Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Stereoselective Synthesis of Spiro-2-oxabicyclo[2.2.2]octane Enabled by Ag(I)/ Brønsted Acid Relay Catalysis Qingyu Zhang,† Jianping Wang,† Yansheng Wei,† Hongbin Zhai,§ and Yun Li*,†,‡
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†
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China ‡ State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China § Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China S Supporting Information *
ABSTRACT: A highly stereoselective synthesis of a spirocineole scaffold that contains four stereogenic centers from readily accessible 2-alkynylbenzaldehydes and styrenes under very mild reaction conditions was reported. This cascade reaction involves a Ag(I)-catalyzed alkyne cycloisomerization and oxa-[4 + 2]-cycloaddition to give an oxonium intermediate which subsequently undergoes a previously unexplored 1,2-alkyl migration to access highly strained spiro-2-oxabicyclo[2.2.2]octanes in high yields with excellent stereoselectivities.
R
Scheme 1. (a) Bioactive Natural Products Bearing Oxabicyclo[2.2.2]octane Frameworks and (b) Synthetic Design for the Oxa-[4 + 2]-cycloaddition/1,2-Migration Cascade Reaction
elay catalysis has emerged as a powerful synthetic tool to assemble complex molecular architectures in a short and efficient manner.1 Such a binary catalyst system can be atomand step-economical, thus capable of forming multiple bonds with one single operation by avoiding protecting group manipulations and tedious purification of the intermediates. The oxacyclic compounds that contain a rigid [2.2.2]octane framework are widely present in numerous biologically active natural products.2 Some typical structures are depicted in Scheme 1 that include dracocequinone A (1),3 granatomycin D (2),4 and formosanolide (3).5 A number of unique and efficient strategies and methods have been developed for the syntheses of such types of molecules.6 However, current synthetic examples often need multiple steps to build the oxabicyclo[2.2.2]octane framework.7 As a consequence, seeking alternative methods for the rapid construction of a highly rigid [2.2.2]octane skeleton via a step-economical approach especially with readily available starting materials is highly desirable. ortho-Alkynylbenzaldehyde is known to readily undergo transition-metal-catalyzed cycloisomerization, leading to benzopyrilium intermediate 6 that allowed the hypothetical [4 + 2]- or [3 + 2]-cycloaddition (Scheme 1, part b) when reacted with proper dipolarophiles.8 A great number of interesting synthetic compounds have been obtained through this versatile methodology.9 The power of such transformations has also laid the ground for several natural product total syntheses.10 Benzopyrilium intermediate 6 is referred to as a well-known oxadiene that could react with electron-rich olefins to give the corresponding oxonium cycloadducts 7 through an inverseelectron-demand Diels−Alder reaction (Scheme 1, part b). It was reported that this active intermediate (when R = alkyl or aryl) is prone to undergo proton elimination between C2 and C3 © XXXX American Chemical Society
and delivered dihydronaphthalenes with the tensile [2.2.2] bicyclic ring system decomposed (O1, C2 bond cleavage).9a,g,11 Received: January 21, 2019
A
DOI: 10.1021/acs.orglett.9b00251 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
to be the best cocatalyst for this cascade annulation (Table 1, entry 10), whereas weak acid such as acetic acid failed to deliver any detectable product (entry 12).15 Notably, the reaction gave none of the desired product when either AgNO3 or 1naphthalenesulfonic acid alone was employed as the catalyst (entries 13 and 14), indicating that both Ag catalyst and protic acid play critical roles in this transformation. With optimized conditions in hand, we next sought to determine the scope of this reaction. As illustrated in Scheme 2,
We became interested in knowing whether this cationic intermediate 7 could be terminated by a semipinacol-type rearrangement12 when there is a tertiary alcohol moiety adjacent to the newly formed oxonium ion. As a result, the highly rigid [2.2.2]octane framework could be retained. Herein, we intend to illustrate a feature of reaction design, that is, the incorporation of a 1,2-alkyl migration step into the Yamamoto-type [4 + 2]cycloaddition,13 which we have found to be particularly beneficial in the synthesis of architecturally complex molecules. To the best of our knowledge, this represents the first example of the synthesis of an oxabicyclo[2.2.2]octane framework involving a 1,2-alkyl migration process. Reaction between o-alkynylbenzaldehyde 4a and styrene 5a was chosen as the examination platform for the abovementioned hypothesis (Table 1). However, no desired product
Scheme 2. Substrate Scopea,c
Table 1. Screening of Reaction Conditionsa
entry
catalyst
additive
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Pd(OAc)2 Pd(OAc)2 PtCl2 NiCl2 AgNO3 AgOTf AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 none AgNO3
none PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA 1-NSA 4-NSA acetic acid 1-NSA none
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DMF CHCl3 MeCN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
0 39 0 53 74 52 0 26 42 79(74)c 69 0 0 0
a
Reactions were performed by adding catalyst (5 mol %) and additive (10 mol %) to a solution of 4a (1.0 equiv) and 5a (1.5 equiv) in solvent (0.2 M) at 25 °C and stirring the mixture until TLC showed full consumption of 4a. bYield based on HPLC with anisole as the internal standard. cIsolated yield. PTSA, p-toluene sulfonic acid; 1NSA, 1-naphthalenesulfonic acid; 4-NSA, 4-naphthalenesulfonic acid.
