Synthesis of the Aminocyclitol Core of Jogyamycin via an

Letter Cite This: Org. Lett. 2018, 20, 3938−3942

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Synthesis of the Aminocyclitol Core of Jogyamycin via an Enantioselective Pd-Catalyzed Trimethylenemethane (TMM) Cycloaddition Barry M. Trost,* Lei Zhang, and Tom M. Lam Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States

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S Supporting Information *

ABSTRACT: The use of β-nitroenamines as a new class of acceptors in the enantioselective Pd-catalyzed trimethylenemethane cycloaddition afforded differentiated 1,2-dinitrogen bearing cyclopentanes with three contiguous stereocenters. The utility of these acceptors was demonstrated with the efficient construction of the core of jogyamycin and aminocyclopentitols. Further elaboration of the cycloadducts provided a concise synthetic approach toward joygamycin.

J

ogyamycin is a metabolite isolated from Streptomyces sp. aWM-JG-16.2.1 from soil samples in Jogjakarta, Indonesia. It is an aminocyclitol derivative that bears close structural semblance to pactamycin and possesses elevated biological activity (see Figure 1).2 Members of this class exhibit potent

Our retrosynthetic plan (Scheme 1) toward jogyamycin involves a late-stage installation of the triol via methylation and Scheme 1. Retrosynthetic Analysis

Figure 1. Aminocyclitol natural products jogyamycin and pactamycin.

dihydroxylation, affording cyclopentenone 2. The enone would be introduced through an alkene ozonolysis with a subsequent α-methylenation. The urea would be accessed through nitrile hydration to a primary carboxamide, followed by a Hofmann rearrangement, leading to intermediate 3. The aryl group of 3 would be introduced through a chemoselective C−N cross coupling. Careful manipulation of the various nitrogen oxidation states would allow us to differentiate between the three core nitrogens in cyclopentane 4. We envisioned that this core would be furnished by the key palladium-catalyzed TMM cycloaddition of donor 5 and dinitrogen acceptor 6. Although these β-nitroenamines have been successfully employed as Michael acceptors and dienophiles, their utility was largely limited by access. Consequently, we developed an efficient method toward these acceptors from the direct nitration of vinylimines.10 The enantioselective and diastereoselective addition onto these acceptors affording differentiated 1,2-

anticancer as well as antiprotozoal activities against malaria (P. Falciparum) and African sleeping sickness (T. Brucei).1−3 The accepted mechanism of action involves the binding to the small subunit of ribosomes across all three kingdoms, leading to cytotoxic properties as well.4 However, studies of analogues have shown the potential for the modulation of target selectivity.5 While the synthesis of pactamycin has been reported by the groups of Hanessian6 and Johnson,7 the synthesis of jogyamycin remains undisclosed.8 The densely heteroatom substituted cyclopentane core has remained a major challenge in the efficient and stereoselective access to this family of compounds. Consequently, we developed the Pd-catalyzed enantioselective trimethylenemethane (TMM) cycloaddition9 to address this synthetic challenge. From readily accessible coupling partners, the TMM cycloaddition offered an efficient construction of the core, establishing three stereocenters diastereoselectively and enantioselectively, providing differentiation of the trans diamine groups on the target core. © 2018 American Chemical Society

Received: May 14, 2018 Published: June 25, 2018 3938

DOI: 10.1021/acs.orglett.8b01518 Org. Lett. 2018, 20, 3938−3942

Letter

Organic Letters Table 1. TMM Optimizationa

dinitrogen compounds via the TMM cycloaddition exemplifies their utility in complex molecule synthesis. Our synthesis began with the development of a highly scalable route to the TMM donor 5,9k synthesized from commercially available phosphonoacetate 7 (Scheme 2). A Scheme 2. Synthesis of TMM Donor

