Letter pubs.acs.org/OrgLett
A Unified Modular Synthetic Strategy for Dictyodendrins F, H, I, and G Sreenivas Banne,† D. Prabhakar Reddy,† Wenxi Li, Chenhui Wang, Jian Guo,* and Yun He* Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, PR China S Supporting Information *
ABSTRACT: A unified modular synthetic strategy has been developed for the first total synthesis of dictyodendrins G and synthesis of dictyodendrin F, H and I in 11 steps. The synthesis features consecutive functionalization of the core aminoquinone by palladium-mediated Suzuki−Miyaura coupling reaction, 1,4-addition, acylation and base mediated formation of a pyrrolinone, and the formation of carbazolequinone moiety through a formal [3 + 2] cycloaddition using arynes generated in situ. Several dictyodendrin analogues were also synthesized using this strategy.
T
was not clear and further optimization of structure is needed for their medicinal applications, we hope to develop a concise and modular route that is amenable to the rapid synthesis of dictyodendrins including previously inaccessible dictyodendrins G, and their analogue library that could illuminate SAR. In addition, using no or less transition metal during the synthesis should be in consideration, not only for reducing cost and trace contamination, but also for synthesizing dictyodendrins H, I and analogues containing a halide on side chains. With above key points in mind, synthetic route of dictyodendrins F−I was planned (Figure 1A). If we attributed aminoquinones as the core structure and the left part as substituted groups or side chains, dictyodendrins F−I could be disconnected as in Figure 1B. It was envisioned that dictyodendrins F−I could be synthesized by consecutive functionalization of the brominated aminoquinone 5, to continuously increase complexity, through palladium mediated Suzuki−Miyaura coupling reaction with 6, 1,4-addition of 7 to quinone, acylation with 8 and subsequent base mediated formation of pyrrolinone, and the construction of carbazolequinone moiety. In our efforts to develop arynes based new chemistries,10a−e we recently reported a formal [3 + 2] cycloaddition of arynes and 2-aminoquinones, which precedes through cascade C−C/C−N bond formations under mild and transition-metal-free conditions.10f,g This method was especially suitable for the synthesis of biologically important carbazolequinone library. We plan to adopt this cascade reaction here to construct the carbazolequinone moeity. To achieve an efficient synthesis of the dictyodendrins, the proper sequence for functionalizing the brominated aminoquinone 5 is critical. Initially, we prepared brominated aminoquinone 5 from 2-bromo-4-methoxy-6-nitrophenol (10) in 75% yield according to a reported procedure.11 Then we
elomerase is overexpressed in >85% of all malignant tumors but largely silent in healthy tissue.1 Telomerase inhibitors have been proposed as a new generation of cancer drugs with improved therapeutic windows.2 Dictyodendrins were the first marine natural products with telomerase inhibitory activity (100% inhibition at 50 μg/mL concentration) and therefore have received considerable attention since their first isolation in 2003.3 Recently, dictyodendrins F−J were also reported to exhibit significant inhibitory activity against β-site amyloid-cleaving enzyme 1 (BACE1), a potential target for the treatment of Alzheimer’s disease.4 Promising biological activities as well as a unique densely substituted pyrrolo[2,3-c]carbazole core structure make dictyodendrins popular targets for synthetic organic chemists. The Fürstner group reported the first total syntheses of dictyodendrins B, C, E, and F using cycloaddition of para-toluenesulfonylmethyl isocyanide (TosMIC) for the formation of the pyrrole ring, and titanium-induced reductive oxoamide coupling reaction to form the adjacent indole nucleus, followed by a photochemical 6π-electrocyclization/aromatization in 2005 and 2006.5 Later on, Tokuyama and co-workers developed an unprecedented one-pot benzyne-mediated indoline formation/ cross-coupling sequence and applied the strategy to the total synthesis of dictyodendrins A−E. However, their synthesis involved 21−22 linear steps.6 The Gaunt, Yamaguchi/Itami/ Davies, and Jia groups7 reported the syntheses of several dictyodendrins using ingenious C−H functionalization strategies in 9−13 synthetic steps. Recently, Ready et al.8 disclosed the first total synthesis of dictyodendrin H and I along with dictyodendrin F using their method of engaging aryl-ynol ethers as key building blocks to construct the carbazole ring system. As this manuscript was under preparation, Ohno et al.9 described the total synthesis of dictyodendrins using gold catalysis for the synthesis of pyrrolo [2,3-c]carbazole core structure through cascade cyclization of diynes with pyrroles. However, their strategy has taken 18 linear steps for the total synthesis of dictyodendrin F. Since the SAR of dictyodendrins © 2017 American Chemical Society
Received: August 14, 2017 Published: August 28, 2017 4996
DOI: 10.1021/acs.orglett.7b02511 Org. Lett. 2017, 19, 4996−4999
Letter
Organic Letters
Scheme 2. Synthesis of the Core of Dictyodendrin F (1)
Table 1. Optimization of the Cyclization Conditionsa
Figure 1. (A) Structures of dictyodendrins F−I. (B) Retrosynthetic analysis of dictyodendrins F−I.
