Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Synthetic Studies toward Plumisclerin A Yang Gao, Yi Wei, and Dawei Ma* State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
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ABSTRACT: A concise approach to synthesize the tetracyclic framework of the marine diterpenoid plumisclerin A is described. Starting from commercially available iridoid genipin, a highly selective intermolecular Diels−Alder reaction was utilized to construct the A/B/C tricycle. Later, a four-step sequence involving stereoselective epoxidation and Dauben oxidative rearrangement was developed to introduce the requisite enone moiety. The unique tricyclo[4,3,1,01,5]decane motif was successfully forged via a late-stage SmI2-mediated reductive coupling.
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lumisclerin A was isolated and characterized in 2010 by Reyes and co-workers from the samples of the soft coral Plumigorgia teminosclera collected at Mayotte Island.1 As a novel xenicane-related marine diterpenoid, it possess seven stereogenic centers, including two all-carbon quaternary stereocenters, and an unprecedented tricyclo[4,3,1,01,5]decane skeleton. Besides its structural complexity, plumisclerin A exhibits moderate cytotoxic activities against several human tumor cell lines, including lung cancer A549 cells (GI50 = 4.8 μM), colon cancer HT29 cells (GI50 = 2.1 μM) and breast cancer MDA-MB-231 cells (GI50 = 6.1 μM).1 Its intriguing structure and medicinal potential render it an attractive and challenging target for synthetic chemists. In 2015, Yao and coworkers reported the synthesis of tricyclo[4,3,1,01,5]decane core of plumisclerin A using a Pauson−Khand annulation and SmI2-mediated radical cyclization.2a Recently, the first and enantioselective total synthesis of plumisclerin A have been achieved in 27 longest linear steps by the same group.2b Herein, we wish to report a concise approach to the tetracyclic framework of plumisclerin A featuring a highly selective intermolecular Diels−Alder reaction and a SmI2-mediated reductive coupling. Our retrosynthetic analysis is illustrated in Figure 1. We envisioned that plumisclerin A could be assembled from compound 1 through a late-stage epimerization of its C11a to transform cis-fused dihydropyran ring to the desired trans-one. Next, disconnecting the cyclobutane ring based on a SmI2mediated reductive coupling3 led to enone-aldehyde precursor 2, which could be derivated from tricyclic intermediate 3. A key intermolecular Diels−Alder disconnection of the aldehyde 3 would split it into diene 5 and the known dienophile 4.4 Consequently, we identified commercially available iridoid © XXXX American Chemical Society
Figure 1. Structure of plumisclerin A and its retrosynthetic analysis.
genipin 6 (∼$5/g)5 as the starting material for synthesizing diene 5. Received: January 8, 2019
A
DOI: 10.1021/acs.orglett.9b00095 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
alcohol 11 was then protected as the triethylsilyl ether and the trisubstituted alkene moiety was oxidized with mCPBA to afford epoxide 12 as a single diastereomer in 82% yield. Next, the epoxide 12 was smoothly rearranged to tertiary allylic alcohol 14 in 60% yield over two steps, according to Sharpless’s procedure,13 where epoxide was first opened by in-situ-generated sodium phenylselenide, and the resulting phenylselenyl group in 13 underwent oxidative elimination to give the allylic alcohol 14. Next, PCC-mediated Dauben oxidative rearrangement14 of 14 successfully yielded enone 15 (56%) and the desired cyclization precursor 2 (13%) directly. Finally, 15 was transformed to 2 via selective desilylation and subsequent oxidation in 75% overall yield. (See Scheme 2.)
