Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rapid Construction of the Common [5−5−6] Tricyclic Ring Skeleton in Polycyclic Cembranoids and Norcembranoids via Intramolecular 1,3-Dipolar Cycloaddition Meng Deng,† Xiao Zhang,† Zining Li,† Hongbin Chen,† Shaoli Zang,† and Guangxin Liang*,†,‡ †
State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
‡
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S Supporting Information *
ABSTRACT: A synthetically challenging bowl-shaped [5−5−6] tricyclic framework commonly seen in many polycyclic cembranoids and norcembranoids was strategically established in a convenient six-step sequence featuring an intramolecular 1, 3-dipolar cycloaddition reaction. Synthetic manipulations of such a valuable intermediate were explored for future applications.
T
he cembranoid natural products comprise a vast and diverse family of marine or terrestrial-derived diterpenes and norditerpenes, most of which possess fascinating architectures and important biological activities.1 Biosynthetically related to the enormous amount of macrocyclic cembranoid diterpenes, polycyclic cembranoids and norcembranoids are a relatively small class of highly fused and extensively oxygenated furanobutenolide derivatives.2 Limited by the scarce supply from natural sources, systematic biological research of these fascinating polycyclic cembranoid congeners is reluctantly hampered. Compared to other polycyclic cembranoids and norcembranoids, such as verrillin,3 intricarene,4 ineleganolide,5 and recently accomplished pavidolide B,6 etc., synthetic studies toward [5−5−6−7] tetracyclic norcembranoids such as 1−6 (Figure 1) and relevant cembranoids 7 and 8 (Figure 1) have achieved limited success. In 2011, Pattenden and co-workers disclosed biomimetic semisynthesis of sinulochmodin C (3) along with ineleganolide from a common precursor 5-episinuleptolide in spite of the low yield.5a In the same year, Ito and co-workers reported a synthesis of the [5−5−6] tricyclic core in yonarolide (5), featuring a Diels−Alder reaction and an intramolecular aldol condensation.7 In 2001 and 2010, respectively, the groups of Mehta8 and Barriault9 individually described their syntheses of the tetracyclic framework of havellockate (7). To date, no completed total synthesis of these appealing natural products was reported. In our recent synthetic efforts toward this group of terpenoids, we envisioned that a common intermediate 9 (Figure 1) containing the [5−5−6] tricyclic framework could be applicable to a collective synthesis of these molecules. The principal synthetic method toward a β-hydroxy ketone moiety such as that in intermediate 9 is the aldol reaction.10 © XXXX American Chemical Society
Figure 1. Representative polycyclic noncembranoid (1−6) and cembranoid (7 and 8) natural products.
However, the complicated stereoselectivity of the aldol addition and dehydration tendency of the aldol adduct restricted its application in such complex molecular environments, as Ito’s work has shown.7 Alternatively, an intramolecular 1, 3-dipolar cycloaddition reaction between a nitrile Received: January 23, 2019
A
DOI: 10.1021/acs.orglett.9b00285 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
crystallographic analysis. It merits mention here that the addition sequence of the reagent is critical for suppressing the self-polymerization of 14; otherwise, the trimer 13b would be produced in up to 30% yield. The alkylate 13a, bearing an undesired C-12 stereocenter, could be easily converted to 13 in 90% yield through a deprotonation/kinetic protonation procedure. Upon removal of the TBS group in 13 by HF· pyridine−NEt3 and subsequent oxidation of primary alcohol 16 by Dess−Martin periodinane, aldehyde 12 was obtained in excellent yield. It should be noticed that alkaline conditions such as TBAF and (COCl)2/DMSO/NEt3 were not suitable for this deprotection/oxidation procedure, as these conditions would cause palpable epimerization at the C-12 position in 16 and 12 ,respectively. Compound 12 was then transformed into an oxime, which was treated with NaOCl producing a nitrile oxide 11 for the key 1,3-dipolar cycloaddition reaction. Delightfully, the desired transformation underwent smoothly, generating the desired tetracyclic isoxazoline 10 as a single diastereomer in good yield. The stereochemistry of 10 was confirmed through single-crystal X-ray crystallographic analysis, which clearly displayed a bowl-shaped tetracyclic architecture. With a sufficient supply of intermediate 10 in hand, we moved on to investigate dehydrogenation of 10 in order to achieve unsaturation for synthetic manipulations in our future synthesis (Scheme 3). Enolate formation followed by treat-
oxide and an alkene in 11, along with subsequent N−O bond cleavage, could serve as an ideal solution to the formation of 9 (Scheme 1).11 Applying this strategy, single C12 chirality in a Scheme 1. Synthetic Blue Print for Quick Construction of [5−5−6] Tricyclic Skeleton 9
humble starting material 12 can just provide perfect stereochemical control at C7 and C8 due to the structurally restricted facial selectivity, while 12 could be readily prepared through alkylation between the known Mulzer bicyclolactone 1412 and alkyl iodide 15, followed by deprotection and oxidation. To prove the concept, we carried out the synthesis in a racemic fashion (Scheme 2).12b Alkylation of 14 with iodide 15 gave 13, 13a, and a surprising trimeric byproduct 13b, whose structure was unambiguously elucidated through X-ray
Scheme 3. α-Selenylation/Oxidative Elimination of 10
Scheme 2. Preparation of Tetracyclic Isoxazoline 10