sequential acylation/decarboxylation step provided access to the ketophosphonate 8.11 Subsequent alkylation of the ketophosphonate to install the methylene trimethylsilane was realized with the use of ICH2TMS in dimethoxyethane (DME) with Cs2CO3.12 These conditions favorably promoted Cinstead of O-alkylation, along with minimal desilylation. In addition, the alkylation conditions were compatible for the addition of the reagents for the subsequent Horner−Wadsworth−Emmons reaction to furnish the enone 9 in a convenient one-pot fashion. Finally, cyanohydrin formation was achieved using TMSCN in the presence of ZnI2, and the TMM donor 5 was formed after silyl group exchange with Ac2O in the presence of TMSOTf in good yields. The synthesis of the nitroenamine TMM acceptor 6 started with the condensation of benzophenone with ethanolamine (Scheme 3). Mesylation and elimination afforded the stable

entry

equiv 5:6

additive (equiv)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12d,e 13d,e,f

1:1 1:1 1:1 1:1 1:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 1.5:1

BSA (1) In(acac)3 (1) Me3SnOAc (1) B(OEt)3 (1) B(OEt)3 (1) B(OEt)3 (0.5) B(OiPr)2Me (1) Et2BOMe (1) BEt3 (1) B(OEt)3 (0.15), Et2BOMe (0.15) B(OEt)3 (0.15), Et2BOMe (0.15) B(OEt)3 (0.15), Et2BOMe (0.15)

40 b 60c 57 47 67 50c 78c 46c b 85 89 95

dr 1:1 3:1 1.6:1 5:1 2:1 6:1 1.9:1 11:1 5.3:1 10:1 13:1

a ee = 89% unless indicated. bDecomposition. cConversion. d[Pd(cinnamyl)Cp] was used instead of [Pd(allyl)Cp]. eee = 88%. f [Pd(cinnamyl)Cp] (2 mol %), (S,S,R,R,S,S)-TL (3 mol %), dioxane (1.33 M), 1.5 h.

In(acac)3 and Me3SnOAc led to marginal improvement in conversion and selectivity (Table 1, entries 3 and 4). However, the borate additives proved to be notably beneficial. At 50% conversion, B(OEt)3 afforded a 6:1 diastereomeric ratio (dr) for the desired product (Table 1, entry 6). Although Et2BOMe did not improve the conversion, it significantly enhanced the diastereoselectivity (Table 1, entry 9). Thus, the combination of both B(OEt)3 and Et2BOMe conferred both the respective conversion and selectivity of the reaction, affording the cycloadduct with an 85% yield, 89% ee, and 5:1 dr (Table 1, entry 11). Further refinement with the use of [Pd(cinnamyl)Cp] as a more stable Pd(0) precursor allowed reduction of the catalyst/ ligand loading. In addition, decreasing the donor equivalence and increasing reaction concentration were beneficial practically, but also were important for improving the diastereoselectivity upward to 13:1 (Table 1, entry 13). The relative stereochemical assignment of the cycloadduct was determined using NOE experiments (Figure 2).15 Based on the ligand chirality, the stereoconfiguration of the cycloadduct is predicted to be the enantiomer of the natural product.9k The natural enantiomer can be accessed by employment of readily prepared (R,R,S,S,R,R)-TL.

Scheme 3. Synthesis of TMM Acceptor

vinylimine 10 in high yields with no need for purification. Nitration of the vinylimine using the procedure reported by Maiti and co-workers10 provided 6. Nitroenamines bearing other protecting groups were synthesized in a similar fashion. The efficient access to the coupling partners allowed the development of the palladium-catalyzed TMM cycloaddition to furnish the highly functionalized cyclopentane core 11 of jogyamycin with three defined contiguous stereocenters (see Table 1). Employing a Pd(0) precursor, [Pd(allyl)Cp], and a diamidophosphite ligand,9i preliminary investigation of the amino protecting group on the acceptor including phthalimide and carbamates indicated that the benzophenone imine conferred the most optimal enantioselectivities and diastereoselectivities.13 In the initial results, the cycloadduct 11 was isolated in a 40% yield as a mixture of diastereomers about the carbon bearing the nitro group (Table 1, entry 1). The other stereocenters created remained cis. Interestingly, the enantiomeric excess (ee) was maintained at 89% throughout the optimization. To further improve the reactivity and selectivity, the use of Lewis acids14 to activate the acceptor/donor was examined. The precedented use of BSA in TMM did not lead to reactivity in this case (Table 1, entry 2). The use of