As demonstrated in Scheme 1, our synthesis commenced with the preparation of known compound 7 starting from Scheme 1. Preparation of Tricyclic Intermediate 3 via an Intermolecular Diels-Alder Reaction
Scheme 2. Synthesis of Enone 2
inexpensive iridoid genipin.5a Dess−Martin oxidation6 of the alcohol 7 produced aldehyde 8, which was subjected to a Wittig reaction and subsequent Weinreb amide formation to afford diene 5. The pivotal Diels−Alder reaction of the diene 5 and the known dienophile 4 proceeded smoothly in toluene at 80 °C for 3 days in the presence of catalytic amount of hydroquinone to afford the expected cycloadduct 3 and its diastereoisomer (5:1) in 90% combined yield. To confirm the stereochemistry of this cycloadduct, it was further converted io alcohol 9 in three steps, including Pinnick oxidation, alkylation, and subsequent deprotection. The structure of 9 was unambiguously verified by its X-ray crystallographic analysis. With the desired cycloadduct 3 in hand, we initially tested the crucial SmI2-mediated aldehyde-alkene reductive coupling to forge the strained cyclobutane ring. Unfortunately, we had never detected the desired cyclobutane product after conducting this reaction by employing various solvents, additives, and temperatures.7 Considering precedent elegant reports on SmI2-mediated radical 1,4-addition to form cyclobutane ring,2,7 we decided to synthesize enone 2 as a new cyclization precursor. However, attempts on direct allylic oxidation8 of 3 were met with failure. For example, common transition-metal-catalyzed conditions such as CrO3/3,5-dimethylpyrazole,9 Mn(OAc)3·2H2O/t-BuOOH,10 palladium on charcoal/t-BuOOH,11 and Rh2(cap)4/t-BuOOH12 resulted in complex mixtures or total decomposition. In light of these unsuccessful approaches, we then explored an expedient route to access the desired enone 2. This sequence began with reduction of aldehyde 3 and following Grignard addition to Weinreb amide 10. The resultant primary
Once the desired enone-aldehyde 2 was obtained, we embarked on the key SmI2-mediated reductive cyclization. The initial attempts under typical conditions (SmI2/HMPA/tBuOH, 7b SmI 2 /MeOH, 7d SmI 2 /t-BuOH, 2a SmI 2 /LiBr/ HFIP,7k between −78 °C and 0 °C) all failed to give the desired product 16. Much to our delight, we smoothly isolated the cyclized product 16 containing tricyclo[4,3,1,01,5]decane motif in 50% yield by slowly adding the aldehyde 2 to a refluxing solution of SmI2 in THF in the absence of any additives,15 indicating that the elevated temperature was essential to forge the strained cyclobutane ring. Moving B
DOI: 10.1021/acs.orglett.9b00095 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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forward, the cyclized product 16 was elaborated further toward plumisclerin A by deprotection of PMB group to provide diol 17, which was treated with acetic anhydride to give diacetate 18 in 85% overall yield. The next task was removal of the unnecessary oxidation on D ring. Chemoselective reduction of the ketone 18 on the D ring afforded alcohol 19 as a single diastereomer in 70% yield, in which the hydroxy group was condensed with TCDI to form the corresponding thiocarbamate 20 in 87% yield. Barton-McCombie deoxygenation of 20 under classic conditions16 (AIBN, n-Bu3SnH, toluene, 100 °C) furnished the desired intermediate 1 in 80% yield. (See Scheme 3.)
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00095. Experimental procedures, spectra data and copies of all new compounds (PDF) Accession Codes
CCDC 1889543 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 3. Synthesis of the Tetracyclic Core of Plumisclerin A
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Dawei Ma: 0000-0002-1721-7551 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to Chinese Academy of Sciences (supported by the Strategic Priority Research Program, Grant Nos. XDB20020200 and QYZDJ-SSW-SLH029) and the National Natural Science Foundation of China (Grant No. 21572249) for their financial support.
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REFERENCES
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In summary, we have developed a concise and efficient approach for building the core tetracyclic carbon skeleton of plumisclerin A. The key elements include a highly selective intermolecular Diels−Alder reaction and a SmI2-mediated reductive coupling as key steps to construct the unprecedented tricyclo[4,3,1,01,5]decane motif. Further studies on late-stage epimerization of 1 are still in progress. C
DOI: 10.1021/acs.orglett.9b00095 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b00095 Org. Lett. XXXX, XXX, XXX−XXX
