-0-12-814805-1.00001-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

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2 Strategies and Tactics in Organic Synthesis

incompatibility, poor stereocontrol, or undesired reactivity can arise. They may require a study of model compounds and alternative pathways to reach the target. And so it was with cyclopiazonic acid (CPA). We planned a route that did not work due to one of the key reactions giving multiple products. Investigation of model compounds showed that our key steps did engage in the desired chemistry. We then modified the model compounds, but these led to us to a series of dead ends. Finally, we returned to our original route and with improved equipment were able to detect the desired products in the key steps, albeit in low yield. This enabled us to launch a campaign to optimize the reaction conditions and explore closely modified pathways before we reached our desired target. Little did we know that the total synthesis of such a deceptively simple natural product would take us 17 years to complete and would provide such a tough testing ground for chemical creativity, rigorous and systematic analysis, unrelenting perseverance, and diligent practical execution.1

1. Introduction a-Cyclopiazonic acid (a-CPA, 1, Scheme 1) was isolated in 1968 by Holzapfel from the fungus Penicillium cyclopium Westling, which gave the compound family its name.2 Later, three related compounds were discovered from other Penicillium and Aspergillus fungi: b-CPA (4), iso-a-CPA (2), and a-CPA imine (3).3,4 Slightly more distant congeners include speradines AeD5,6 and aspergillines AeE.7 While b-CPA 4 has been conclusively established as a biosynthetic precursor to a-CPA, 2 and 3 could be no more than isolation artifacts.8e12 It was later found that P. cyclopium does not actually produce cyclopiazonic acidsda situation all too common in the world of natural products, and that the real sources include Penicillium commune, Penicillium griseofulvum, and Penicillium camemberti.13 Representing a class of prenylated indole alkaloids, the CPA molecules all contain an acetyltetramic acid fragment,14,15 which, being highly polar and

SCHEME 1 Cyclopiazonic acids and related alkaloids. a-CPA, a-cyclopiazonic acid.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

3

SCHEME 2 Biosynthesis of cyclopiazonic acids (CPA).

unstable, renders these natural products difficult to work with. For example, a-CPA reacts with ambient oxygen, absorbs onto plastic, and reacts with the stationary phase during conventional chromatography.16 Biosynthetically, a-CPA is derived from L-tryptophan (Scheme 2). The tetramic acid is installed at an early stage by the Dieckmann condensation onto an activated ester derivative 5. Prenylation then leads to b-cyclopiazonic acid 2, and a flavin-mediated oxidation and subsequent double cyclization then gives a-CPA. When we commenced this work in 2000, only two total syntheses of a-CPA were known.17,18 Since then, two more have been reported (Scheme 3).19e22 In all four routes, the molecule was built up from an indole fragment AB, onto which the C and D rings were appended, before the construction of the tetramic acid E ring. The acid unit itself was installed using the same strategy across all of the syntheses, whereby amino ester 9 was treated with diketene in the presence of KOt-Bu to give an intermediate 8, which then underwent a biomimetic Dieckmann condensation. The differences among the published routes lay primarily in the means employed to construct the CD fragment and the key stereotriad incorporated therein. In the earlier syntheses, Kozikowski17 and then Natsume18 closed the C ring through intramolecular Michael additions, followed by the D ring after a number of synthetic manipulations, while Knight19,20 elegantly closed both C and D rings simultaneously with a cationic cyclization cascade on alkene 11. Scherkenbeck21,22 then achieved the first enantioselective synthesis of a-CPA by using an Evans auxiliary to access Knight’s key intermediate 11 in optically pure form from amide 12.

4 Strategies and Tactics in Organic Synthesis

SCHEME 3 Previous syntheses of a-cyclopiazonic acid (a-CPA).

In our approach to a-CPA, we envisaged a different strategy that would mimic the biosynthesis much more closely. Our group has long been interested in the asymmetric syntheses of aziridines and epoxides and reactions thereof.23e28 We thus set out to prepare the key pyrrolidine ring D (compound 13, Scheme 4) by an intramolecular aziridine-alkene formal cycloaddition of aziridine 15.

SCHEME 4 Retrosynthetic analysis of cyclopiazonic acid (CPA).

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

5

As mentioned, this approach was inspired by the biosynthesis of a-CPA, passing as it would through a cation 14 related closely to species 7. We therefore hoped and expecteddgiven the long-standing observations that biomimetic syntheses often lead to the natural isomersdthat this would favor the formation of the naturally occurring anti-syn stereotriad. Enantioenriched aziridine 15 would be prepared from an indole imine 16 and a chiral sulfonium salt 17 using the sulfur ylide methodology developed in our lab.26,28 We deemed this a highly attractive approach, as our aziridination chemistry in general allows for high enantiocontrol at the carbon derived from the sulfonium salt. Although it gives poorer control of diastereoselectivity, and thus of the configuration of the second aziridine carbon, this stereocenter would in any case be destroyed in the intermediate zwitterion of the formal cycloaddition. Should our hypothesis prove correct, the configuration of this stereocenter would be of no consequence and the C-11 stereocenter would then be set by the same factors at play in the biosynthesis, resulting in the desired cis ring fusion. Our aziridination chemistry being well suited to the addition of semistabilized ylides to electron poor imines, we also saw in this approach the possibility of installing all of the carbons necessary to form the E ring in the aziridination step, by use of an appropriately masked tetramic aciddnamely an ester-substituted isoxazole such as 19 (Scheme 5). The use of an isoxazole as a masked 1,3-dicarbonyl group has been described previously29 and has the advantage of carrying through a synthetic sequence an unreactive aromatic moiety that can be unmasked when required. Stork introduced this approach in his elegant synthesis of tetracycline where a 3-benzyloxyisoxazole was used as a masked b-ketoester, which was later unraveled to reveal the A-ring of the natural product.30 However, this strategy has scarcely been used in the synthesis of tetramic acidsdand never applied to compounds this complex.15 Should the chosen tactics fail, we saw sufficient flexibility in our approach, as several other potential R groups could be utilized in the key aziridination and formal cycloaddition steps prior to conversion to a suitable dicarbonyl functionality thereafter. Before recounting our own efforts, we will provide a brief introduction to the key methodologies we sought to employ: the asymmetric aziridination technique, and the somewhat underutilized formal (3 þ 2)-cycloaddition of an aziridine and an alkene.