Figure 2. NOE of TMM cycloaddition product. 3939

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Organic Letters

the rearrangement smoothly to form the isocyanate in situ, which was trapped with the addition of dimethylamine to furnish the urea. Ozonolysis of the exocyclic alkene afforded the cyclopentanone 16. Subsequent efforts to install an α-methylene group proved to be difficult. Although α-deprotonation using lithium amide bases to form the enolate could be observed indirectly via D2O quench and 95% deuterium incorporation, efforts to trap the enolate with a one-carbon electrophile proved to be unsuccessful. Screening bases such as LDA, Li-, Na-, and KHMDS against a variety of electrophiles including Eschermoser’s salt, paraformaldehyde, methyl formate, MOMCl, and chlorosilanes invariably led to decomposition. Methods to access silyl enol ethers using amine bases and silyl chlorides and triflates did not achieve the desired reactivity. Upon exploration of alternative strategies for the functionalization of the α-position, the treatment of 17 with MCPBA led to the elimination of the dimethylamine, forming the isocyanate 17′ (see Scheme 5). This peculiar transformation of the urea

The TMM cycloaddition effectively accessed the densely substituted cyclopentane core of the natural product. Subsequent efforts in functionalizing the core steered toward the reduction of the nitro group (see Scheme 4). As the carbon Scheme 4. Accessing Cyclopentanone Intermediate

Scheme 5. Accessing Cyclopentanone Intermediate

bearing the nitro group was prone to epimerization and the benzophenone imine was prone to hydrolysis, acidic and basic conditions were not well-tolerated. For example, various Clemenson reductions and metal hydrides caused epimerization, led to decomposition, or lacked reactivity. Metalcatalyzed reductions such as metal borides, metal silanes, and hydrogenation, were also ineffective. Invariably, the use of SmI2,16 which is a highly effective reducing agent in pH neutral conditions and at ambient temperatures, proved to be key. The excellent reducing power of SmI2 led to the concomitant reduction of the nitro and imine groups, furnishing diamine 12. Several methods for N-arylation were investigated subsequently. Although both Chan-Lam and Ullman cross couplings provided reactivity affording the desired product with selective arylation of the primary amine, the lack of desirable yields along with significant amounts of overoxidation of the product to the benzophenone imine were observed. Consequently, the Buchwald-Hartwig coupling was investigated. Ligand/catalyst screening identified XPhos palladacycle G217 as the catalyst of choice and afforded the arylated product 13 with high yields with minimal overoxidation and scalability. In preparation for the conversion of the nitrile to the urea, the protection of the diamine was examined. Surprisingly, various methods to form carbamates lacked reactivity. Treatment with TFAA also resulted in the monoprotection of the aniline, indicating the significant steric bulk of the benzhydryl (Dpm) amine. Conveniently, the diamine reacted with oxalyl chloride to form the cyclic oxalamide 14.18 Treatment of the protected diamine with the Parkins− Ghaffar catalyst19 under neutral aqueous conditions led to nitrile hydration to the carboxamide 15, setting the stage for a Hofmann rearrangement. The mild and pH neutral conditions afforded by Zhdankin’s hypervalent iodine reagent20 effected

has been reported by Johnson7 in the synthesis of pactamycin and was proposed to occur through nucleophilic attack of the dimethylamine on the peracid to generate an N-oxide, which eliminated to form the isocyanate. The nucleophilic character of the urea could account for the lack of compatibility of the enolate for electrophiles. Thus, α-methylenation was investigated prior to the formation of the urea. Rerouting the synthetic path, the exocyclic methylene of 14 was cleaved with ozonolysis after oxalamide protection to introduce the ketonitrile 18 (see Scheme 6). Extended time under ozone saturation was required to cleave the electronpoor exocyclic methylene. α-Methylenation methods were Scheme 6. Accessing the Frontier Intermediate

