The Leucetta alkaloids: Synthetic aspects

Chapter 3

The Leucetta alkaloids: Synthetic aspects Ravi P. Singh and Carl J. Lovely* Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States * Corresponding author: e-mail: [email protected]

Chapter Outline Introduction C4 substituted derivatives Leucettamine B Preclathridine A Naphthimidazole derivatives Kealiinines A, B and C 2-Deoxy-2aminokealiiquinone Kealiiquinone Other synthetic approaches Isokealiiquinone

43 45 45 45 46 46 51 52 54 57

Oxidized derivatives Calcaridine A Azide-tetrazole tautomerism Spiroleucettadine Spirocalcaridines A and B Newly isolated examples Summary Acknowledgments Abbreviations References

58 58 60 60 68 73 74 75 76 76

Introduction Marine invertebrates, and in particular marine sponges, have served as a productive source for the isolation and identification of natural products possessing novel structural frameworks and exhibiting useful biological properties [1]. These features have rendered such molecules as targets of interest for synthetic organic chemists as they frequently provide inspiration for the development of new synthetic methods, as a means to confirm structural identities and as leads in medicinal chemistry campaigns. In this vein, this chapter provides an overview of the Leucetta family of alkaloids isolated from a group of calcareous sponges. We and others have reviewed aspects of the biosynthesis, synthetic chemistry and bioactivity of this group of alkaloids previously and refer the reader to these articles [2–5]; this chapter will provide an overview of these alkaloids, describing new family members isolated since our review

Studies in Natural Products Chemistry, Vol. 63. https://doi.org/10.1016/B978-0-12-817901-7.00003-4 Copyright © 2019 Elsevier B.V. All rights reserved.

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in 2011, but the bulk of the content focuses on the synthesis of and synthetic approaches to the more highly oxidized congeners which have been described over the last 5 years or so [3]. Examples of the Leucetta alkaloids were first reported in 1987 by Carmely and Kashman and over the following 30 years, an additional 70+ members have been reported (e.g. see Fig. 3.1) [6,7]. Characteristic of this class of natural products is the presence of a 2-amino-1-methylimidazole which is typically substituted with oxygenated benzyl groups. Broadly speaking, these alkaloids can be divided into five subfamilies which depend upon the location of the substituents around the 2-aminoimidazole core and any additional functionalization. These subgroups include (a) naamines/naamidines which contain oxidized benzyl groups at C4 and C5 (e.g. naamine J (1) and naamidine J (2), Fig. 3.1), (b) isonaamine/isonaamidines in which the C5 benzyl group has been relocated to N1 (e.g. isonaamidine E [3]), (c) naphthimidazoles/ naphthquinones an additional bond is formed between the two benzyl moieties at C12 and C13, (d) spiro fused derivatives and (e) miscellaneous derivatives. It is subfamilies (c) and (d) that will constitute the major focus of this contribution, however, for completeness, a brief overview of new approaches to naamine/naamidine-type congeners will be provided. Recently reported

FIG. 3.1 Selected examples of Leucetta alkaloids.

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examples of naamines and naamidines, representative of members of group (a), include naamine J (1) [8,9] and naamidine J (2) [10] which were isolated by Chinese groups from a Leucandra sp. organism and Pericharax heterophyes (family Leucettidae), respectively (Fig. 3.1); in both cases, the organisms were isolated from sites in the South China Sea. In the case of group (b) one of the benzyl groups is now found on nitrogen, e.g., isonaamidine E (3) [11]. Examples of alkaloids found in groups (c) and (d) include kealiiquinone (4) [12] and spiroleucettadine (5) [13,14], respectively (Fig. 3.1). In group (e), mono benzyl systems such as preclathridine A (6), leucettamine B (7) and the lone 4,4-disubstituted system, calcaridine A (8) [15], reside. In general, two synthetic strategies have been employed for the synthesis of examples of the Leucetta alkaloids, one in which the heterocyclic core is constructed in a de novo fashion or one in which a pre-existing heterocycle is functionalized.

C4 substituted derivatives Leucettamine B In our prior review, synthetic approaches to groups (a, b, and e) were discussed and only new syntheses will be outlined here. Drazˇi
c et al. have described a nice approach to the leucettamine subfamily of alkaloids through the guanidinylation and rearrangement/elimination of amino β-lactams (9 +10 ! 11, Scheme 3.1) [16]. Methanolysis of the benzamide then affords leucettamine B (7); the authors prepared the related leucettamine C (12) via similar chemistry [16].

Preclathridine A A new approach to the mono benzyl substituted derivatives was reported by Wolfe and coworkers that employed an intramolecular Pd-catalyzed hydroamination of TMS-substituted propargyl guanidines to afford the TMS-substituted imidazole derivative (13 + 14 ! 15, Scheme 3.2) [17]. Acid-mediated desilylation of 15 and reductive desulfurization then delivered preclathridine A (6)

SCHEME 3.1 Drazˇi
c approach to leucettamine B and C.

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SCHEME 3.2 Wolfe arylative–aminative cyclization—synthesis of preclathridine A.

in good overall yield. The key reaction is formulated in terms of anti-amino metalation of 13 to afford 16 which upon reductive elimination produces 17, isomerization of 17 delivers the aromatized derivative 15 (Scheme 3.2).

Naphthimidazole derivatives Kealiinines A, B and C The kealiinines (19–21), of which three congeners are currently known (Fig. 3.2, see also Fig. 3.6), were reported by Proksch and coworkers in 2004 isolated from a Leucetta sp. [18]. These derivatives are related to the kealiiquinones in their general framework but at a lower oxidation state [12]. These 2-aminonaphthimidazoles were shown to be toxic in the brine shrimp assay but no other biological screening was performed. In addition, there are no reports concerning the biosynthesis of these alkaloids, but a net dehydrogenative carbon–carbon bond forming process between C12 and C13 on an appropriate naamine precursor, cf. 22 and subsequent oxidative aromatization would deliver the natural product framework (Fig. 3.2). It is of note that several C13-oxidized derivatives of naamines are known and these may be precursors to the naphthimidazole framework via a Friedel– Crafts-like cyclization (see Scheme 3.4) [19]. To date, three groups have reported total syntheses of the kealiinines.

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FIG. 3.2 Naphthimidazole-containing alkaloids.