2. Aziridinations and epoxidations using chiral sulfur ylides Epoxides and aziridines are ubiquitous in organic synthesis. Unsurprisingly, numerous methods have been developed for their synthesis and further transformations.31e34 Our group has long been interested in the synthesis of aziridines and epoxides using sulfur ylides. The origin of this methodology can be traced back to the JohnsoneCoreyeChaykovsky reaction (Scheme 6),

6 Strategies and Tactics in Organic Synthesis

SCHEME 5 Deadends en route to the synthesis of a-cyclopiazonic acid (a-CPA).

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

7

SCHEME 6 The JohnsoneCoreyeChaykovsky and (aza-)Darzens reactions.

which was reported by A. William Johnson,35 Corey, and Chaykovsky.36 In this reaction, a sulfonium (or sulfoxonium) salt is treated with a base followed by the addition of an aldehyde or ketone. The salt is deprotonated to give a sulfur ylide, which then adds to the ketone, and the resulting zwitterionic intermediate cyclizes giving an epoxide. This chemistry was rapidly extended to convert imines activated with electron-withdrawing groups into aziridines in the same way. The JohnsoneCoreyeChaykovsky reaction and its aza analogue are conceptually similar to the much older (aza-)Darzens reaction, in which an a-halo enolate is used in the same role as the sulfur ylide.37e39 Many years since, our group has shown that a judicious choice both of the sulfide used to prepare the sulfonium salts and of the electronic nature of the substituents borne by the anionic carbon allows for control of both the diastereoselectivity and, if a chiral sulfide is used, the enantioselectivity of the reaction (Scheme 7). Among the many auxiliaries that we developed, camphor- and isothiocineole-derived chiral sulfides 27 and 28 have enabled aziridinations and epoxidations with spectacular levels of stereocontrol.25,26 Critical to the success of this methodology is that the steric bulk around the sulfur leaves only one lone pair accessible to the electrophile used to form the sulfonium saltdtypically an alkyl halide or triflate. The selectivity of the alkylation step leads to high levels of control over the configuration of the resulting salt. Subsequent treatment with a base generates a sulfur ylide, the conformation of which is controlled by steric factors, with the R group occupying the less hindered position. The addition of the ylide to the imine or carbonyl proceeds through a dipole-minimizing cisoid approach, on the less encumbered face of the ylide, resulting initially in cisoid betaines. Bond rotation then leads to transoid betaines, which undergo intramolecular SN2 reaction to yield the three-membered ring products. In the case where R1 is an aryl group the sulfur ylide is semistabilized and its addition to the imine is nonreversible, resulting in high levels of

8 Strategies and Tactics in Organic Synthesis

SCHEME 7 Enantioselective aziridination and epoxidation using sulfur ylides.

enantioselectivity. In the case of more strongly electron-withdrawing R1 groups, the more stabilized ylide can undergo reversible addition to the substrate, resulting in an erosion of enantioselectivity. In such cases the ring closure step determines the cis/trans ratio (the barrier for the formation of the more stable product is usually lower), while with semistabilized ylides it is the addition to the imine that controls the cis/trans ratio. The enantioselectivity is also intimately related to which step is rate determining, and whether it is reversible. While in the case of epoxides, trans isomers are always more stable, an important and easily overlooked feature of N-SO2Ar aziridines is that cis aziridines are usually more thermodynamically stable than the trans isomers. This can be rationalized by considering that the large activating group on nitrogen is positioned out of the plane and must therefore clash with one or the other of the respective trans-positioned C-substituents, making this configuration less stable than that of the cis diastereomer (Scheme 8). As shall be seen, this cis-trans equilibration played an important role in the development in our synthesis of a-cyclopiazonic acid.