could be isolated when 10 mol % of Pd(OAc)2 was solely employed as catalyst at room temperature. An extensive condition survey indicated that the desired 10a could be isolated in 39% yield as a single isomer14 (Table 1, entry 2) when additional p-TsOH (10 mol %) was added as a cocatalyst in the reaction. The full structural information on 10a was secured by both NMR spectroscopic data and the X-ray crystallographic analysis. This interesting observation prompted us to further evaluate more Lewis acid/Brønsted acid combinations in this reaction. A number of metal catalysts (10 mol %) such as PtCl2, NiCl2, AgNO3, and AgOTf were further screened together with pTsOH (10 mol %). Among them, AgNO3 gave the best yield (Table 1, entry 5). The reaction also proceeded in other solvents, such as chloroform and acetonitrile, but gave the products in lower yields (Table 1, entries 8 and 9). Variation of the Brønsted acid was proven to be effective to improve the yield (entries 10−12), and 1-naphthalenesulfonic acid was identified
a
The reactions were performed by adding AgNO3 (5 mol %) and 1NSA (10 mol %) to a solution of 4 (1.0 equiv) and 5a (1.5 equiv) in CH2Cl2 (0.2 M) at 25 °C and stirring the mixture until TLC showed full consumption of 4. bAgNO3 (2 mol %) and 1-NSA (5 mol %) at 0 °C. cIsolated yield. 1-NSA, 1-naphthalenesulfonic acid.
with styrene 5a, an array of o-alkynylbenzaldehyde derivatives (4a−4r) bearing various substituents was first evaluated in the cyclization reaction. In general, both electronic-rich and electron-deficient aldehydes performed well and delivered their respective products 10a−10r in good yields. It is noteworthy that electronic effects had remarkable influence on this cycloaddition reaction. Substrates with electron-neutral (4a, 4b) or electron-deficient substituents (4g−4k) reacted faster B
DOI: 10.1021/acs.orglett.9b00251 Org. Lett. XXXX, XXX, XXX−XXX
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5x), although with longer reaction time. Substrates with oxetane, azetidine, and cyclopentane rings could also be employed to give the desired polycyclic scaffold (10y−10ac). The relative configuration of 10z was confirmed by X-ray crystallographic analysis. To demonstrate the reliability and practicality of the present synthetic methodology, a gram-scale experiment was carried out with o-alkynylbenzaldehyde 4a and styrene 5a, affording 1.4 g of product 10a in 66% yield with complete regioand diastereocontrol (Scheme 4), indicating the good scalability of the present method.