Looper synthesis In this synthetic approach, the authors adopted a nominally bio-inspired oxidative cyclization using 2-aminoimidazolines 32 and 33 as precursors (Scheme 3.3). The requisite precursors were constructed through a three component (A3)-coupling using an aryl-substituted acetaldehyde 23–24, N-methyl allylamine and 4-ethynylanisole to produce a propargyl amine 25–26 in good yields [20]. Pd-catalyzed deallylation and conversion to the guanidines 30–31 were performed via a mercury-mediated reaction of the isothiourea derivative; silver catalyzed, kinetically controlled, anti-hydroamination delivered the required precursors 32–33. In both cases, reaction of the imidazolines 32–33 with NBS in acetonitrile afforded single naphthimidazoles 34 and 35 which was rationalized in terms of formation of the bromonium ion 36 that undergoes ring opening by addition of the electron-rich aromatic ring (inset, Scheme 3.3). A sequence of rearomatization, dehydrobromination and oxidative decarboxylation deliver the complete framework of the kealiinines 34 and 35. TFA-induced removal of the remaining BOC group delivered two of the kealiinines, kealiinine C (21) and kealiinine B (20) in good yields as the TFA salts. The structures of both synthetic versions of the natural products were confirmed by X-ray crystallography. As noted above, the kealiinines had only been evaluated in the brine shrimp toxicity assay and so Looper and coworkers screened both synthetic kealiinines against four cancer cell lines (MCF-10A, MCF-7, MDA-MB-231, and T47D) [20]; interestingly kealiinine B (20) exhibited anti-proliferative

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SCHEME 3.3 Looper synthesis of kealiinines B and C.

activity with almost identical IC50 values, c. 12 μM, for each cell line, whereas kealiinine C (21) showed little growth inhibition at concentrations below 100 μM (vide infra). Initial experiments to assess the mechanism of action for kealiinine B (20) were directed toward apoptotic pathways, based on existing precedent for naamidine A, for which it has previously been demonstrated that it exerts its anti-proliferative effects through activation of the MAPK pathway and ensuing caspase-3-dependent apoptosis [21–23]. However, no evidence was found to support apoptosis through a caspase-dependent pathway in the case of the naphthimidazole leading the authors to suggest that this molecule may display a novel mechanism of action.

Lovely synthesis An alternative, bio-inspired synthesis of all three kealiinines 19–21 has been reported which relies on the elaboration of a pre-existing imidazole [24] rather than a de novo synthesis of the heterocycle as described above [25].

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The synthesis began by conversion of the diiodoimidazole 38 into the corresponding Grignard by treatment with EtMgBr and subsequent reaction with the appropriate benzaldehyde derivative to afford 39–41 (Scheme 3.4); the identity of the kealiinine congener dictated by the choice of benzaldehyde derivative in this first step. Exposure of the resulting alcohol 39–41 to excess EtMgBr results in a second exchange reaction and ensuing treatment with N-methylformanilide introduces an aldehyde group. A third Grignard reaction, this time with p-methoxyphenylmagnesium bromide permits the introduction of the remaining aryl substituent in the form of the diol 45–47. A tandem Friedel–Crafts-dehydration sequence was initiated by treating the crude diols 45–47 with HCl and delivering the naphthimidazole frameworks 48–50 of all

SCHEME 3.4 Lovely synthesis of kealiinines A–C.

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three kealiinines in good yields over two steps. In the cases of the intermediates leading to kealiinine B (20) and C (21), deprotonation at C2 with n-BuLi at low temperature and subsequent trapping with trisyl azide produced the 2-azido derivatives 51 and 52, which upon hydrogenolysis delivered the corresponding amines kealiinine B (20) and kealiinine C (21), respectively. Initial attempts to apply the same sequence of the reactions to the benzyl protected intermediate 48 were not successful due to competitive lateral deprotonation of the benzylic position; reductive debenzylation and C2-metallation of the free phenol set the stage for introduction of the 2-azido group. Catalytic hydrogenation converted the azide 53 to the amine which provided kealiinine A (19). Evaluation of these synthetic materials against MCF7 cancer cells determined that both kealiinine A (19) and B (20) inhibited cell growth using an MTT assay at similar levels (IC50 20μM), but kealiinine C was essentially inactive [26]. These results mirrored those reported by Looper and coworkers. Recently, Wang et al. have described the synthesis of N-substituted analogs of the kealiinines, the basic natural product frameworks were constructed using the method described in Scheme 3.4 [27].

Van der Eycken synthesis In some respects, this synthesis (Scheme 3.5) is a telescoped version of the Looper synthesis (Scheme 3.3) wherein the earlier strategy involves two distinct cyclizations of a propargyl guanidine, first to the imidazoline and then oxidation cyclization of this intermediate to afford the naphthimidazole. Van der Eycken and coworkers take the same precursors 30–31 but on subjection to the hypervalent iodine reagent, iodosobenzene diacetate (IBDA) [28], affords the naphthimidazole 34–35 in one synthetic operation and intercept identical intermediates to those reported by Looper. Presumably, the reaction proceeds via the intermediacy of the vinylic cation and an intramolecular Friedel–Crafts reaction and further oxidation (for more details, see Scheme 3.25). It is pertinent to note that the spectroscopic data for the as isolated natural products and the synthetic versions did not match well, indeed some resonances were significantly different [20,25]. It is not unusual for differences in NMR data to be observed with polar molecules as a result of concentration

SCHEME 3.5 Van der Eycken synthesis of kealiinines B and C.