SCHEME 8 Basis for the stability of cis aziridines.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

9

3. Aziridine cycloadditions and related reactions Cycloadditions between an aziridine and a dipolarophile (such as alkene or alkyne) are an important but underappreciated class of reactions (Scheme 9).40,41 Depending on the aziridine structure, they can occur by two distinct modes: (1) through the cleavage of the CaeCb bond, leading to a pericyclic reaction, or (2) with CeN cleavage, leading to a formal (3 þ 2)cycloaddition. Both reactions are aided by the strain release of the small ring and give pyrrolidine-type products. Reactions of the first type proceed via a delocalized dipole 29, which is formed by a pericyclic ring opening of the aziridine. These are typically promoted by photochemical excitation or thermal activation. The formal cycloadditions through CeN cleavage, on the other hand, are typically catalyzed by Brønsted or Lewis acids or with Pd complexes. They are highly sensitive to substrate substitution and reaction conditions: the intermediate zwitterion 30 does not benefit from delocalization, and thus has to be stabilized by other means, for example by placing an electron-withdrawing group, such as a sulfonamide, on the nitrogen and a cation-stabilizing substituent on the chargebearing carbon Ca (typically an electron-rich alkene or aromatic ring, or, as in our case, an indole). Although the early procedures of Yamamoto42 and Knight43 originally required electron-poor dipolarophiles, which limited the applicability of the approach, later developments have allowed for a broadening of the substrate scope. An important feature of such formal cycloadditions through CeN bond cleavage is their stereospecificity. While the stereocenter Ca is scrambled through carbocation formation, that of Cb remains intact, permitting the transfer of stereochemical information back to Ca of the product 32. We have previously employed intermolecular formal aziridine-alkene cycloadditions in our syntheses of (
)-a-kainic acid and (þ)-allo-kainic acid (Scheme 10) and showed that even singly activated alkenes, such as methyl vinyl ketone, can be viable coupling partners.44,45

SCHEME 9 Possible routes to 1,3-dipoles from aziridines.

10 Strategies and Tactics in Organic Synthesis

SCHEME 10 Syntheses of (
)-kainic acid and (þ)-allo-kainic acid.

The analogous retrosynthetic disconnection employed in the a-CPA project (15 / 13, Scheme 4) was in our view still more ambitious, as it would involve a heavily substituted and electron-rich dipolarophile. We, however, anticipated that the intramolecular nature of the hypothesized reaction would bring the two partners together and promote the formal cycloaddition in a similar manner to the biosynthetic pathway. Furthermore, we hypothesized that the desired stereochemistry could then be expected to dominate, given the similarity between our proposed system and that thought to operate in nature.

4. Synthesis of building blocks 4.1 Indole building block Our retrosynthetic analysis of a-CPA required access to an activated imine 16 (“indole building block”) and a sulfonium salt 17. Conceptually, there were two ways to arrive at the desired prenylated indole: with either the indole or the prenyl (allyl) fragment serving as the nucleophile and the other moiety being the electrophile, albeit most likely through a transition metalemediated coupling (Scheme 11). Given the electron-rich nature of the prenyl unit and its

SCHEME 11 Retrosyntheses for a prenylated indole.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

11

capacity to stabilize an organometallic species, of which many examples were known, it was obvious that we should disconnect to accommodate the intrinsically favored polarity of the system. We therefore set out to access the novel aryl halide 34. Initially, indole 34a (X ¼ Br) was prepared de novo from nitroarene 38 using LeimgrubereBatcho indole synthesis (Scheme 12).46 This approach in general benefits from the widespread availability of o-nitrotoluenes and allows the synthesis of indoles with controlled substitution of the A ring. In our synthesis, we were pleased to find that treatment of 38 with DMFDMA (39) under basic conditions initiated a condensation cascade resulting in the formation of enamine 40. Reduction of the nitro group with Zn/AcOH then gave an aniline, which cyclized in situ to give 5-bromoindole 41 in 55% overall yield. VilsmeiereHaack formylation readily afforded indole 42, which was tosylated to give 34a. All attempted one-step prenylations of bromoindole 34a typically gave alcohol 43 or its 1,3-regioisomer and not the desired compound 33. Several approaches were tested to solve this problem, with coupling partners based on organotin, boron, zinc, magnesium, copper, and other nucleophile equivalents. Eventually, it was found that decagrams of 33 could be accessed through the Stille coupling of an iodoindole, which presumably benefited from a faster oxidative addition (Scheme 13). The regiochemistry of these couplings also proved problematic at first, but it was found that this could be exquisitely controlled through judicious choice of ligands with larger cone angles, which we assumed to be exerting a steric influence on the reductive elimination.47

SCHEME 12 Early approach to indole 33.

12 Strategies and Tactics in Organic Synthesis

SCHEME 13 Prenylation of indole 44 via a Stille reaction.

This route furnished sufficient material for much of the later synthesis to be scoped out, but we remained keen to replace the use of mercury in the haloindole synthesis. It was later found that good yields were achievable in the allylation of the LeimgrubereBatcho bromide, with carefully optimized Suzuki coupling conditions, where allyl-Bpin was added dropwise to the refluxing reaction mixture (Scheme 14). This approach of course also removed all potential regiochemical issues from the equation. Subsequent tosylation provided allylated compound 45 in excellent yield (91% over two steps). The terminal alkene was conveniently exchanged with neat 2-methyl-2-butene under Grubbs metathesis conditions to give 33.48 Presumably, the reaction is driven by the huge excess (ca. 50-fold) of 2-methyl-2-butene, a cheap commodity chemical. By this stage in the project, the requisite bromide could now be purchased from commercial suppliers rather than prepared in house, meaning this route now involved fewer steps than that through the iodide, giving superior yields as well as avoiding highly toxic metal residues. These developments significantly bolstered our efforts to produce sufficient material to complete the end game. We hoped that the next two steps would prove straightforward, and indeed, efficient imine formation was achieved by employing TsNH2/NsNH2 and Ti(OEt)4. The latter reagent combines mild Lewis acidity with strong

SCHEME 14 Prenylation of 42 via Suzuki coupling and Grubbs olefin metathesis.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