Scheme 1. Initial Approach To Synthesize Dictyodendrins entry
F source
solvent/temp
1 2 3 4
TBAT TBAT KFd CsF
THF/25 °C THF/60 °C THF/60 °C CH3CN/60 °C
yieldb (12/12′)c 42 50 16 24
(4/1) (4/1) (4/1) (4/1)
a
16a (0.1 mmol), 9a (0.125 mmol), F source (0.25 mmol), solvent (4.0 mL), 6 h. bIsolated yields. cRatio was determined by 1H NMR spectroscopy. d1.25 equiv of 18-crown-6 ether as an additive. Abbreviations: TBAT = tetrabutylammonium difluorotriphenylsilicate.
Scheme 3. Completion of Dictyodendrin F (1) Synthesis
explored the Suzuki−Miyaura12 coupling reaction with 6 first, followed by sequentially reacting with 9, 7 and 8 (Scheme 1). However, base mediated formation of pyrrolinone from 11 could not happen, although various conditions were attempted (further details on the synthesis of 11 are found in the Supporting Information (SI)). We next focused on a different synthetic sequence that reverses the construction of carbazole and pyrrolinone. As outlined in Scheme 2, palladium catalyzed Suzuki−Miyaura cross coupling of brominated aminoquinone 5 with 4methoxyphenylboronic acid (6a) gave the initially functionalized aminoquinone 13a in 79% yield. Treatment of aminoquinone 13a with 4-methoxy phenethylamine (7a) in ethanol at room temperature furnished the second-round functionalized aminoquinone 14a as a thick red solid in 96% yield. The excellent yield and regioselectivity of this 1,4addition presumably resulted from both the electrostatic and steric-hindrance effects. However, direct acylation of 14a with acyl chloride 8a failed, since quinones as electron-withdrawing
groups lead to apparently reduced nucleophilicity of the newly introduced amino group. Alternatively, reduction of aminoquinone 14a with sodium dithionate and then acylation with acyl chloride 8a followed by oxidation with PIFA yielded compound 15a in 92% overall yield in one pot. Due to the instability of compound 15a, it was subjected to cyclization immediately using triethylamine as a base in refluxing benzene and subsequent deprotection of Boc with TFA in dichloromethane to give pyrrolinone 16a in 84% yield, which completed the third round of functionalization and paved the way for the fourth round functionalization in the meanwhile. With the required key intermediate 16a and aryne precursor 9a (prepared following the reported procedures13) in hand, the 4997
DOI: 10.1021/acs.orglett.7b02511 Org. Lett. 2017, 19, 4996−4999
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Organic Letters Scheme 4. First Total Synthesis of Dictyodendrin G (2)
Scheme 5. Synthesis of Dictyodendrins H (3), I (4) and Analogues
formal [3 + 2] cycloaddition to construct the carbazolequinone moiety and complete the pyrrolo[2,3-c] carbazole core of dictyodendrins was explored. Our previous work was focused on reactions of arynes with 2-amino-1,4-naphthoquinones and 2-amino-quinones,10 5-Amino-1H-indole-2,6-diones were the first used in this formal [3 + 2] cycloaddition. Initially, we followed the standard conditions (TBAT (2.5 equiv)/THF/25 °C), but unfortunately the yield of desired product was unsatisfied. Then, we examined the effects of solvent, fluoride source and temperature again, and found that TBAT as the fluoride source in THF at 60 °C could result in the cyclized product in 50% yield (Table 1). Usually, the aryne produced from 9a resulted in highly regioselective products,10f,g,14 but the cyclization of 16a and 9a led to two regioisomers. Fortunately, the desired product 12a was the major isomer as expected, and it resulted from carbon in enamine moiety as a nucleophile to attack aryne to initiate the cascade cyclization.10g The formation of the minor isomer 12a′ may be attribute to the reduced carbon nucleophilicity to aryne in enamine moiety because of larger steric hindrance and conjugation, and consequently amine nitrogen acting as a nucleophile to attack aryne to initiate the cascade cyclization. Finally, deprotection of all methyl groups