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B

FIG. 3.3 (A) Alternative structure considered for kealiinine C. (B) Imidazonaphthquinone— 2-deoxy-2-aminokealiiquinone.

differences or the presence of impurities. Attempts to replicate the reported NMR data for the natural products through dilution effects and changing the pH of the solutions used in the analysis resulted in only minor changes in the chemical shifts. It is of note that the isolation group reported the structures as the 2-imino tautomers whereas each of the synthetic materials was isolated as the 2-amino tautomers. These latter structures were confirmed through X-ray analysis (from two independent syntheses) and were consistent with the NMR data for the synthetic materials [20,25]. Interestingly, synthetic materials from the Looper synthesis and the Lovely synthesis were evaluated chromatographically by Proksch and found to co-elute with the isolated natural materials [20,25]. One outcome of this analysis was the revelation that kealiinine B (20) and kealiinine C (21) were actually isolated as a mixture which co-elute by HPLC [18]. In the course of our studies, we prepared isokealiinine C (54) as we hypothesized that a mistake might have been made in the structure determination in the location of the methoxy groups (Fig. 3.3) [25]. The NMR data for this material did not match the natural material nor did the chromatographic properties, although the cytotoxicity data were similar to that of kealiinine A (19) and B (20) [26]. Taken as a whole, these data suggest that the core frameworks are the same, but that the natural material and synthetic materials are different tautomers. However, these materials do not appear to interconvert and as such a better description would be that these two forms are actually stable isomers rather than interconverting tautomers as there does not appear to be a kinetically accessible pathway for their interconversion. This raises the question of whether the natural products have actually been synthesized (vide infra).

2-Deoxy-2-aminokealiiquinone This imidazonaphthquinone alkaloid 55 was isolated from Leucetta chagosensis harvested off the coast of Chuuk Atoll, Micronesia by Schmitz and coworkers (Fig. 3.3B) [29]. This natural product is closely related to kealiiquinone (4)

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(vide infra) with the difference lying in the presence of a 2-amino group rather than an enol moiety as found in kealiiquinone at C2 [12]. It is conceivable that the 2-oxo derivative is an isolation artifact from hydrolysis of the 2-aminoimidazole. The dichloromethane extract from the sponge was shown to have cytotoxicity against P-388 cell line (IC50 ¼ 2 μg/mL) but the activity of the purified material was not reported by the isolation group. There has been only one total synthesis of this molecule reported to date by Lovely and coworkers which relies on the oxidation of a late-stage intermediate 52 en route to kealiinine C (21) [26]. Specifically, it was found that oxidation of the 2-azidonaphthimidazole 52 with hydrogen peroxide in a mixture of formic acid and methanol provided the 2,3-dimethoxyquinone derivative 56 in good yield (Scheme 3.6). Reduction of the azide to the amine by catalytic hydrogenation delivered the natural product 55 for which the spectroscopic data were identical in all respects to those reported for the isolated material. It is notable, that in this case both the natural material and the synthetic materials were isolated as the 2-amino congener. As part of a general screening program, a sample of the synthetic natural product was evaluated against MCF7 breast cancer cells exhibiting an IC50 value of 43.8 μM [26].

Kealiiquinone As noted above, kealiiquinone (4) is closely related to the 2-amino congener and was in fact the first quinone derivative reported from a Leucetta sponge and initially described by Clardy and coworkers (Scheme 3.7) [12]. In this report, an X-ray structure of the natural product framework was described, which confirmed the general connectivity but revealed that the 2-imidazolone existed as the enol tautomer, at least in the solid state. Furthermore, the 1H NMR data were supportive of this structural assignment. No screening was reported on this natural product as isolated. In contrast to the 2-amino congener, there has been more activity directed toward the total synthesis of kealiiquinone resulting in two total syntheses and three syntheses of kealiiquinone analogs.

SCHEME 3.6 Total synthesis of 2-deoxy-2-aminokealiiquinone.

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SCHEME 3.7 Ohta total synthesis of kealiiquinone (2-oxo form).

Ohta synthesis The first synthesis of this alkaloid appeared in 1995 and was based on the elaboration of thio ether 57 via a series of sequential metalations and electrophilic trapping reactions (Scheme 3.7) [30,31]. Deprotonation of 57 at C5 with LTMP and reaction with the trisubstituted benzaldehyde derivative 58 afforded the alcohol 59 which was converted to the corresponding methyl ether. Bromination with NBS at C4 set the stage for halogen-lithium exchange and reaction with anisaldehyde and formation of the 4,5-disubstituted imidazole framework 60. An intramolecular Friedel–Crafts reaction and subsequent dehydration was triggered by PPA in acetic anhydride the product of which, upon reductive desulfurization with Ni(BH4)2, afforded the naphthimidazole framework 61. Ester hydrolysis and protection of the free phenolic OH as

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the TBS ether gave 62. Introduction of the C2-oxygen was achieved by metalation with LDA followed by reaction with benzoyl peroxide to provide the imidazolone derivative 63. Fluoride-induced desilylation and subsequent oxidation of the phenol with salcomine and oxygen delivered the kealiiquinone framework 64 as the 2-oxo tautomer (vide infra).

Lovely synthesis Similar to the approach to the 2-amino congener 55, this synthesis again employed a late-stage intermediate from the kealliinine C (21) synthesis described above [26]. In this case, naphthimidazole 50 was metallated with n-BuLi at C2 and then reacted with (TMSO)2 which delivered the corresponding 2-imidazolone 65 in moderate yield (Scheme 3.8) [32]. The imidazolone was then oxidized under the same conditions used en route to 2-deoxy-2-aminokealiiquinone (55) which delivered the bright red kealiiquinone 64 in good yield, again in the keto form. While bearing some similarity to the Ohta’s approach, this synthesis is significantly shorter than the prior synthesis as it avoids the use of any protecting groups. Similar to Ohta’s finding, synthetic kealiiquinone was shown to exhibit only weak cytotoxicity against MCF7 cells (IC50 ¼ 91.9 μM) [26]. Other synthetic approaches Diels–Alder approach to kealiiquinone core In addition to the total synthesis of kealiiquinone, two approaches to the naphthimidazole framework which rely on intramolecular cycloadditions have been described. Our lab has used an intramolecular Diels–Alder reaction of a vinylimidazole 68 to afford the dihydrobenzimidazole 69 (Scheme 3.9) [33,34]. Oxidative aromatization delivered the benzimidazole 70 which upon reduction and oxidation provided the phthalaldehyde derivative 74; of note here is that only the use of the sulfimine allowed access to the dialdehyde whereas other oxidants resulted in the formation of a lactone [35]. With the phthaldehyde 74 in hand, it was treated with the glyoxal derivative in the presence of cyanide which affords the vinylogous diacid 75 in the modest yield. Exposure of the diacid to TMS-diazomethane produced the signature

SCHEME 3.8 Lovely approach to the total synthesis of kealiiquinone (2-oxo form).

