Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthetic Studies on the Kigamicins Ai-Jun Ma†,‡ and Joseph M. Ready*,† †
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States ‡ School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
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S Supporting Information *
ABSTRACT: The kigamicins are polycyclic aromatic natural products featuring a tetrahydroxanthone and up to four sugar residues. They are toxic to human cancer cells under nutrientpoor conditions. A synthesis of the natural product skeleton has been achieved from chiral pool materials. Key steps include a regioselective hydration of a diarylalkyne and two oxidative cyclizations.
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The kigamicins are unusual members of the THX family in two regards. First, the A-ring exists as a cyclic aminal rather than the more usual aromatic pyridone.2 This feature generates a quaternary stereogenic center at C26 that is remote from other stereocenters in the natural product.3 Second, the F-ring features up to four carbohydrate-derived appendages. Four congeners, kigamicin A−D (1−4, Scheme 1) were isolated from the broth of an Amicolatopsis strain and vary based on the number and identity of the sugar residues linearly projecting from C14 on the F-ring. Whereas many other tetrahydroxanthone natural products show nonselective cytotoxicity,4 the kigamicins are reportedly toxic only to nutrient-deprived cells.5 For example, kigamicin A displays LD50 < 0.1 μM against PANC-1 pancreatic tumor cells cultured in nutrient-poor media. LD50’s are >100-fold higher in normal media. Moreover, they are tolerated in nude mice and effected a ∼80% reduction in tumor volume in tumor xenografts derived from three different pancreatic cancer cell lines, making them one of the few THX natural products with demonstrated in vivo activity.6 The intriguing structural and biological properties of the kigamicins attracted our attention as targets for total synthesis. Several xanthone and THX natural products have been synthesized previously,1 including cervinomycin,7 FD-594 aglycon,8 kibdelone C,9 simaomicin α,10 and IB-00208 aglycon.11 Our synthetic strategy targeted the aglycon 5 (Scheme 1), with late-stage construction of the B−D biaryl linkage forming the C ring from simpler precursor 6. A Sonogashira reaction between alkyne 7 and tetrahydroxanthone 8 was expected to serve as a fragment coupling. Finally, the chirality of the aminal 7 could be traced back to D-serine, while the F-ring precursor 10 is a known derivative of (−)-quinic acid.12 We first focused on the synthesis of the TXH subunit of the kigamicins. To this end, known enone 1112 was benzylated
olycyclic tetrahydroxanthone (THX) natural products display remarkable structural complexity and biological activity (Figure 1).1 They are generally isolated from bacterial culture broths and display diverse cytotoxicity. Representative examples include kibdelone C (anticancer, antibiotic, and antifungal activity), simaomicin α (anticancer and anticoccidial), actinoplanone (anticancer and antibiotic), and sch-56036 (antifungal).
Figure 1. Hexacyclic tetrahydroxanthone and xanthone natural products. © XXXX American Chemical Society
Received: January 8, 2019
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DOI: 10.1021/acs.orglett.9b00098 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Synthetic Strategy toward the Kigamicins
Scheme 3. Synthesis of the Tetrahydroxanthone
Scheme 4. Asymetric Synthesis of the Dihydroisoquinolinone
with Dudley’s reagent (Scheme 2).13 A three-step sequence involving iodination, Luche reduction, and benzylation Scheme 2. Synthesis of Iodine 14
under radical conditions to yield dihydroisoquinolone 22.17 Hydrogenolysis effected debenzylation, and selective monotriflation of the more accessible phenol returned triflate 23. Acetylene was installed in a two-step coupling/deprotection sequence to yield terminal alkyne 24. Bromide 18 and alkyne 24 were coupled using Sonogashira conditions optimized by Soheili and co-workers (Scheme 5).18 Hydration of the internal alkyne proceeded with 3:1 selectivity favoring the desired regioisomer 27.19 This reaction performed well on a small scale, although it required high-quality Au precatalyst20 and air-free conditions. However, on scales larger than ∼20 mg, poor conversion was observed. Multiple smallscale reactions could be processed in parallel, providing an effective solution. Additionally, the regioselectivity could be modulated by introducing various groups on the free phenol, but the improvement did not justify the need for two additional synthetic steps (protection/deprotection). The final stereocenter of the natural products was installed with a catalyst-controlled reduction using Noyori catalyst (R,R)-Ru. A MOM group on the C20 alcohol was intended to serve two
provided vinyl iodide 14 in 64% yield over three steps. Next, iodide 14 was lithiated and exposed to benzaldehyde 1510 to generate an inconsequential mixture of diastereomers (Scheme 3). Dess−Martin oxidation returned the enone 16 in 69% yield over the two steps. The phenolic MOM group was removed with trifluoroacetic acid, and an oxidative cyclization using SeO2 constructed the THX ring system.14 Reinstallation of the C14 TBS group provided 18, a substrate for Sonogashira coupling with the AB rings of the natural products. The terminal alkyne required for Sonogashira coupling was assembled as shown in Scheme 4. Adapting a procedure from Hosokawa and co-workers,15 triflate 1916 was coupled with isopropenyl acetate with the assistance of a Pd catalyst. The resulting α-aryl ketone was condensed with D-serine to form the cyclic aminal as a single diastereomer following Obenzylation. In this transformation, serine’s stereocenter was used to control the isolated C26 stereocenter of the kigamicins but now needed to be removed. To this end, the benzyl ester was converted to a selenoester, and decarboxylation proceeded B
DOI: 10.1021/acs.orglett.9b00098 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 5. Synthesis of the Kigamicin Skeleton
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roles, first as a protecting group and then as a precursor to the methylene ketal spanning the C and D rings. Selective removal of the benzyl group from the D-ring phenol yielded bisphenol 29, a substrate for oxidative coupling. A Cu-mediated, oxidative cyclization completed the full carbon skeleton of the kigamicins (30).15 Optimal yields were observed by heating to 135 °C for only 5 min. By contrast, the Pd(OAc)2-medated cyclization used in the synthesis of simaomicin α proved ineffective.10 The only tasks that remained to access the aglycon were the installation of the methylene ketal and deprotection. The D-ring O-methyl group could be removed without difficulty to provide phenol 31. Unfortunately, all attempts to cyclize the ketal met with failure. Trace amounts of product could be observed following exposure to MgBr2, while other Lewis acids proved ineffective. The corresponding MTM (−CH2SMe) group was no more effective. The MOM group could be removed, but attempts to install the methylene ketal using doubly electrophilic methyl groups (CH2Br2, etc.) were foiled by the instability of the THX moiety under basic conditions. A similar substrate reacted to form the a methylene ketal in the context of simaomicin α,10 underlining the subtle difference between the two natural products. Likewise, we were unable to install the ketal prior to oxidative coupling on substrates derived from alcohol 28. In summary, we have outlined means to construct the three stereochemical units of the kigamicins with complete control (aminal, C20 hydroxyl, F-ring). Furthermore, we have described a strategy to construct the entire carbon skeleton of the natural products. Future efforts will aim to install the methylene ketal prior to introduction of the base-sensitive THX moiety.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00098.
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Spectra, characterization data, and experimental details (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Joseph M. Ready: 0000-0003-1305-9581 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Funding provided by the Welch Foundation (I-1612) and the Petroleum Research Fund (58264-ND1).
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00098 Org. Lett. XXXX, XXX, XXX−XXX
Letter
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DOI: 10.1021/acs.orglett.9b00098 Org. Lett. XXXX, XXX, XXX−XXX