13

dehydrating properties. Although thin-layer chromatography (TLC) was rather misleading in these reactions (the product was unstable on acidic silica, reverting to the starting sulfonamide and aldehyde), the reactions were easily shown to be complete within 1e2 h at room temperature by liquid chromatographyemass spectrometry (LCMS). The major drawback with this approach was that the aqueous workup produced horrible suspensions of titanium hydroxides, which significantly compromised extraction, and blocked filters including Celite plugs. In the end, we found that the offending residues could best be filtered off with a loose glass wool plug, allowing for smooth extraction of the resulting solutions. Product purification was, however, still required, and presented another challenge, as tosyl imine 16a partially hydrolyzed on silica, and thus had to be passed through very short silica plugs. The nosyl imine 16b, which was deployed later, was even more sensitive, and underwent substantial decomposition within minutes. Unexpectedly, even neutral alumina, a commonly used and generally milder alternative to silica, led to complete imine hydrolysis in 30 s. This process in fact proved to be useful for aldehyde recovery from insufficiently pure imine batches, but it did not help us to move the synthesis forward! A satisfactory solution to the purification problem was eventually achieved by exploiting the markedly different solubilities of 16b and the accompanying impurities (mostly the excess NsNH2). The imine nicely dissolved in a 1:1 DCMepetrol mixture, in which NsNH2 was essentially insoluble. Thus, crude reaction mixtures were suspended in small amount of DCM and treated with equal volume of pentane, which led to precipitation of the impurities. Simple filtration through Celite yielded the product 16b free from NsNH2 and with just 1%e3% of the aldehyde present.

4.2 Synthesis of the sulfonium salts Of course, while the work described in the previous section was ongoing, we had also been exploring multiple routes toward the required sulfonium salts 51a-b. That which eventually proved most successful was a route based on the classical chemistry of ethyl acetoacetate, 46 (Scheme 15). Treatment of magnesium enolate of 46 with chloroacetyl chloride delivered furanone 47 in 44% yield.49 This moderate yield did not concern us since all reagents were readily available commodity chemicals and the isolation of the desired product was straightforward. Reaction of furanone 47 with NH2OH then resulted in an interesting rearrangement giving isoxazole 48 in quantitative yield.50 The alcohol 48 was activated using Tf2O and pyridine 49, the steric bulk of the base being required to prevent its alkylation. The resulting triflate was then treated with cyclic sulfides 27, 28, or 52 in ether. The use of ethereal solvent is a commonly deployed tactic in the formation of such sulfonium salts, and allowed for the precipitation of salts 51a-b directly from the reaction mixtures, thus reducing side reactions such as oligomerization, as well as simplifying the

14 Strategies and Tactics in Organic Synthesis

SCHEME 15

Isoxazole sulfonium salts.

purification. Unfortunately, the sulfonium salt derived from our favored sulfide 28 was found to be prone to decomposition. Nevertheless, we were now delighted to find ourselves armed with two appropriate aziridination reagents, 51a-b, bearing the desired ester isoxazole functionalitydone for initial racemic work and the other to enable an ultimate enantioselective route. Later in the project, a second series of less complex sulfonium salts 56, 58, 59 was accessed from the common intermediate 53 (Scheme 16). Oxidation of acetaldoxime with bleach into acetonitrile oxide (CH3eC^NþeO
) and its (3 þ 2)-cycloaddition with propargyl alcohol in situ gave isoxazole 53, which proved highly volatile, perhaps accounting for the rather moderate yield (65%). The aromatic ring in 53 could then be brominated with N-bromosuccimide in AcOH. Although undesired Fisher esterification to acetate 54 was observed, basic workup of the reaction mixtures hydrolyzed this ester almost instantly and in quantitative yield to give the desired alcohol 55. This was then converted into sulfonium salts 56a-c as before, via the corresponding triflates. Compounds 56a-b were prepared in good yields, while the isothiocineolederived sulfonium salt 56c again proved extremely unstable and could be obtained only in 47% unoptimized yield (it decomposed in CDCl3, protic solvents, and even MeCN). Building blocks 58e59 could also be accessed from 53. An Appel reaction converted 53 cleanly to 57, which could, if desired, also be readily brominated on the isoxazole ring. Both sulfonium salts 58 and 59 could then be prepared in reasonable yield (65%e70%) from the appropriate parent bromide by slow (2e4 days) reaction with tetrahydrothiophene 52 in biphasic CH2Cl2eH2O mixtures. Our attempts to improve the yields by varying the concentration or degassing the solvents were not successful. Analogues of 56a with perchlorate

Synthesis of chiral and achiral sulfonium salts.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

SCHEME 16

15

16 Strategies and Tactics in Organic Synthesis
(ClO
4 ) and hexafluorophosphate (PF6 ) counterions could be prepared by salt metathesis in acetone, but we later discovered that these alternative salts did not afford better results in the crucial aziridinations. Nevertheless, we were confident that we had developed practical routes to suitably diverse isoxazolesubstituted sulfonium salts to examine the key steps of the envisaged synthesis.