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SCHEME 3.9 Diels–Alder approach to kealiiquinone core.

dimethoxyquinone 76. Unfortunately, the remaining key functional group, the 2-imidazolone could not be introduced at this point via standard metalation/ oxidation protocols.

Synthesis of desmethyl and desmethoxy congeners In order to circumvent this issue, a new method for oxidizing imidazolium salts using bleach was developed which permitted the introduction of the 2-oxo group in the naphthimidazole derivative thus avoiding the use of strong bases (71 ! 77, Scheme 3.10) [36]. Reduction of lactone to the corresponding diol 78 and subsequent oxidation produced the phthalaldehyde derivative 79. Reaction with glyoxal derivative delivered the vinylogous bis acid 80 which upon methylation provided the completely functionalized framework 81 of kealiiquinone. Completion of the synthesis simply required removal of the N-benzyl protecting group; a variety of classical methods for accomplishing this transformation were unsuccessful, only exposure to TfOH resulted in

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SCHEME 3.10 Synthesis of desmethyl and desmethoxy congeners of kealiiquinone.

debenzylation, however, this was accompanied by O-demethylation of the C40 -anisyl group producing 82. Attempts to selectively remethylate the phenolic OH were unsuccessful, resulting in concomitant N-methylation. In addition to the preparation of 70 -desmethylkealiiquinone (82), similar chemistry was employed to access the 40 -desmethoxy analog 83.

Garratt–Braverman cyclization approach to kealiiquinone congener Basak and coworkers have employed a Garratt–Braverman cyclization of a propargylimidazole derivative 88 to construct a furanonaphthimidazole framework 89 (Scheme 3.11) [37]. The cyclization precursor 88 was constructed from the benzyl protected 4-iodoimidazole 84 derivative by methylation to afford the imidazolium salt 85 and bleach-mediated oxidation to provide the 2-imidazolone derivative 86. A Sonogashira reaction with the bis propargylic ether 87 afforded the cyclization precursor which upon

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SCHEME 3.11 Garratt–Braverman cyclization to an advanced kealiiquinone congener.

SCHEME 3.12 Total synthesis of isokealiiquinone.

reaction with KOBu-t delivered the furanonaphthimidazole skelton 89. Bis benzylic oxidative cleavage produced the phthalaldehyde derivative 79 and intercepting the Lovely synthesis described above in Scheme 3.10.

Isokealiiquinone Ohta’s lab has reported the synthesis of a non-natural derivative isokealiiquinone which followed essentially the same route as depicted in Scheme 3.7 excepting the ordering of the reactions of the two benzaldehyde substrates was inverted [38]. In addition, they reported a new approach for incorporating the 2-oxo group via basic hydrolysis of the 2-thioimidazolium salt (Scheme 3.12); this served as inspiration for development of the bleach oxidation described in Schemes 3.10 and 3.11. One other point of note is that the benzyl group in this regioisomer derivative was removable under reductive conditions which may reflect the steric accessibility of this substituent in the isomeric position (cf. 81 in Scheme 3.10). In this same report, Ohta and coworkers describe the anticancer activity of both kealiiquinone and isokealiiquinone and although only overall data were provided (no IC50s), the activity profile for both natural products was consistent with a unique mechanism of action.

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A similar conundrum in the kealiiquinone syntheses was encountered relative to the reported structure of the natural product (enol form) and the synthetic variants (keto form). In both cases, X-ray structures were obtained confirming that at least in the crystalline forms they are distinct molecules, furthermore differences in the NMR shifts were consistent with the assigned structures and thus not simply a consequence of the crystallization process. Ohta and our group have conducted calculations on the two tautomers and have found the keto form to be substantially more stable than the enol form (Ohta—PM3 ΔΔHform ¼  13.4 kcal mol1 [31]; Lovely—DFT ΔΔHform ¼ 15 kcal mol1) which suggest that at equilibrium the keto form is heavily favored. Although thermodynamically favorable, it is not clear what the kinetic barrier is for this interconversion and whether these tautomers may in fact be kinetically stable. Both Ohta and our group attempted to locate samples of the isolated natural products from the original group which reported this molecule. Further, in our case we contacted several other groups which have reported the isolation of other Leucetta alkaloids in the hope that they might have samples of kealiiquinone from other searches for new natural products in order to directly compare the spectroscopic and chromatographic properties, but to no avail. Additionally, it had been our hope to establish whether the naturally occurring material would transform into the 2-oxo form or whether it is a discrete and stable material. Again, this raises the question of whether any of these reported syntheses constitute actual total synthesis of kealiiquinone as all of these synthetic reports report the construction of the keto tautomer. As noted above, are these two derivatives really tautomers if they are not actually interconverting? One further issue warranting discussion here is the difference between the synthetic 2-oxo derivatives and 2-amino derivatives. In our hands [26,33,34,36] and in the Ohta lab [30,31,38], naphthimidazolone derivatives have all been isolated as the 2-oxo isomer whereas with a nitrogen substituent, the 2-amino isomer has been isolated for both naphthimidazoles and naphthquinone derivatives [20,25,26,28]. Taken in sum, this suggests that the C]O bond strength outweighs the increase aromaticity presumably present in the enol isomer, whereas the increased aromaticity outweighs the C]N strength in the imino tautomer. Although, this analysis does not conform with the isolation of the imino tautomers of the kealiinines reported by the Proksch group which reports the use of RP-LC for the purification of these materials in which TFA is part of the eluent.

Oxidized derivatives Calcaridine A Calcaridine A (8) was reported by the Crews lab in 2003 and was one of the first intrinsically chiral Leucetta alkaloids to be identified [15]; it is also the

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only member of this family to contain a rearranged 4,4-dibenzyl 5-imidazol(on)e framework. The constitution of calcaridine A was secured through spectroscopic means, however, the relative stereochemistry of the two chiral centers was not defined. As noted above, no biosynthetic studies have been performed on this family of natural products, but Crews and coworkers speculated that it might arise biosynthetically via oxidative rearrangement of a naamine-type derivative. The isolation of 14-oxygenated naamine derivatives has been described and provide some circumstantial evidence for such a hypothesis [19]. Koswatta et al. investigated such a bio-inspired approach starting from methyl imidazole derivative 38 (Scheme 3.13) [39,40]. The synthesis began by introduction of a formyl group via magnesium-iodine exchange and trapping of the resulting Grignard with N-methylformanilide to produce 93. Protection of the aldehyde 93 as the acetal 94 with ethylene glycol set the stage for a second magnesium-iodine exchange reaction, this time reacting the Grignard with the protected benzaldehyde derivative 95 to afford 96. Hydrolysis of the acetal was followed by

SCHEME 3.13 Total synthesis of calcaridine A.

