Asymmetric Total Synthesis of (+)-Majusculoic Acid via a Dimerization

Letter Cite This: Org. Lett. 2018, 20, 1477−1480

pubs.acs.org/OrgLett

Asymmetric Total Synthesis of (+)-Majusculoic Acid via a Dimerization−Dedimerization Strategy and Absolute Configuration Assignment Renzhi Chen, Linbin Li, Na Lin, Rong Zhou, Yuhui Hua, Hejun Deng, and Yandong Zhang* Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China S Supporting Information *

ABSTRACT: The first total synthesis of (+)-majusculoic acid, the enantiomer of naturally occurring antifungal cyclopropane fatty acid (−)-majusculoic acid, was accomplished in 13 steps, leading to the assignment of the absolute configuration of the natural product. The synthesis featured a ring closing metathesis dimerization, a conformationally controlled cyclopropanation, a dedimerization, and a bromoolefination. ATCC 14503 (MIC of 8 μM). Structurally, majusculoic acid features a trans-4,6-dialkylcyclopropane moiety and a conjugated (E,Z)-bromodiene system. Its structure was only assigned through NMR spectroscopic investigations and in analogy to grenadadiene (4, Figure 1). The absolute configuration of the cyclopropane motif remained ambiguous. The promising therapeutic value and the extremely low availability (0.000029% isolated yield) demonstrate the need for chemical synthesis both to secure the structure and to provide material to further profile the antifungal activities. As part of our continuing interest in developing novel synthetic strategies toward halogenated marine natural products,5 we herein report the first asymmetric total synthesis of (+)-majusculoic acid, the enantiomer of the natural product, which both confirms the structure and enables the assignment of the (4R,6R) absolute configuration of the natural majusculoic acid. As outlined in Scheme 1, we envisioned that majusculoic acid (1) could be obtained from enal 6 by a bromoolefination. Stereospecific construction of trisubstituted bromoolefin is a challenging problem in the syntheses of related marine natural products.6 We here developed two kinds of bromoolefination reagents to effect this transformation (vide infra). To secure the absolute stereochemistry of the isolated trans-4,6-dialkylcyclopropane motif,7 we devised a novel strategy involving a dimerization−cyclopropanation−dedimerization process (Scheme 1). Specifically, RCM dimerization8 of diene ester 9 could generate the C2-symmetric 14-membered dilactone 8, which could then undergo stereoselective cyclopropanation9 to deliver dilactone 7. We anticipated that the rigid crownlike

C

yclopropane fatty acids (CFAs) are ubiquitous in the seed oils of subtropical plants, bacteria, and other microorganisms.1 From a structure−activity relationship perspective, the cyclopropane moiety can not only provide special steric, electronic, and stereoelectronic effects but also serve as a high energy element to induce some biological processes.2 Although less abundant, a number of CFAs and their derivatives have also been discovered in marine organisms in the last two decades3 (Figure 1), and many of them have unique structural features,

Figure 1. Cyclopropane fatty acid natural products.

especially those containing halogen atoms. Most of these marine CFA natural products display intriguing bioactivities, such as antifungal,4 anticancer,3d topoisomerase I inhibitory,3a and antitrypanosomal bioactivities.3d Majusculoic acid (1, Figure 1) is a halogenated CFA from an uncharacterized cyanobacterial mat assemblage in the Bahamas and was first disclosed by MacMillan and Molinski in 2005.4 It displays significant antifungal activity against Candida albicans © 2018 American Chemical Society

Received: January 30, 2018 Published: February 15, 2018 1477

DOI: 10.1021/acs.orglett.8b00349 Org. Lett. 2018, 20, 1477−1480

Letter

Organic Letters Scheme 1. Retrosynthetic Analysis of Majusculoic Acid (1)

Table 1. Condition Optimization of Cyclopropanation

conditions

1 2 3

Me3S(O)I (2.5 equiv), NaH (2.5 equiv) DMSO, rt Me3S(O)I (5.0 equiv), NaH (5.0 equiv) THF/DMSO, rt Me3S(O)I (5.0 equiv), t-BuOK (5.0 equiv) THF/DMSO, rt Me3S(O)I (5.0 equiv), t-BuOK (5.0 equiv) THF, rt Me3S(O)I (5.0 equiv), t-BuOK (5.0 equiv) DMSO, rt Me3S(O)I (5.0 equiv), t-BuOK (5.0 equiv) DMSO, 60 °C ZnEt2, ClCH2I, DCE, 0−50 °C CH2N2, Pd(OAc)2 (10 mol %), Et2O, −78 °C to rt

4 5 6 7 8

conformation of the 14-membered dilactone 8 would dictate the facial selectivity of cyclopropanation from the less hindered outside face of the C4−C6 double bond, thereby realizing a long-distance chirality transfer from C9 stereocenter (Scheme 1). The DFT-calculated lowest energy conformation of 8 is consistent with our preliminary prediction (see the Supporting Information). Dedimerization of 7 would release two molecules of the trans-disubstituted cyclopropane with the defined stereochemistry. To reduce this unusual strategy to practice, our synthesis commenced with the synthesis of the C2-symmetric 14membered dilactone 8 (Scheme 2). Nucleophilic addition to

yielda (%)

entry

a

trace trace 40 trace 41 55 0 80

Isolated yield.