ment with PhSeCl gave an α-selenylated product 17, which was then oxidized with m-CPBA triggering elimination of PhSeOH to afford a bridged unsaturated lactone 18a in 74% yield, but no desired lactone 18b was observed. To understand such an unexpected regioselectivity, we examined the X-ray crystallographic data of 17 and noticed that the torsion angle of H11−C11−C12−Se (33.65°) was much smaller than that of H13−C13−C12−Se (62.60°), which could suggest that the cis elimination of PhSeOH from C11 is more convenient than from C13. Attempted isomerization of the double bond to the desired position under Rhodium catalyzed conditions13 was unsuccessful. The fruitless result encouraged us to seek other solutions. In an alternative strategy, we found that isoxazoline 10 could undergo selective dehydrogenation to successfully install a double bond between C5 and C13 when treated with selenium dioxide to furnish an unsaturated isoxazoline 19. However, this reaction progressed rather sluggishly, and the yield was regretfully low (Scheme 4). To increase the efficiency of B
DOI: 10.1021/acs.orglett.9b00285 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Selenium Dioxide Induced Dehydrogenation of 10
Scheme 6. Attempted N−O Bond Cleavage of 10
such a desired dehydrogenation, an upgraded procedure was investigated. We discovered that 20, a trifluoroacylated product of isoxazoline 10, is a more suitable substrate for such a selenium dioxide induced transformation, and the desired product 19 was generated smoothly in up to 66% yield. Further explorations based on imine−enamine tautomerism of 10 led to a C5−C4 bond formation, producing the acylated aldol addition product 21 in moderate yield (Scheme 5). After deacetylation and subsequent IBX oxidation,14 21 can be converted into C5-formyl tetracyclic intermediate 22 in good yield. Scheme 5. C5-Derivatization of 10
framework 9, which could serve as a common synthetic intermediate for a group of polycyclic cembranoids and norcembranoids depicted in Figure 1. Our chemistry features an intramolecular nitrile oxide 1, 3-dipolar cycloaddition reaction performed in a simple substrate 12. The C12 stereochemistry established in 12 allowed for perfect stereochemical control while establishing the β-hydroxy ketone moiety bearing C7, C8 stereogenic centers. N−O bond cleavage in isooxazoline 9 as well as chemical derivatization on both 9 and 10 were demonstrated in order for future synthetic applications. Continued efforts toward collective total syntheses of polycyclic cembranoid and norcembranoid family of natural products are currently underway in our laboratory.
Finally, an appropriate reaction condition for effecting the N−O bond cleavage was investigated (Scheme 6). When Raney Ni/H2 and additives (boric acid or acetic acid) were employed,15 no conversion of 10 was observed. The use of Mo(CO)6 in CH3CN/H2O16 or O3 in CH2Cl2/MeOH17 generated 9 in rather low yield. We were pleased to find that treatment of 10 with Fe/NH4Cl in EtOH/H2O18 resulted in clean reduction of the N−O bond, affording β-hydroxy ketone 9 in 71% yield. Under the same reaction conditions, when the reaction time was extended to 16 h, the C7−C8 unsaturated enone 23 was obtained in 81% yield. Furthermore, a dialkylzinc-assisted stereoselective carbonyl addition approach was investigated on the bowl-shaped tricyclic architecture 9. To our delight, this tactic could afford both C6-allylated product 24 and C6-propargylated product 25 smoothly. The configurations of 9 and 25 were both confirmed by X-ray crystallographic analysis. It is notable that the unsaturated enone 23 bearing the same C7−C8 double bond as in yonarolide (5) could be potentially used in the total synthesis of this natural product. Furthermore, the carbonyl addition products 24 and 25 contain the same [5−5−6] tricyclic framework as in havellockate (7), along with identical stereochemistry in six contiguous stereogenic centers. In summary, we have developed an efficient synthetic approach for rapid construction of the [5−5−6] tricyclic
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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.9b00285. Experimental procedures and characterization data; copies of NMR spectra for new compounds; ORTEP drawings and crystallographic data (PDF) Accession Codes
CCDC 1871340, 1871751, 1871342, 1871341, 1871339 and 1884458 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www. ccdc.cam.ac.uk/data_request/cif.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. C
DOI: 10.1021/acs.orglett.9b00285 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
(13) (a) Disanayaka, B. W.; Weedon, A. C. Synthesis 1983, 1983, 952. (b) Bi, X.; Xu, W.; Yao, Y.; Zhou, L.; Liang, G. J. Org. Chem. 2018, 83, 5825. (14) Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852. (15) (a) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826. (b) Curran, D. P.; Scanga, S. A.; Fenk, C. J. J. Org. Chem. 1984, 49, 3474. (16) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D. Synthesis 1987, 1987, 276. (17) Jäger, V.; Grund, H.; Buss, V.; Schwab, W.; Müller, I. Bull. Soc. Chim. Belg. 1983, 92, 1039. (18) Jiang, D.; Chen, Y. J. Org. Chem. 2008, 73, 9181.
Meng Deng: 0000-0003-0194-9296 Guangxin Liang: 0000-0003-3122-0332 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Key Research and Development Program of China (2017YFD0201404) and the National Natural Science Foundation of China (21772097, 21572104) for financial support. We also thank Prof. Haibin Song of the Institute of Elemento-organic Chemistry, Nankai University, for X-ray crystallographic analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00285 Org. Lett. XXXX, XXX, XXX−XXX