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silane-mediated reductive deoxygenation to provide 97. Reaction of the aldehyde with the p-anisyl Grignard introduced the final aryl moiety and completed the carbon skeleton 98. Introduction of the methyl ether was accomplished via Williamson ether synthesis and then the remaining nitrogen at the C2 position was incorporated by lithiation and trapping with tosyl azide giving the fully substituted imidazole 100. In earlier studies on closely related systems, the azido group and the O-benzyl protecting group were removed by hydrogenolysis and then the 2-amino compound subjected to rearrangement. The rearrangement occurred upon treatment with an N-sulfonyloxaziridine 101 [41] to afford two diastereomeric imidazolones 8 and epi-8, but unfortunately these proved difficult to separate. It was subsequently found that the rearrangement also occurred on the 2-azido derivative 100 to deliver a 1:1 mixture of diastereomers that was separable through chromatography. Subjection of each diastereomer to hydrogenolysis resulted in reduction of the azide to the amine and removal of the O-benzyl protecting group. One of the diastereomers exhibited spectroscopic properties that matched with the natural product but assigning the relative configuration was not possible by NMR spectroscopy. Fortunately, the non-natural diastereomer epi-8 provided crystals suitable for X-ray analysis which provided the relative configuration of the two stereocenters and by analogy, the relative stereochemistry of the naturally occurring diastereomer was assigned.

Azide-tetrazole tautomerism One point of note emerged in the context of other projects which cast doubt on the validity of the structures of the intermediate azides 102 and epi-102. Closer examination of the characterization data for these intermediates revealed the absence of stretches attributable to the azido groups in the IR spectra; this was not recognized as being significant per se as the intermediates underwent reduction to afford the expected amines, one of which was characterized by X-ray crystallography. However, in related chemistry it was discovered that some 2-azido imidazolones were prone to valence tautomerism with the corresponding tetrazole, these too lacked the characteristic azide stretch. Few 2-azidoimidazole derivatives have been prepared and studied in this context in the literature, but those that have appear to exist predominantly in the 2-azido form; although the precise conditions (solvent, temperature, etc.) make a difference [42–49]. IR data for 103 and epi-103 are more consistent for the tetrazole form, but the presence of the azido tautomer facilitates its conversion to the 2-amino derivative (Scheme 3.14).

Spiroleucettadine This alkaloid 104 was isolated from the same sponge sample as calcaridine A and in addition to the 4,4-disubstituted imidazolone, which it shared with

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SCHEME 3.14 Azide-tetrazole tautomerism.

FIG. 3.4 Spiroleucettadine and related structures.

calcaridine A, it contained several structurally unusual features; among them the trans fused [3.3.0] bicyclic system, an ortho amide and the spiro fused cyclohexadienone (Fig. 3.4) [13]. In addition to the structural challenges embodied in this framework, this natural product exhibited antibiotic activity and as a result attracted the attention of the synthetic community. It was in the light of three unsuccessful approaches (see Schemes 3.17–3.20) to the natural product questions arose regarding the veracity of the structural assignment [50–52]. As a result, Crews and coworkers reinvestigated the structural assignment and were ultimately able to obtain an X-ray structure and this revealed that the structure had been erroneously assigned [14]. The revised structure 5 still contained the 5,5,6-tricyclic framework, including the spiro cyclohexadienone, but the [3.3.0] framework was now cis in addition to the presence of an N-methyl aminal and a 2-imidazolone. The closely related spironaamidine (105) was isolated from a sample of Leucetta microphis collected in Indonesia [53]. To date there has been one total synthesis of the revised structure, confirming the revision, along with three approaches to the originally proposed structure.

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The Hawkins synthesis The total synthesis commenced by formation of the α-amino ketone derivative 110 through formation of the Weinreb amide 108 and subsequent reaction with the benzyl Grignard derivative (Scheme 3.15) [54–56]. The precursor Weinreb amide 108 was constructed from the commercially available L-tyrosine derivative 106 which was converted to the O-benzyl ether, hydrolyzed to the carboxylic acid 107 and then converted to the amide under standard coupling conditions. After some experimentation, it was found that removal of the benzyl group by catalytic hydrogenation prior to acid-mediated removal of the carbamate delivered the α-amino ketone 112 (as the TFA salt) which upon reaction with N-methyl carbamoylimidazole delivered a mixture of the urea 113 and the carbinolamine 114. Direct treatment of this mixture with iodosobenzene diacetate (IBDA) resulted in an oxidative dearomative spirocyclization reaction via the carbinolamine oxygen which afforded the complete spiroleucettadine framework 115, which was confirmed by X-ray crystallography in a low, but usable yield (Scheme 3.15). Completion of the synthesis required two additional steps, oxidation of C5 and incorporation of the remaining N-methyl amino group. This was readily accomplished by employing Dess–Martin periodinane in an extension of chemistry developed by the Nicolaou group which incorporated an acetoxy group, presumably through the intermediacy of an imine or iminium ion producing 116 (Scheme 3.16) [57–59]. Substitution of the acetoxy group was readily accomplished by reaction of 116 with N-methylamine hydrochloride in THF in the presence of triethylamine. The resulting material 5 was identical in all respects to the natural material including the optical rotation. In addition to this enantiospecific synthesis, the authors performed a racemic version of spiroleucettadine and in the process were able to show that their synthesis afforded a single enantiomer and that the natural material is also produced as a single enantiomer rather than as a scalemic mixture [14]. While in this age of powerful tools for structure determination, the total synthesis of natural products to confirm structural identity may have lost some of its apparent impact, there are still many cases, including molecules like spiroleucettadine, which are deficient in hydrogen atoms where total synthesis plays a pivotal role in structure determination. Danishefsky approach Two strategically different approaches were investigated by Li and Danishefsky to access the originally reported structure of spiroleucettadine [51]. In the first approach, the authors proposed to construct the central furano B-ring last via a dearomatizing spirocyclization using an intact imidazole precursor. Creatinine (117) was subjected to a Knoevenagel reaction with anisaldehyde to give 118 as an inconsequential mixture of alkene isomers (Scheme 3.17), which upon N-methylation and catalytic reduction produced the

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SCHEME 3.15 The Hawkins synthesis of spiroleucettadine.