(ca. within 1 h) and gave a yield much higher than those with electron-donating ones (4c−4f). Regardless of the substitution pattern of the aryl ring (ortho, meta, or para) of the oalkynylbenzaldehyde used in the reaction, the corresponding cyclized products (10g−10k) were obtained in good yields. Moreover, naphthalene substrate 4l was also proven to be a suitable substrate and gave the desired product 10l in 80% yield. Meanwhile, substrates carrying oxetane/azetidine rings could also be employed to give the polycyclic scaffold without any difficulties (10m−10p). Substrates with five-membered rings proved more challenging because the lack of enough ring tensile force delivered the corresponding ring-expansion products in relatively lower yields (10q, 10r). Remarkably, exceptional regio- and diastereoselectivities were achieved in all cases: no regio- or diastereoisomers of product 10 were detected in the reaction mixtures. Next, we continued to investigate the substrate generality with a range of substituted styrenes (5s−5z, Scheme 3).16 Generally, the electron-rich substrate gave a yield of desired product higher than that of electron-neutral and electron-deficient ones (5t−
Scheme 4. Preparative Scale Synthesis of 10a (1.4 g)
Finally, the utility of this method was demonstrated by the derivatization of the spiro-2-oxabicyclo[2.2.2]octane 10a into its derivatives (Scheme 5). The spirolactone 11 was prepared by a
Scheme 3. Substrate Scope Continueda,c
Scheme 5. Derivatization of 10aa
a Reagents and conditions: (a) m-CPBA (3.0 equiv), NaHCO3 (3.0 equiv), CH2Cl2, rt, 8 h, 53% yield; (b) NaBH4 (1.5 equiv), MeOH, 0 °C, 2 h, 95% yield; (c) CH3PPh3I (1.2 equiv), t-BuOK (1.2 equiv), THF, rt, 1.5 h, 96% yield; (d) TMSOI (1.5 equiv), NaH (1.5 equiv), DMSO, 0 °C to rt, 20 h, 83% yield; (e) 2-propynylamine (3.0 equiv), CuCl2·2H2O (3 mol %), EtOH, 120 °C, overnight, 44% yield. TMSOI = trimethylsulfoxonium iodide.
Baeyer−Villiger oxidation with a complete stereoselective control. Treatment of 10a with NaBH4 delivered the corresponding alcohol 12 as a single diastereoisomer.17 Methylene compound 13 was steadily prepared from 10a with decent yield by Wittig reaction. A stereoselective Corey− Chaykovsky epoxidation was also achieved and gave compound 14 in 83% yield. Its relative configuration was assigned by X-ray single crystallographic analysis. Interestingly, a pyridine motif could be successfully incorporated into the carbonyl precursor 10a according to Arcadi’s method18 with moderate yield. In conclusion, we have demonstrated that the Ag(I)/ Brønsted acid binary catalyst system enables an oxa-[4 + 2]-
a
The reactions were performed by adding AgNO3 (5 mol %) and 1NSA (10 mol %) to a solution of 4 (1.0 equiv) and 5 (1.5 equiv) in CH2Cl2 (0.2 M) at 25 °C and stirring the mixture until TLC showed full consumption of 4. bAgNO3 (2 mol %) and 1-NSA (5 mol %) at 0 °C. cIsolated yield. 1-NSA, 1-naphthalenesulfonic acid. C
DOI: 10.1021/acs.orglett.9b00251 Org. Lett. XXXX, XXX, XXX−XXX
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cycloaddition and subsequent 1,2-alkyl migration cascade to give 2-oxabicyclo[2.2.2]octanes with readily available oalkynylbenzaldehydes as the substrates. A wide range of substrates are tolerated in this transformation, and various products can be obtained in good yields. The operational simplicity coupled with the mild reaction conditions of the present approach has established a new entry to a diverse set of valuable 2-oxabicyclo[2.2.2]octanes with up to four new stereogenic centers that are excellently controlled.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00251. Synthetic procedures; 1H and 13C NMR spectra for all organic products (PDF) Accession Codes
CCDC 1873169−1873170 and 1883278 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, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hongbin Zhai: 0000-0003-2198-1357 Yun Li: 0000-0003-2236-9880 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This paper is dedicated to the Lanzhou University on the occasion of its 110th anniversary. We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21572089), the Program for Changjiang Scholars and the Innovative Research Team in Universities (PCSIRT: IRT_15R28), the FRFCU (lzujbky-2018-61), and the Gansu Provincial Sci. & Tech. Department (2016B01017).
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00251 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters indicating endo selectivity of the first-step Diels−Alder reaction; while the following 1,2-migration at less hindered face of the oxonium intermediate 7 and delivered the product 10 with the observed stereochemistry.
(15) Listed chiral ligands and phosphoric acids were employed to attempt the asymmetric version of this cascade reaction. However, no enantioselectivities were observed in all cases.
(16) Some failed substrates are indicated in the Supporting Information. (17) Relative configuration of 12 was determined by NOE experiment. Please find detailed information in the Supporting Information. (18) Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959−6966.
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DOI: 10.1021/acs.orglett.9b00251 Org. Lett. XXXX, XXX, XXX−XXX