trimethylsulfoxonium iodide as a sulfur ylide source. To our great delight, no matter whether the yield was high or low (trace to 55%), the facial selectivity of the cyclopropanation was always excellent and 7 was the sole isolable diastereomer (Table 1, entries 1−6). A Simmons−Smith condition15 was ineffective in this conversion (Table 1, entry 7). Gratifyingly, palladiumcatalyzed cyclopropanation16 with diazomethane afforded 7 in 80% yield probably via an active palladium carbene species. The absolute stereochemistry of 7 was confirmed by an X-ray crystal structure in conjunction with the absolute stereochemistry of C9 inherited from epoxide 10. Treatment of dilactone 7 with N,O-dimethylhydroxylamine hydrochloride and isopropylmagnesium chloride afforded the corresponding monomeric Weinreb amide, which was then reduced by DIBAL-H to give aldehyde 13 in high yield (Scheme 3). Homologation through Wittig reaction and reduction and subsequent TBS group deprotection furnished 1,3-diol 14. Then a selective oxidation of primary alcohol was achieved by using TEMPO and NaOCl17 to deliver a β-hydroxy aldehyde, which was converted

Scheme 2. Synthesis of Intermediate 8

the known chiral epoxide 1010 by allylmagnesium chloride in the presence of CuI furnished alcohol 11 in 64% yield, which was then converted to the diene ester 9 in 72% yield. After a brief screening of metathesis catalysts, solvents, and reaction temperatures, we found when 9 was treated with Grubbs II catalyst11 in refluxing CH2Cl2 (0.02 M) the best results in terms of reactivity (79% overall yield) and selectivity (8/12 = 2:1) were obtained. It is noteworthy that neither (4E,4′Z)- nor (4Z,4′Z)-cyclodimer product was observed in this conversion. With an effective synthesis of the dilactone 8, our investigation focused on the pivotal cyclopropanation step. Biosynthetically, a cyclopropanation involving a methyl transfer from S-adenosyl-L-methionine to the unsaturated fatty acid in CFA synthesis has been supported by recent studies,12 although the facial selectivity of the cyclopropanation has not been elucidated. Here, we utilized a conformationally controlled5,13 cyclopropanation to establish the stereochemistry of the isolated cyclopropane in majusculoic acid. As shown in Table 1, we first tested the Corey−Chaykovsky reaction14 with

Scheme 3. Synthesis of Majusculoic Acid Methyl Ester

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DOI: 10.1021/acs.orglett.8b00349 Org. Lett. 2018, 20, 1477−1480

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Organic Letters to the α,β-unsaturated aldehyde 6 through an acetylation− elimination cascade. With 6 in hand, the stereospecific construction of a conjugated (E,Z)-bromodiene system posed a significant challenge. Wittig reaction with Li’s method18 only afforded an inseparable mixture of (E,Z)-bromodiene 16 and (E,E)bromodiene 17 (35% yield, 16:17 = 1.5:1). To solve this problem, we developed a new Kocienski−Julia19-type reagent 15 for the introduction of the trisubstituted bromoolefin. To our delight, treatment of enal 6 with 1-phenyl-1H-tetrazol-5-yl sulfone 15 and nBuLi at −78 °C produced the bromodienes in high yield (95%, 16/17 = 1.8:1). The minor isomer, (E,E)bromodiene 17, was them removed through a Suzuki coupling manipulation due to its relatively high reactivity (see the Supporting Information). At this point, we successfully acquired methyl majusculoate (16) in a pure form. Additionally, we also developed an alternative approach to 16. Ozonolytic cleavage of the double bond of 6 afforded aldehyde 18 in 78% yield (Scheme 4). To our delight, when 18

applicable for the syntheses of other halogenated marine CFAs and their derivatives.

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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.8b00349. Experimental details and spectral data for all new compounds (1H NMR, 13C NMR, IR, and HRMS) (PDF) Accession Codes

CCDC 1820454 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Scheme 4. Total Synthesis of (+)-Majusculoic Acid

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yandong Zhang: 0000-0002-5558-9436 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge Natural Science Foundation of China for financial support of this work by grants (21772164, 21572187, and U1405228). We thank the FRFCU (20720160025), NFFTBS (J1310024), NCETFJ, and PCSIRT for support. We thank Prof. T. F. Molinski (UCSD) for helpful discussions about NMR data analysis.

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was treated with a newly developed Horner reagent (see the Supporting Information) and NaHMDS at low temperature (−78 to −40 °C), (E,Z)-bromodiene 16 was obtained solely. Notably, the reaction temperature was crucial for the fine stereochemical control, and running the reaction at 0 °C produced a mixture of geometric isomers. Finally, hydrolysis of ester 16 with LiOH afforded majusculoic acid in 90% yield. The synthetic sample exhibited spectroscopic properties identical with those reported for the natural product20 except for the sign of its optical rotation [synthetic: [α]25 D = +12.6 (c = 0.1 in MeOH); natural: [α]25 D = −15.8 (c = 0.1 in MeOH)]. Thus, the absolute configuration of naturally occurring 1 was assigned as that of 20 on the basis of our total synthesis. In summary, we developed an efficient synthetic strategy for the synthesis of the enantiomer of majusculoic acid, an antifungal halogenated marine cyclopropane fatty acid, and assigned the absolute configuration of the natural product through our synthesis. A conformationally controlled cyclopropanation based on a dimerization−cyclopropanation− dedimerziation strategy secured the configuration of the isolated cyclopropane moiety. In addition, two kinds of bromoolefination reagents were developed for the stereoselective construction of the conjugated bromodiene system. The reported strategy and technologies are expected to be

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