Letter Cite This: Org. Lett. 2017, 19, 6004-6007
pubs.acs.org/OrgLett
Total Synthesis of (+)-Pochonin D and (+)-Monocillin II via Chemoand Regioselective Intramolecular Nitrile Oxide Cycloaddition Hyeonjeong Choe,†,‡ Hyukjoon Cho,§ Hyun-Jeong Ko,∥ and Jongkook Lee*,†,∥ †
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 34114, Republic of Korea University of Science and Technology, Daejeon 34114, Republic of Korea § College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea ∥ College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon 24341, Republic of Korea ‡
S Supporting Information *
ABSTRACT: Asymmetric total syntheses of (+)-pochonin D (1) and (+)-monocillin II (2), Hsp90 inhibitors with potent anticancer activity, have been accomplished where the macrolactone 3 was constructed through a chemo- and regioselective intramolecular nitrile oxide cycloaddition of diene 4. (+)-Pochonin D (1)1 and (+)-monocillin II (2)1b,2 are fungal polyketides with a resorcylic acid lactone skeleton. Resorcylic acid macrolides have attracted considerable interest due to their strong antitumor activities by inhibiting heat shock protein 90 (Hsp90), a molecular chaperone that guides the correct folding of nascent polypeptides.3 Hsp90 inhibitors show a broad spectrum of antitumor activity and act via a combinatorial blockade of the cellular pathways in cancer cells because a number of oncoproteins including EGFR, Her2, Raf, VEGFR2, PDGFR, Flt3, HIF-1, and BCR-ABL are Hsp90 clients.4 More interestingly, Hsp90 inhibitors reduced the growth and survival of cancer stemlike cells both in vitro and in vivo.5 The significant attention directed toward resorcylic acid macrolides also stems from their ability to stimulate hair growth by downregulating the expression of Wnt5A.6 Since the report of the pioneering work by Asaoka et al. on the use of the intramolecular nitrile oxide cycloaddition (INOC) to form macrolactones,7 acrylate groups have been used as cyclization partners for the nitrile oxide moiety in the INOC-based macrocyclic natural product syntheses.8,9 We recently expanded the general utility of the INOC reaction by demonstrating that a terminal alkene, not conjugated with carbonyl group, could also be a good dipolarophile in the synthesis of a macrocyclic natural product, (+)-11β-hydroxycurvularin, wherein a remote stereoinductive INOC was showcased.10 To further explore its utility, we set out to investigate the preference for an unconjugated terminal alkene over an internal alkene as a cyclization partner for the nitrile oxide moiety in an INOC-based macrocyclization. We envisioned that the structural simplicity of (+)-pochonin D © 2017 American Chemical Society
(1) and (+)-monocillin II (2) would provide an opportunity to clarify the effect of the alkene environment on the chemoselectivity in an INOC-based macrocyclization. Described herein are asymmetric syntheses of (+)-pochonin D (1) and (+)-monocillin II (2) that feature a macrocycle construction based on a novel chemo- and regioselective INOC reaction, highlighting the selectivity for terminal alkene against internal alkene as well as bridged-ring over fused-ring product. Our retrosynthetic analysis for (+)-pochonin D (1) and (+)-monocillin II (2) called for macrolactone 3 as a key intermediate, and this could be chemo- and regioselectively constructed from acyclic precursor 4 by INOC (Scheme 1). Diene 4 could be prepared from carboxylic acid 5 by esterification with alcohol 6. The requisite INOC substrate 4 was derived from commercially available nitro compound 1011 in a straightforward manner as shown in Scheme 2. Julia−Lythgoe−Kocienski olefination of readily available aldehyde 7 with sulfone 8 selectively produced E-diene 9 along with Z-isomer 9′ in 93% yield (9/9′ = 10:1, 500 MHz 1H NMR spectrum analysis).12 The silyl group of diene 9 was removed to afford alcohol 6 by treatment with HCl (AcCl/MeOH) in almost quantitative yield.13 Nitro compound 10 was formylated to give aldehyde 11 by the Vilsmeier−Haack reaction,10,12b,14 and subsequent oxidation of 11 produced carboxylic acid 5 in 70% yield for the two steps.15 Carboxylic acid 5 was transformed to ester 4 by coupling with alcohol 6 in 92% yield.16 Received: September 29, 2017 Published: October 19, 2017 6004