SCHEME 3.16 Completion of the total synthesis of spiroleucettadine.

aminoimidazolone derivative 119. Alkylation with the benzyl bromide 120 delivered the 4,4-disubstituted imidazolone 121, which was protected as the BOC derivative 122 in good yield. Reductive removal of the O-benzyl group set the stage for the key dearomatizing spirocyclization reaction. Oxidation of the phenol 123 with PIFA resulted in the formation of the hydroxycyclohexadienone 124, but cyclization to form the spiroleucettadine framework was not observed. Interestingly, altering the oxidation state of the amide 122 to the carbinolamine 126 and then subjecting this intermediate to the dearomatizing spirocyclization delivered the required framework 127, but subsequent attempts to oxidize C4 to introduce the remaining hydroxyl group were unsuccessful. In an alternative approach (Scheme 3.18), these investigators sought to construct the BC rings prior to the imidazole A-ring formation [51]. In this

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SCHEME 3.17 Danishefsky approach to the original structure of spiroleucettadine—part 1.

case the synthesis commenced by a sequential double alkylation of the glycine imino ester 128 to afford the amino ester 130. Ester hydrolysis was followed by conversion of the amino group to the BOC derivative 131. Catalytic hydrogenation removed the O-benzyl protecting group which then set the stage for dearomatizing spirocyclization to afford the amino lactone 133. N-methylation and removal of the BOC group then allowed the construction of the imidazole fragment from 134. This process involved reaction of 134 with the isothiourea derivative in the presence of silver, however this too resulting in the formation of the hydroxycyclohexadiene 124 obtained in the first generation route described above.

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The authors speculated that in the second route “the formation of 124 virtually requires the intermediacy of a structure of the general type 135” and further go on to suggest that caution should be exercised with respect to the provenance of the assigned structure of spiroleucettadine [51].

Ciufolini approach This investigation began by lithiation and alkylation of the tyrosine analog 136; TFA-mediated removal of the BOC group then provided the secondary amine 139 (Scheme 3.19) [50]. Incorporation of the BOC-protected guanidine was accomplished through reaction with the isothiourea derivative. N-methylation of 140 followed by base hydrolysis afforded the mono-BOC carboxylic acid 142. Exposure of 142 to neat TFA delivered the imidazolone 143, but with nominally the incorrect methylation pattern. However, removal of both the BOC groups in 140 with TFA also triggered cyclization to a related imidazolone 144 which upon treatment with (BOC)2O produced 145. N-methylation of 145 and hydrolytic cleavage of the sulfonated hydroxyl group provided the free phenol 123; TFA treatment gave the completely unprotected precursor imidazolone 146. These three imidazolones, 123, 143 and 146, were subjected to oxidative dearomatization reactions with

SCHEME 3.18 Danishefsky approach to the original structure spiroleucettadine—part 2.

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hypervalent iodine reagents in the presence of water; imidazolones 123 and 143 underwent dearomatization–water addition whereas imidazolone 146 delivered a complex mixture of products. Evidence from ESI-MS analysis suggested the presence of a species consistent with the formation of spiroleucettadine (or an isomer) but attempts to isolate this material was unsuccessful. On the basis of these failures to access the proposed natural product framework, these authors concluded that the structure of spiroleucettadine was probably incorrect.

Watson approach This synthetic route involves the intermediacy of an α-aminoamide 152 using a readily available tyrosine derivative 147 (non-natural enantiomer) [52]. The synthesis began by converting the N-protected amino acid to the oxazolidinone 148 in order to facilitate the stereoselective introduction of the second

SCHEME 3.19 Ciufolini approach to the original structure of spiroleucettadine.

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benzyl group (Scheme 3.20). The oxazolidinone was prepared by treating 147 with the dimethyl acetal of benzaldehyde in the presence of a Lewis acid, which upon deprotonation and reaction with the p-methoxy substituted benzyl bromide 129 delivered the desired disubstituted amino acid 149. Hydrolysis of the oxazolidinone gave the amino acid 150 which was converted to the dimethyl amino amide 151 through N-methylation of the Cbz-protected nitrogen, formation of the acid fluoride and thereafter the N-methyl amide. Removal of both benzyl containing protection groups (O-benzyl and Cbz) was readily achieved upon catalytic hydrogenation and the resulting amino amide 152 reacted with cyanogen bromide to afford the glycocyamidine 146 in low yield, but sufficient for the ensuing scouting experiments. Attempts to construct the spiroleucettadine framework via an oxidative dearomatization-nucleophilic trapping sequence were unsuccessful, mirroring observations of the Ciufolini group using the same substrate. These unsuccessful attempts prompted Watson and coworkers to suspect that the assigned structures were incorrect and proposed several alternatives [52]. The 13C NMR shifts for the proposed new structures and the original structure were calculated using DFT methods (B3LYP/6-31G(d)—geometries and then MPW1PW91/6-311 + G(2d,p)—NMR) and then compared. Two of these

SCHEME 3.20 Watson approach to the original structure of spiroleucettadine.

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results are shown in Scheme 3.20. The trans structure 153 was considered feasible on the basis of biosynthetic considerations and fit the experimental data better than the original structure 104 (MAE ¼ 4.3 ppm); the cis structure of 153 was evaluated by Crews and coworkers at a later date [14]. An alternative structure 154 was posited possessing an N-OH group which appeared to fit the data even better, but was considered less likely due to biosynthetic considerations. It should be noted that similar NMR calculations conducted by Crews, when performed on the actual structure of spiroleucettadine showed excellent fit (MAE ¼ 1.7 ppm) [14].