5. Initial Cyclization and formal synthesis of a-CPA Having secured access to both the indole and the isoxazole building blocks, we turned our attention to their union through aziridination, and the formal cycloadditions that were to follow. These studies took us in directions we did not previously anticipate, but which nevertheless, we believe, are informative to recount. We originally set out, as per our original plans, to install an ester-bearing isoxazole in the aziridination step, which could be converted to the tetramic acid after the formal cycloaddition. Initially, this seemed a promising approach, as reaction of N-Ts imine 16a with sulfur ylide derived from sulfonium salt 51a$ClO4 delivered the desired aziridine 20 in very good yield and high diastereoselectivity (trans/cis 9:1; Scheme 17). However, treatment of this compound with a range of Lewis and Brønsted acids under various conditions invariably led to complex mixtures or outright decomposition, with no desired pyrrolidine 19 being isolated. Indeed, the results seemed so unpromising that we were led to conclude that the isoxazole, with its several Lewis basic sites, was incompatible with our proposed formal cycloaddition strategy. As shall be seen, and as we realized only with hindsight, this conclusion was incorrect. The results we had obtained forced us to change tack. Surmising that the high number of Lewis basic groups of the isoxazole could be the source of our troubles, we next attempted the formal cycloaddition on a far simpler system (Scheme 18).51 The phenyl-bearing compound 85 was therefore prepared, and,

SCHEME 17

Aziridination, but no pyrrolidine formation.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

SCHEME 18 Successful aziridination and pyrrolidine formation.

17

18 Strategies and Tactics in Organic Synthesis

gratifyingly, underwent the desired formal cycloaddition with the desired stereocontrol, albeit in poor yields and with rather low selectivity. Optimization of this reaction was not undertaken, since it did not offer a path forward in terms of conversion of the phenyl group to the desired functionality. Nevertheless, this model reaction hinted at a possible way forward, since a more electron-rich aromatic could potentially be oxidized to a carboxylic acid. Dimethoxybenzyl-substituted compound 62 was therefore targeted (Scheme 19) and was successfully accessed using the established protocols, albeit with poor selectivity (dr 1:1). However, treatment of 62 with RuCl3/NaIO4 (the system commonly used to oxidize electron-rich aromatics into carboxylic acids)52,53 did not give any of the desired product 63, invariably leading to decomposition. We then attempted to synthesize vinylogous compound 66, with the intention of cleaving the double bond with Ru- or Osbased reagents. Surprisingly, treatment of the aziridine 64 with Lewis acid did not give the expected pyrrolidine 66 but instead led to the formation of a seven-membered product 65. Presumably, the styrene substituent underwent a semipinacol rearrangement (67 / 68) before a formal (2 þ 2)-cycloaddition took place. While interesting, the rearrangement did not move us closer to the target. We therefore resolved to attempt the reaction with the ester functionality

SCHEME 19 A series of interesting, but unfortunate, rearrangements.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

19

SCHEME 20 Early formal synthesis of a-cyclopiazonic acid (a-CPA) by aziridination/ cycloaddition.

already in place. The aza-Darzens reaction of imine 16a did indeed afford the desired aziridine (Scheme 20), and, although the yield was low, we were delighted to find that it also underwent the desired formal cycloaddition with boron trifluoride. Our elation was, however, short-lived, as we rapidly determined that the 6:1 ratio of diastereoisomers formed was in favor of the undesired trans-cis fused ring junction. All attempts to improve the stereochemical outcome of this reaction, or correct the stereochemistry of the undesired isomer by an oxidationereduction sequence failed. Nevertheless, global deprotection of the minor product did allow for completion of a formal synthesis, through interception of a known intermediate 21. Although a milestone had been reached in showing that a-CPA could be accessed by our aziridinationecycloaddition sequence, it was clear that this was far from satisfactory route. Still keen to achieve an enantioselective synthesis through use of our sulfur ylide chemistry, and cognizant that the only stereochemically satisfactory formal cycloadditions had been achieved with aromatic substituents, we decided to explore systems that might allow us to capitalize on the results so far, and learn more about the reactivity of the system with which we were dealing.

6. Racemic synthesis of a-CPA via ester isoxazole Concluding that good stereoselectivity, and indeed promising yields, had thus far only been obtained in our key cyclization step with aromatic substituents, we elected to revisit the isoxazole motif. If we were correct in assuming that the issue lay with the high number of Lewis basic sites in our original isoxazole substrate, perhaps a simpler isoxazole might prove more amenable to the key formal cycloaddition. We therefore reacted imine 16a with a simple isoxazole salt 59 (Scheme 21), a reaction that gratifyingly proceeded smoothly

20 Strategies and Tactics in Organic Synthesis

SCHEME 21

An all-too-stable carbonyl cyanide thwarts a synthesis of a-cyclopiazonic acid (a-CPA).