in 12a with BBr3 afforded dictyodendrin F in moderate yield (Scheme 3). The total yield of 11 steps from commercially available 10 was 10%, and the spectral data of dictyodendrin F (1) were identical to the reported values.4,15 To continue our effort toward the total synthesis of dictyodendrins, we turned our attention to dictyodendrin G (2) which contains a 10-O-Me group and its total synthesis has not been reported. To achieve the total synthesis of dictyodendrin G (2), all methoxy groups were replaced with benzyl groups so that they could be selectively removed in final stage of the synthesis (Scheme 4). Following the same reaction
sequence and conditions as described in Scheme 4, tribenzyl compound 12b was synthesized in good overall yield. Finally, hydrogenation of 12b with Pd/C under hydrogen atmosphere in ethyl acetate afforded G (2) in 78% yield. Thus, we finished the first total synthesis of dictyodendrin G (2) in 11 steps with the total yield of 12%, and the analytical data of synthetic dictyodendrin G were consistent with the reported values of the natural product.4 To demonstrate the effectiveness and practicability of our modular synthetic route, we extended our efforts to prepare dictyodendrins H, I and their analogues. Dictyodendrins H and 4998
DOI: 10.1021/acs.orglett.7b02511 Org. Lett. 2017, 19, 4996−4999
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I which share the same core skeleton bearing a O-methyl tyramine side chain with a bromo or an iodo group, respectively. Since the O-methyl tyramine side was introduced in the second-round of functionalization, initially functionalized aminoquinone 13a was treated with bromo- or iodo-O-methyl tyramine (7c and 7d) instead of 7a to afford aminoquinones 14c and 14d in excellent yields (Scheme 5). Following the same reaction sequence as for synthesis of dictyodendrins F and G, the target molecules dictyodendrins H (3) and I (4) were obtained in good overall yields (8% and 10%). The analytical data of the synthetic natural products were in full agreement with the reported values of isolated natural products.4 (see SI for detailed analysis). In the fourth-round of functionalization, different arynes generated in situ from precursors 9b−9e could be also used, following the same synthetic protocols as above, to generate dictyodendrins analogues 17−22 with different substituents at positions 7−10 in the total yield of 9%−16%. Similarly, in the first and second-round functionalizations, different side chains could also be introduced if needed. In summary, we have developed an efficient and unified modular synthetic strategy for the first total synthesis of dictyodendrins G and the total synthesis of dictyodendrins F, H and I in 11 steps. This synthetic strategy involves four rounds of functionalization of the core aminoquinone to continuously increase complexity, through the palladium mediated Suzuki− Miyaura cross coupling reaction, 1,4-addition, acylation and base induced condensation to form the pyrrolinone ring, and a formal [3 + 2] cycloaddition to construct the carbazolequinone moeity. In particular, no transition metals were used in the late stage of the synthesis. This modular strategy allows for the rapid synthesis of diverse structures for biological evaluations. The application of this strategy in synthesizing more diverse dictyodendrins and SAR studies are currently underway in our laboratory and will be reported in due course.
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REFERENCES
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02511.
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Letter
Experimental procedures and characterization data for products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yun He: 0000-0002-5322-7300 Author Contributions †
S.B. and D.P.R. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21572027 and 21372267). 4999
DOI: 10.1021/acs.orglett.7b02511 Org. Lett. 2017, 19, 4996−4999