Spirocalcaridines A and B Spirocalcaridines and possible diastereomeric structures Two spirocalcaridines, A and B (155a–b), were isolated from the same sponge sample as calcaridine A (8) and reported in 2003 (Fig. 3.5) [15]. These two congeners differ by virtue of a methyl group but are otherwise similar. Interestingly, spirocalcaridine B (155b) does not appear to be an artifact from the isolation process as both 155a and b were shown by Crews to be stable in methanol solutions [15]. The constitutions of these molecules were secured through NMR spectroscopy but the relative stereochemistry of the three chiral centers was not established. The lack of appropriately positioned protons for use in NOE studies precluded this assignment, furthermore, the authors were not able to assign the location of the methoxy group in spirocalcaridine B and thus the position of this group should be considered tentative [15]. Given these ambiguities, there are four possible stereochemical arrangements 157–160 that can be posited, but on the basis of ring strain considerations, the two cis [3.3.0] diastereomers are more appealing. Out of these two, it is more difficult to conclude definitively which is more likely as these are separated by only c. 2 kcal/mol based on unpublished work from our lab. DFT calculations have been reported for two of the possible cis and trans isomers for both spirocalcaridine A and B which show close agreement for the cis ring junction and endo orientation of the anisyl group [52]. Again, no biosynthetic studies have been performed but they can be related to the naamine framework by a net alkylative dearomatizing spirocyclization (cf. 156, Fig. 3.5), followed by dihydroxylation of the imidazole C4–C5 bond. Approaches to the spirocalcaridine framework Our laboratory, in unpublished work, has explored this direct alkylative dearomatization strategy unsuccessfully and accordingly begun to explore approaches that involve the de novo construction of the imidazole moiety [60]. The basis for this revision was reports from the Larock lab of facile electrophile-induced dearomatizing spirocyclization reactions leading to the formation of highly functionalized spiro fused ring systems containing the 5,6-bicyclic framework of spirocalcaridine in addition to suitable functionality [61], in the form of a

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FIG. 3.5 Spirocalcaridines and possible diastereomeric structures.

masked 1,2-diketone for introduction of the imidazole moiety [62]. In an example of this approach, alkynone 161 was reacted with molecular iodine in acetic acid which delivered an inconsequential 2:1 diastereomeric mixture of acetates 162 (Scheme 3.21) [62]. An Ulmann-like copper-catalyzed amidation delivered the formamide 163 in moderate yield, which for completion of the spirocalcaridine framework required formation of two additional carbon–nitrogen bonds. It was anticipated that this might be accomplished by exposure of 163 to methylamine HCl and a suitable base. In the event, however, under several conditions investigated, the desired product was not obtained, rather either the rearranged naphthimidazole product 164 resulting from the intermediacy of the arenium ion or the hydrolysis product 165 were obtained. In the case of the latter product, the amino moiety was viewed as a potential handle for introduction of the guanidine moiety via reaction with cyanamide; however under the acidic conditions employed, an aminonaphthol ring expansion product 167 was obtained rather than the carbinolamine 166. It is conceivable that conditions might have been identified that circumvented the ring expansion process which resulted in the formation of the imidazole, but another option was considered that if successful would allow construction of the complete natural product framework in one synthetic operation. The electrophile-induced dearomatization was extremely powerful and thus sequencing this process with formation of a nitrogen–carbon bond was considered as a means to telescope the operation. To accomplish this, two possibilities to trigger the cyclization were considered (a) oxidation of nitrogen via a nitrenium ion [63] or (b) oxidation of the aryl ring via a phenoxonium ion [64–68].

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SCHEME 3.21 Exploratory approaches to the spirocalcaridine framework.

SCHEME 3.22 Substrate assembly of phenolic propargyl guanidine.

On the basis of a large body of existing precedent regarding phenoxium, Singh and coworkers elected to pursue the second approach first [69]. The requisite substrates were rapidly assembled through an A3-coupling reaction, delivering the propargyl amine 169 in good yield (Scheme 3.22) [20,28,69–71]. Deprotection of the allyl amine with barbituric acid and Hg(II)-mediated guanylation of amine 170 with the isothiourea provided the guanidine 171; desilylation of the phenol with TBAF then delivered the

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cyclization substrate 172. While there are numerous reagents to effect oxidation of phenols, hypervalent iodine reagents have proven to be especially effective. Accordingly, on exposure of 172 to iodosobenzene diacetate (IBDA) two cyclization products were isolated in 2% and 17% yields, respectively. The structures of the two cyclization products were determined by X-ray crystallography which demonstrated unequivocally that tricyclic molecules containing a cyclohexadienone moiety were formed but only the minor product 174 had the desired 5,5-spirocyclohexadienone framework arising from a 5-endo-dig pathway. The major product 173, formed via a 4-exo-dig pathway, contained a 6,4-spirocyclohexadienone framework. On closer analysis of the reaction it became apparent why the cyclobutane was formed (Scheme 3.23). Specifically, upon formation of the phenoxium ion 175, cyclization onto the alkyne can occur to form two vinylic cations, in the case of the 4-exo-dig pathway the cation 176 is stabilized by the electron donating p-anisyl group whereas this stabilization is absent in the cation 177 formed via the 5-endo-dig pathway. On this basis the cyclobutane intermediate is more favorable and this pathway is favored leading to the “major” product. The analysis of cation stability suggested that the alternative pathway via a nitrenium ion might be more fruitful, although this would involve the intermediacy of the unknown guanidenium ion equivalent (see Scheme 3.25) [72]. Accessing the requisite substrates only required a minor modification of the A3-coupling reaction by substituting the silyl protected phenol for the methyl substituted congener 178 (as outlined in Scheme 3.24). Subjecting the guanidine 181 to reaction with IBDA and Cs2CO3 in HFIP delivered a single product 173 in 80% yield containing the complete framework of the spirocalcaridines. This reaction was extended to other protected guanidines and found to proceed with similar yields.

SCHEME 3.23 Mechanistic rationale for the formation of two spiro cyclic products.

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SCHEME 3.24 Alternative synthesis of spirocalcaridine framework.

SCHEME 3.25 Mechanistic rationale for dearomatizing spirocyclization.

Mechanistically, this process was formulated in terms of oxidation of the guanidine nitrogen which then adds to the alkyne to deliver the corresponding resonance stabilized vinylic cation (Scheme 3.25). Ipso addition of the pendant electron-rich aromatic followed by demethylation affords the spirocalcaridine framework [72]. Other pathways, including a concerted process or a radical-based pathway cannot be ruled out at this time.