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class of acceptors in the development of the TMM methodology.

investigated again. Although deprotonation/electrophilic trapping remained unsuccessful, the use of Ac2O/(Me2N)2CH2 as a mild and acidic methylenation method proved to be pivotal.21 The methylenation readily occurred at 4 °C. Comparatively, under the same conditions, the substrate bearing the urea did not afford reactivity and decomposed upon heating. Diligent isolation, handling, and storage under argon in a freezer were important in attenuating the decomposition and polymerization of the exocyclic enone 19. Because of its sensitivity, the enone did not tolerate subsequent nucleophilic epoxidation and many metal-catalyzed epoxidation/dihydroxylation methods. Stoichiometric use of OsO4 proved to be essential. In addition, the use of the chiral ligand (DHQ)2PHAL was important in affording optimal yield and diastereoselectivity of diol 20. The use of the pseudo enantiomer of the ligand, (DHQD)2PHAL, afforded sluggish conversion with mismatched diastereoselectivity. While the diastereoselectvity could be attained with achiral amine ligands, the osmate ester hydrolysis under acidic conditions also led to the deprotection of the ketal. NOE analysis provided the assignment of the relative stereoconfiguration of the diol and further corroborated with the stereochemical assignment of the TMM adduct 11.22 The stereoselective installation of the diol provided a pathway for the formation of the urea. Again, the nitrile was hydrated to carboxamide 21 with the Parkins−Ghaffar catalyst. The protection of the diol into a cyclic ketal was unsuccessful, which led to the alternative regioselective TBDPS protection of the primary hydroxyl. While the Hofmann rearrangement of this α-ketoamide 22 was a concern due to the inherent decreased migratory aptitude of the α-carbon, the rearrangement did occur. However, the isocyanate that was formed in situ was unstable and readily hydrolyzed to the tertiary amine 23, and trapping with dimethylamine was unsuccessful. Several attempts to form the isocyanate from the amine and trap in situ for example, with triphosgene or diphosgene in NEt3, then dimethylamine, only led to recovery of the starting amine. Importantly, switching the base to pyridine led to the formation of the carbamoyl chloride,23 which is a more stable species, instead of the isocyanate. Quenching the carbamoyl chloride with dimethylamine led to the desired urea 24. With the urea in hand, the installation of the last piece of the natural product, the methylation of the ketone, was attempted. Both the Hanessian6 and Johnson7 groups utilized this 1,2addition strategy to stereoselectively install the C5 methyl group with the use of MeMgBr. However, a variety of attempts to install the methyl group, including halide counterions of the methyl Grignard, MeLi, MeCuLiI, AlMe3, Me2Zn alone or in combination with CeCl3, remained unsuccessful. As a plausible side product, the ring opening of the oxalamide was observed. In summary, the densely functionalized cyclopentane core of joygamycin was constructed expediently through a palladiumcatalyzed enantioselective TMM cycloaddition. The establishment of three contiguous stereocenters with control of diastereoselectivity, along with the differentiation of three amino moieties, provided an efficient approach toward the installation of the heteroatom-rich functional groups. This synthetic strategy demonstrated the effectiveness of the use of β-nitroenamines as TMM acceptors. The efficient access via direct nitration, coupled with the high enantioselectivity and diastereoselectivity to access differentially substituted dinitrogen compounds, demonstrate their utility as a powerful new

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01518. Experiment details, compound characterization data, and spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Barry M. Trost: 0000-0001-7369-9121 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NIH (No. GM-033049) and the NSF (No. CHE-1360634) for their generous support of our programs. L.Z. thanks NSERC for a postdoctoral fellowship award.

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REFERENCES

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