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

21

on gram scale and afforded the product in 70% yield (trans/cis 3:1). Perhaps surprisingly, the formal cycloaddition also proved successful and provided us with ample amounts of pyrrolidine 25, favoring the desired cis ring fusion (dr 3.5:1). Using carefully optimized conditions, we then removed both tosyl protecting groups and cleaved the NeO bond in one pot. This was achieved by treating 25 with freshly prepared sodium naphthalenide in thoroughly degassed DME. The reaction was almost like a titration: the first two equivalents of the reductant cleaved the indole tosylate, another two removed the pyrrolidine N-Ts, while the final portion of the naphthalenide reduced the isoxazole. Acylation of the pyrrolidine 70 with (CN)2C¼O gave 24 in moderate yields. The compound was surprisingly stable and could be columned without special precautions. In fact, it was too stable: all our attempts to deprotonate 24 and effect the cyclization invariably led to either quantitative recovery of the starting material or complete decomposition. When 70 was treated with COCl2, the product of undesired O-alkylation (71) was isolated. These observations, along with some molecular modeling, showed that the formation of the C7eC8 bond was challenging and impeded either by poor orbital overlap or introduction of ring strain, depending on the substrate. Around this time, multiple factors came together. First, we had evidence that cycloadditions could take place in the presence of an isoxazoledalbeit a simple one that proved synthetically unviable. Second, we surmised that the use of a nosyl in place of a tosyl group could aid both our aziridinations and our formal cycloadditions (as well as the later deprotection).54 Thirdly, and perhaps most pivotally, since it was becoming clear that traditional TLC monitoring and standard silica chromatography were inadequate for analysis and separation of the complex reaction mixtures, we obtained access to a reverse-phase LCMS machine and switched our existing preparative highperformance liquid chromatography (HPLC) instrument into the reverse phase mode. The use (and sometimes abuse) of these instruments, together with the practice of measuring compound purity and reaction yields by quantitative NMR spectroscopy was critical to allowing us to solve the a-CPA conundrum. This third point, the use of reverse phase analysis together with quantitative NMR, allowed us to pinpoint at which synthetic or purification step a given loss of the desired product occurred, and in some cases to reassess protocols that had previously seemed unviable.55 It helped us to optimize many new reactions, but also to revisit old ones we had discarded. Thus, armed both with the knowledge that formal cycloadditions could be effected in the presence of an isoxazole, and with the more strongly electron-withdrawing nosyl group, we attempted the aziridinationeformal cycloaddition sequence on the imine 16b using the originally envisaged sulfonium salt 51a to form the ylide (Scheme 22). This strategy, which was largely what we had originally set out to do, turned out all along to work (!), although there were still some small hurdles to overcome.

22 Strategies and Tactics in Organic Synthesis

Ns N + N Ts 16b

SCHEME 22

O

S EtO2C TfO

51a

N

Cs2CO3 72%

H

Ns N H

O

N

N EtO2C Ts 72 trans/cis 9:1

A diastereoselective aziridination with an achiral sulfonium salt.

Aziridination of 16b with the ester-containing salt 51a was indeed facile and surprisingly high yielding. However, the diastereomeric ratio, as measured by 1H NMR in chloroform, fluctuated widely from experiment to experiment. Almost accidently, we found that solutions of 72 in CDCl3 were unstable and trans-72 underwent rapid isomerization into cis-72 (half-life ca. 1 h at rt). What we mistook for the diastereoselectivity was a reflection of the NMR queue length! As the two isomers coeluted under the conditions used for TLC, the isomerization was not spotted earlier. From here on, all subsequent NMR measurements on N-Ns aziridines were performed within 5 min of sample preparation. The initial results in the aziridineealkene cyclization were even less encouraging. Treatment of 72 with In(OTf)3 led to the formation of complex crude mixtures with incomprehensible LC traces. However, preparative reverse-phase HPLC allowed for the collection of all six individual peaks, one of which corresponded to the desired pyrrolidine product (Scheme 23)! For the

SCHEME 23 Preparative HPLC to the rescue. HPLC, high-performance liquid chromatography; LCMS, liquid chromatographyemass spectrometry.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

23

first time, the ester-bearing isoxazole-substituted tetracycle we had targeted over a decade ago was isolated. At this point even the modest 20% yield did not dampen our excitement! To emphasize the importance of the purification and analysis technology to which our group had recently obtained access, it is perhaps worth stressing that the six-component crude mixture appears as a single spot on TLC or a Biotage trace under all attempted conditions, thus making all forms of silica chromatography unsuitable for purification. The low yields meant that the product peaks in crude quantitative NMR spectra were barely visible, which in retrospect explains why we discarded this route 13 years ago in the closely related N-Ts aziridine series. When performing preparative HPLC on large batches of 73, we encountered another stroke of luck. The crude mixtures, being readily soluble in large volumes of the injection solvent (9:1 MeCNeH2O), crashed out almost immediately from concentrated solutions. NMR analysis of these precipitates showed them to be a singledand, gratifyingly, the correctdisomer of the desired product! This allowed for a remarkably simple purification protocol, especially considering the initial 20%e30% purity: filtration through silica followed by crystallization from hot 9:1 MeCNeH2O. Single crystal X-ray analysis removed any remaining doubt regarding the relative configuration of 73. The nosyl group in 73 was removed easily by treatment with PhSNa (Scheme 24), while the ester was hydrolyzed uneventfully with LiOH in THFewater mixtures (LiOH is moderately soluble in organic solvents and often used when too high a concentration of water would lead to the undesired

SCHEME 24

Synthesis of racemic a-cyclopiazonic acid (a-CPA).

24 Strategies and Tactics in Organic Synthesis

precipitation of the substrate). Initially, we had some reservations about the practicality of the subsequent lactamization step, since the expected lactam 75 would be highly strained. Indeed, molecular modeling showed that the angles j1 and j2 in strained system 76 deviate significantly from those in the strainfree model 77. For this reason, we deployed what are generally considered to be the most robust coupling conditions, the “letter soup” of HATU/DIPEA/DMF.56 Pleasingly, the very first experiment, conducted at 70 C, led to the smooth formation of lactam 75, along with some NeO-cleaved side product! The optimized coupling was performed at room temperature and led to a peak-topeak formation of 75 within 10 min. The angle strain in 75 manifested itself in a very facile NeO cleavage upon hydrogenolysis on Pd(OH)2/C (Pearlman’s catalyst).57 This catalyst is nonpyrophoric and undergoes in situ reduction to form highly active Pd0 particles with a large surface area. Hydrolytic cleavage of the tosyl group and concomitant NH2 hydrolysis under Natsume’s conditions (KOH, EtOH, reflux) provided us with small amounts of synthetic ()-a-CPA (along with its epimer, ()-iso-a-CPA), which matched the commercial material by LCMS, TLC, and 1H NMR. The racemic synthesis of a-cyclopiazonic acid was thus achieved in 15 steps (11 steps longest linear sequence).