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With the main framework in hand, attempts were made to elaborate this into the natural product by first deprotecting the t-BOC groups. Disappointingly, but not unexpectedly, when TFA was used to remove these groups dienone-phenol rearrangement occurred to afford a mono BOCdihydronaphthimidazole which was characterized by X-ray crystallography. Interestingly, the more sterically hindered BOC group was removed first which confirmed the initial assignment based on the relative chemical shift of the two t-Bu groups. The one on the imidazole nitrogen (N3) was further upfield as it is positioned in the shielding cone of the p-methoxybenzene group. It was subsequently found that upon extended treatment with TFA both t-BOC groups were removed and the rearranged dihydronaphthimidazole underwent oxidation to afford the fully aromatized heterocycle [72]. The process described in Schemes 3.24 and 3.26 is closely related to chemistry reported by van der Eycken and coworkers (see Scheme 3.5) [28] but in our case it suggests a possible biosynthetic connection between the naphthimidazole branch of the family and the spirocyclic branch of the Leucetta alkaloids.

Newly isolated examples While this manuscript was in review, three additional examples of this family of alkaloids were isolated and will be mentioned here as they possess some unique features (Fig. 3.6). The first two examples are isomers of clathridine A (190) containing the same basic imidazole framework, but the methyl parabanic acid has rearranged to the oxazolone in leuchagodine A (188) and undergone decarboxylation in leuchagodine B (189) [73]. Given the extensive

SCHEME 3.26 Spiro cyclohexadienone-phenol rearrangement.

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processing of the samples during the isolation and purification process, it is tempting to suggest that these two molecules are in fact artifacts of the isolation process rather than genuine Leucetta alkaloids, but analysis of the crude extracts show the presence of 188. Further a family member was isolated from the same sponge and named kealiinine D (191) [73]. This congener contains the basic naphthimidazole framework of the kealiinines, cf. kealiinine B (20), there are notable differences. Kealiinine D (191) appears to the first example in this subgroup to contain oxidation in the B-ring, although there are examples of benzylic oxidation in naamidine congeners [19]. However, the most notable difference is in the apparent position of imidazole methylation which in contrast to all of the other known naphthimidazoles, including the kealiiquinone and the 2-amino congener is proximal to the p-methoxyphenyl D-ring (cf. isokealiiquinone (92), Scheme 3.12) [38]. In addition to the three new Leucetta alkaloids, this group also isolated a sample of kealiinine B (20) [73], in contrast with the initial report from the Proksch lab, this material was isolated as a single species and most notably exhibited NMR data consistent with the synthetic materials described by Looper and our labs [20,25].

Summary In summary, this chapter has provided an overview of the progress made toward the total synthesis of the more highly oxidized members of the Leucetta alkaloids. By many measures, these molecules may be considered relatively simple, but the high densities of sensitive functionality in the more highly oxidized congeners offer distinct challenges to contemporary synthetic methods, in particular to avoid skeletal rearrangements. Two distinct approaches to these natural products are utilized (a) involving elaboration of pre-existing imidazoles or (b) de novo construction of the heterocycle. Both methods have their advantages in the case of the first approach this permits the ready construction of deletion analogs whereas in the second approach similar intermediates, by suitable choice of reaction conditions can be coaxed into producing different family members. Despite the power of modern spectroscopic techniques, synthesis has proven valuable in confirming the structural identity of several family members (spiroleucettadine) and addressing stereochemical issues (calcaridine A). In other cases, synthetic materials have been prepared which are isolated in alternative tautomeric forms in comparison to naturally occurring materials, these materials do not appear to be interconvertible leading to a question of whether the natural products have actually been synthesized. However, direct comparison of the chemistry of natural and synthetic versions of these alkaloids have yet to be performed to elucidate these unresolved issues. In many cases, only limited studies of the utility of these molecules as potential medicinal agents have been reported, although

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FIG. 3.6 Some newly isolated examples of Leucetta alkaloids.

the synthetic studies described herein are enabling screening programs to establish their activity in a broad array of biological screens [26,27,74,75]. After acceptance of the manuscript for publication and during the production of the galley proofs for the article, additional papers appeared describing synthetic efforts toward these natural products. Van der Eycken and coworkers described a Pd-catalyzed approach to kealiinine C [76]. Solorio-Alvarado and coworkers describe their efforts toward the total synthesis of kealiiquinone and congeners in a series of publications [77].

Acknowledgments Our contributions described in this chapter have been supported by the Robert A. Welch Foundation (Y-1362) to whom we are immensely grateful. We would also like to thank Professor Fan Yang (Shanghai Jiao Tong University) for sharing NMR and other characterization data for kealiinine B.

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Abbreviations BOC CSA DAST DBU DCC DFT DIBAL-H DIEA DMBA DME DMEDA DMF DMP EDCI ESI-MS HFIP HOBT IBDA KHMDS LDA LTMP MAE MAPK NBS NIS PIFA PPA TBAF TBAI TBSCl TFA TFE THF TMS TrisN3

tert-butoxycarbonyl (1R)-()-10-camphorsulfonic acid (diethylamino)sulfur trifluoride 1,8-diazabicyclo[5.4.0]undec-7-ene N,N0 -dicyclohexylcarbodiimide density functional theory diisobutylaluminum hydride N,N-diisopropylethylamine 1,3-dimethylbarbituric acid dimethoxyethane N,N0 -dimethylethylenediamine dimethylformamide Dess–Martin periodinane N-(3-dimethylaminopropyl)-N0 -ethylcarbodiimide hydrochloride electrospray ionization mass spectrometry 1,1,1,3,3,3-hexafluoro-2-propanol 1-hydroxybenzotriazole iodosobenzene I,I-diacetate potassium bis(trimethylsilyl)amide lithium diisopropylamide lithium 2,2,6,6-tetramethylpiperidide mean absolute error mitogen-activated protein kinase N-bromosuccinimide N-iodosuccinimide [bis(trifluoroacetoxy)iodo]benzene polyphosphoric acid tetrabutylammonium fluoride tetrabutylammonium iodide tert-butyldimethylsilyl chloride trifluoroacetic acid 2,2,2-trifluoroethanol tetrahydrofuran trimethylsilyl 2,4,6-triisopropylbenzenesulfonyl azide

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