DOI: 10.1021/acs.orglett.7b03054 Org. Lett. 2017, 19, 6004−6007
Letter
Organic Letters
encounters two possible sites of attack (internal olefin vs terminal olefin), with two possible orientations of approach by the respective olefin to the nitrile oxide moiety. Although the chemo- and regioselectivity of addition was a concern initially, the INOC of 4 was conducted under conventional conditions. Delightfully, we observed that the INOC proceeded selectively at the terminal alkene of 4 to produce the two bridged isomers 3a,b as major components along with a fused isomer 3c in high yield and with good regioselectivity (3a/3b/3c = 4:4:1, 90%, Scheme 3). We found no appreciable quantities of products
Scheme 1. Retrosynthetic Analysis of (+)-Monocillin II (1) and (+)-Pochonin D (2)
Scheme 3. Intramolecular Nitrile Oxide Cycloaddition
Scheme 2. Preparation of an Intramolecular Nitrile Oxide Cycloaddition Substrate
resulting from the INOC of the internal olefin of diene 4. The observed high chemoselectivity is presumably attributed to steric hindrance by the butenyl group attached to the internal olefin and/or strain in the incipient 9- or 10-membered ring of the resultant INOC product. To the best of our knowledge, such a chemo- and regioselective INOC has not been reported in the construction of macrocycles for either natural or unnatural products. Chemoselective N−O bond cleavage of dihydroisoxazole ring of macrolactone 3a,b with Mo(CO)6 and subsequent elimination of the β-hydroxyl group of the resulting product were carefully carried out to afford α,β-unsaturated ketone 12 overall in 67% yield.7,8,17 With ketone 12 in hand, we proceeded to the completion of the syntheses of (+)-pochonin D (1) and (+)-monocillin II (2) (Scheme 4). Debenzylation of dibenzyl ether 12 with BCl3 produced (+)-monocillin II (2) in 85% yield, with the α,β-unsaturated ketone moiety remaining intact.18 (+)-Monocillin II (2) was regioselectively chlorinated with sulfuryl chloride to produce (+)-pochonin D (1) in 69% yield.19 The spectral results from both of our synthetic macrolides 1 and 2 are in good agreement with the reported data.1,2 In summary, we have achieved a 7- and 8-step asymmetric synthesis, respectively, of two Hsp90 inhibitors with potent anticancer activity, (+)-monocillin II (2) and (+)-pochonin D (1), from readily available nitro compound 10 in respective overall yields of 29 and 20%. This highly practical approach demonstrates that a terminal alkene is preferred to an internal alkene as the dipolarophile in the INOC-based macro-
The INOC reaction of diene 4 was quite challenging because the nitrile oxide moiety generated during the reaction 6005
DOI: 10.1021/acs.orglett.7b03054 Org. Lett. 2017, 19, 6004−6007
Organic Letters
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Scheme 4. Completion of the Syntheses of (+)-Monocillin II (2) and (+)-Pochonin D (1)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03054. Experimental procedures and characterization data for all products including 1H and 13C NMR spectra (PDF)
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REFERENCES
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cyclization, emphasizing the greater scope of this useful method.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jongkook Lee: 0000-0003-0739-7963 Notes
The authors declare no competing financial interest. Taken in part from the Master’s Theses of H. Choe (University of Science and Technology, 2012) and H. Cho (Seoul National University, 2011).
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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2012R1A1A1038686 and NRF2015R1A2A2A01004708). We thank the Central Laboratory of Kangwon National University for providing us with technical assistance on the spectroscopic experiments.
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DEDICATION This paper is dedicated to Prof. Deukjoon Kim (Seoul National University) on the occasion of his 70th birthday. 6006
DOI: 10.1021/acs.orglett.7b03054 Org. Lett. 2017, 19, 6004−6007
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DOI: 10.1021/acs.orglett.7b03054 Org. Lett. 2017, 19, 6004−6007