7. Enantioselective synthesis of a-CPA using bromoisoxazole At this point, excitement was building up in the project team. A racemic route had been developed and we believed that all that remained was to screen a few chiral sulfonium salts in the aziridination step, perform the cycloaddition of the enantioenriched aziridine, and carry out the end game! Unfortunately, as sometimes happens with an enantioselective version of a racemic synthesis, things did not go exactly according to plan. First, we rapidly discovered that we could not optimize the formal cycloaddition (72 / 73) beyond the 30% yield already achieved, but, even more importantly, our chiral sulfideemediated aziridination failed to deliver aziridine 72 with acceptable levels of enantioselectivity (Scheme 25). Camphor-derived salt 51b reacted very sluggishly and gave the product in only 30% NMR yield and an enantiomeric ratio (er) of 60:40. As previously described, sulfonium salt 51c, derived from the isothiocineole auxiliary, was extremely unstable and underwent decomposition upon formation to give the ring-opened product 78. Attempted use of the in situ prepared 51c was also unsuccessful. There are several plausible explanations for the observed lack of enantioselectivity. Our initial thought was that the ester group in 72 might stabilize the negative charge on Cb to allow undesired equilibration by the CaeCb bond cleavage through zwitterion 79 (Scheme 26). It could also be that the ylide derived from 51 is simply too stabilized and that its addition to imine 16b is

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

25

SCHEME 25 Low yields and an unstable sulfonium salt.

therefore reversible (cf. Scheme 7).23,58 This would then allow for the reaction of the (more reactive) minor ylide conformer and thus lead to an erosion of enantioselectivity. Whatever the reason, it looked like the ester substitution on the isoxazole was incompatible with our plans once more and that the enantioselective aziridination would require a less anion-stabilizing substituent. We therefore turned to bromoisoxazole salts 56 (Scheme 16). Bromoisoxazoles had been explored earlier in the N-Ts imine route but rejected because they were incompatible with detosylation. Since we now worked with a more labile N-Ns protecting group on the nitrogen in question, we hoped to achieve a clean deprotection and use the Br atom as a handle for carbonyl installation after the tetracycle was constructed in enantiopure form. To test the viability of this route, we performed a quick-and-dirty synthesis of enantioenriched aziridine 80, using in situ generated sulfonium salt (Scheme 27). Happily, the aziridination proceeded smoothly, delivering the product in a vastly improved 85:15 er, both in the crude reaction mixture (cis/ trans 60:40) and after the trans/cis isomerization in CDCl3. This implied that the isomerization occurred through the CaeN bond cleavage, as opposed to CaeCb. Treatment of aziridine 80 with In(OTf)3 then delivered small amount of pyrrolidine 82 with conservation of enantiopurity. This was highly encouraging, and we thus embarked on a campaign to convert the bromine atom into a carbonyl group, concurrently attempting to improve the enantioselectivity of the aziridination. Exploration of aziridination conditions showed that camphor-derived auxiliary 56b allowed for the best diastereo- (trans/cis 9:1) and enantioselectivity (er 98:2 for trans-80, 98:11 for cis-80; Scheme 28). The use of unstable sulfonium salt 56c resulted in lower er and dr. The formal (3 þ 2)-cycloaddition of 80 could be performed interchangeably with In(OTf)3 or TfOH, giving pyrrolidine 82 in 50%e52% yields (dr 3.5:1 at C-11). It was

26 Strategies and Tactics in Organic Synthesis

SCHEME 26 Possible reversible reactions en route to aziridination.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

SCHEME 27

27

Conservation of enantiopurity in a pyrrolidine ring formation.

of paramount importance to use strictly anhydrous TfOH because this reagent is highly hydroscopic, and adventitious water readily hydrolyzed 80 to an amino alcohol. It was also discovered by one of our team members that neat TfOH reacted with disposable needles, leading to an exposure hazard if not dispensed immediately. In(OTf)3 is also highly hydroscopic but delivered good results as long as it remained a free-flowing powder. Unfortunately, purification of 81 by crystallization was not possible, since both diastereomers precipitated together. The isomers were thus separated by preparative HPLC, either at this step or later in the synthetic sequence. The relative configuration of 81 was secured by X-ray analysis. It was now necessary to convert 81 into lactam 75. We first elected to attempt palladium-mediated carbonylations that could deliver the desired lactam in one step. In 2016, Guo et al. reported carbonylative lactamization of related systems,59 and we felt it may be possible to exploit these conditions in our case. The nosyl group in 81 was thus removed with potassium thiophenolate prepared in situ from PhSH, K2CO3, and 18-crown-6 in degassed DMF. Degassing was required to prevent an undesired aerobic oxidation of the thiophenolate ion and was performed by a remarkably simple and efficient procedure from Buchwaldd2e3 min of sonication under vacuum.60,61 The denosylated product 83 was then treated with Pd(OAc)2, DABCO, and n-BuPAd2 (aka cataCXium A)62 in degassed DMSO under CO atmosphere. LCMS monitoring indicated slow but clean formation of two diastereomeric products with m/z 490, which was 2 units above the expected m/z 488 of 75 (Scheme 29). Two explanations for this observation presented themselvesdeither the bromide 83 had simply undergone formylation into 84 or the

28 Strategies and Tactics in Organic Synthesis

SCHEME 28

Enantioselective synthesis of the cyclopiazonic acid family.

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

SCHEME 29 Unexpected carbonylation product.

29

30 Strategies and Tactics in Organic Synthesis

N
O bond of the expected and desired lactam product 75 was cleaved under the reaction conditions to give 82. We were delighted to learn through NMR analysis that this in situ NeO cleavage was indeed occurring; the reaction did not stop at the lactam 75, but instead proceeded smoothly to deliver the vinylogous amide 82 directly. This unexpected reaction cascade was met with great excitement, even if its mechanism was not completely understood at the time: no identifiable intermediates were observed in the LCMS traces. The facility of the reduction must stem from the high strain in lactam 75, which the NeO cleavage would of course relieve. But the reducing agent was not apparent. To shed some light on the mechanism, we performed a series of exclusion experiments, whereby 75 (prepared orthogonally by HATU coupling of amino acid 74) was subjected to carbonylation conditions in the absence of one or several reaction components. It was shown that DABCO and CO were each capable of reducing the NeO bond (the latter more efficiently), while phosphine was apparently a bystander. One possible explanation could be that the carbon monoxide was participating in a wateregas shift reaction63 with adventitious water (CO þ H2O % CO2 þ H2) and the resulting hydrogen was acting as the stoichiometric reductant. The mechanism of reduction by DABCO was less clear and would require further exploration. The last remaining operations required to complete our journey were removal of the indole nitrogen tosyl group and the expected concomitant NH2/OH hydrolysis. It was easily performed with Cs2CO3 in refluxing THFeMeOHeH2O, with conditions modified from the Scherkenbeck report.22 The reaction, while sluggish (4 days), was surprisingly clean, provided degassed solvents were used. Multiple preparative HPLC runs were then required to purify the final product, which eluted as a remarkably broad peak. After two agonizing days, the many CPA-containing fractions were combined and were finally shown to be identical to the commercial sample by LCMS and TLC. Still, the CPA project did not want to succumb so easily and delivered another blowdthe IR and NMR spectra did not match those previously reported! While the peak pattern was similar, the peaks themselves were broadened and shifted from the expected positions. This last problem was readily overcome when we realized that the original isolations involved elutions with acidic solventsdwhat we had in our hands was in fact the conjugate bases of 1 and 2. Addition of a drop of formic (pKa 4) or trifluoroacetic (pKa <0) acid to the solutions produced matching IR and NMR spectra. The results were cleanly reproduced in subsequent experiments, in which we added 0.3% of TFA to our prep-HPLC mobile phase. In these cases, the peak shapes were much better defined, and high-quality spectra were acquired. Interestingly, when detosylation of 82 was performed under strictly anhydrous conditions, a-CPA imine (3) was formed as the major intermediate, along with its C5 epimer. We have thus achieved the first direct synthesis of 3, since previously it was prepared by aminolysis of a-CPA itself.22

Total synthesis of (
)-a-cyclopiazonic acid Chapter j 1

31

In summary, (
)-a-CPA and (þ)-iso-a-CPA were obtained in nine steps (longest linear sequence, 13 total steps).1 The key pyrrolidine ring was assembled by the biomimetic intramolecular formal cycloaddition of an aziridine and an alkene, the aziridine itself being assembled from an activated imine and a chiral sulfur ylide using our group’s asymmetric aziridination methodology. Satisfyingly, our route ultimately resembled, very closely, our original synthetic plans.

8. Conclusion When one embarks on almost any project, it is impossible to predict exactly how long it will take. The total synthesis of natural products in particular is notorious as an endeavor that consistently takes more time and more effort than expected. Even when one is cognizant of this at commencement, one can still find oneself surprised by just how much more. As one of the authors remarks, “Make your best guess and multiply by four.” Perseverance is an indispensable attribute for a successful organic chemist, and, as the CPA project has shown, this must be combined with a methodical approach. One should first generate a hypothesis and design a series of experiments to unambiguously probe it. An irreproducible reaction or an unexpected outcome indicates that some factors remain unaccounted for, whether in the flask, or in the manner of analysis or purification. Following up on such results with suitably designed experiments can lead to the discovery of new reactivity, or the identification of weaknesses in the technological arsenal at one’s disposal. In our case, the use of new tools to revisit old routes proved critical to the eventual success. One should not be afraid to change strategy based on new information, even if such a change takes you back to an old strategy, instead of on to a new one!

Acknowledgments We are indebted to the following talented individuals who devoted heroic amount of effort to make this project happen: Dr. M. Ahmad, Dr. C. C. Chen, Dr. M. R. Crimmin, Dr. M. Ferrara, Mr. L. E. Lo¨ffler, Mr. J. Matlock, Dr. V. A. Moorthie, Dr. M. Ostovar, Dr. M. A. Shaw, Dr. Y. E. Tu¨rkmen, and Dr. O. Zhurakovskyi. This work was supported by EPSRC, ERC, and the University of Bristol.

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