Organocatalytic Asymmetric Synthesis of Spiro-Bridged and Spiro

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Organocatalytic Asymmetric Synthesis of Spiro-Bridged and SpiroFused Heterocyclic Compounds Containing Chromane, Indole, and Oxindole Moieties Zhi-Hao You,† Ying-Han Chen,† Yu Tang,†,‡ and Yan-Kai Liu*,†,‡ †

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Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China ‡ Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China S Supporting Information *

ABSTRACT: Following the reactivity inversion strategy, two different two-step sequences were designed and successfully applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane, indole, and oxindole, three potential pharmacophores, in one molecule. The power of these two organocatalytic pathways is underscored by mild reaction conditions and high efficiency in the production of synthetically challenging, but biologically important heterocyclic products, which could be transformed into more biologically interesting heterocyclic structures.

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hiral spiro-bridged and spiro-fused heterocyclic frameworks are widely encountered in numerous natural products and biologically active compounds.1 However, the asymmetric construction of these spirocyclic structural motifs is quite challenging due to their molecular complexity with multiple stereogenic centers.2 New transformations that could provide rapid access to the aforementioned heterocyclic frameworks in an asymmetric catalytic manner are thus particularly appealing. The combinatorial pharmacophore strategy has played a central role in the search of leading compounds for new drug development.3 Chromane,4 indole,5 and oxindole6 fragments are three well-known heterocyclic pharmacophores and are found in various natural and bioactive molecules. Despite extensive efforts that have been devoted to the asymmetric construction of molecules containing such three potential pharmacophores, all the established protocols furnished the chiral products containing only two of these three potential pharmacophores in spiro-fused heterocyclic systems (Figure 1),7 and to the best of our knowledge, there have been no reports on a catalytic enantioselective construction of compounds combining all of them in one spiro-bridged or spiro-fused heterocyclic molecule,8 which may be potentially © XXXX American Chemical Society

Figure 1. Selected compounds containing chromane, indole, and oxindole moieties.

applied as pharmaceutical agents. Therefore, it is highly desirable to develop enantioselective catalytic procedures for the synthesis of spiro-fused and spiro-bridged heterocyclic compounds containing these three potential pharmacophores. Received: August 26, 2018

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DOI: 10.1021/acs.orglett.8b02731 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

hand, by inversing the reactivity of 1a and 2a, respectively, to give chroman-2-ol 6a and 3-methoxy-3-indolyl-disubstituted oxindole 7a, 6a reacts with 7a via the enamine-catalyzed C−C bond formation, resulting in the production of intermediate 8 bearing a lactol moiety, followed by treatment with acid furnishing the target spiro-fused heterocyclic products 9 (Scheme 1, path B). Therefore, both of the spiro-fused and spiro-bridged heterocyclic molecules containing three potential pharmacophores, such as chromane, indole, and oxindole fragments, in one molecule have been constructed in a highly stereocontrolled manner by a two-step sequence using simple and easily available starting materials. To prove the viability of our envisioned design, we initially investigated the asymmetric catalytic two-step sequence of reactions between 1a and 2a in the presence of aminocatalyst 3 and o-fluorobenzoic acid (o-FBA). As shown in Scheme 2

Reactivity inversion turned out to be useful as a heuristic principle in the design of synthetic strategy for the synthesis of structurally diverse products.9 3-Indolyl-substituted oxindoles 2a have emerged as valuable nucleophiles (3-position of oxindole moiety) for the synthesis of natural products and biologically active compounds,10 but the application of 2a to construct chiral spiro-bridged heterocycles has not been reported until now.11 By introduction of a leaving group, such as a hydroxy or alkyloxy group, an inversion of the general nucleophilic nature of 3-position of 2a will be observed (Scheme 1). Thus, 3-indolyl-substituted oxindoles 7a could be Scheme 1. Design of Synthetic Strategies

Scheme 2. Synthesis of Spiro-Bridged Heterocyclic Products 5a and 5′a

potentially used as electrophiles to construct spiro-fused oxindole derivatives.12 It is noteworthy that the indole moiety in both 2a and 7a could serve as potential nucleophilic partners to react with an oxocarbenium ion for further transformations,13 which allows the possibility of creating structurally complex enantioenriched fused and bridged heterocycles. Meanwhile, under conditions of asymmetric aminocatalysis, 2-hydroxy cinnamaldehyde 1a is generally employed as an electrophile (β-position).14 In contrast, we have recently found that the simple chroman-2-ol 6a, which was easily obtained by reduction of 2-hydroxy cinnamaldehyde 1a and thus showed inverse reactivity, could be directly used as a nucleophile (α-position) in the synthesis of structurally diverse polycyclic compounds via lactol intermediates,15 which are the precursors of an oxocarbenium ion under acidic conditions.16 Herein, for the first time we report two different two-step sequences for the asymmetric construction of spirobridged and spiro-fused heterocyclic compounds, containing chromane, indole, and oxindole moieties in one molecule. Based on these considerations and also as a continuation of our interest in the application of 2-hydroxy cinnamaldehyde 1a,15b,c chroman-2-ol 6a,15 and 3-substituted oxindole17 as useful starting materials to construct complex heterocyclic compounds, we sought to further extend the concept of reactivity inversion in the construction of spiro-fused and spiro-bridged heterocyclic frameworks. Our design plan is illustrated in Scheme 1; the asymmetric Michael addition between 1a and 2a leads to a lactol intermediate 4 via iminium catalysis, which subsequently undergoes acid-catalyzed intramolecular Friedel−Crafts alkylation by the nucleophilic attack of the indole moiety to an oxocarbenium ion, providing the desired spiro-bridged heterocyclic products 5 that bear one tetrasubstituted spiro stereogenic carbon center and two chiral bridgehead carbon centers (Scheme 1, path A). On the other

(TBS = tert-butyldimethylsilyl; optimization studies are detailed in Table S1 of the Supporting Information, SI), the first Michael addition step proceeded smoothly in tetrahydrofuran (THF) at −20 °C, producing the corresponding lactol intermediates 4a and 4′a as two separable diastereomers, which were efficiently transformed into the desired spirobridged heterocycles 5a and 5′a, respectively, in good isolated yields (5a, 22%; 5′a, 61%; over two steps based on 2a) with excellent enantioselectivities (>99% for each diastereomer) through the BF3·Et2O catalyzed intramolecular Friedel−Crafts alkylation at 0 °C in CH2Cl2 within 10 min. Next, the substrate scope of the designed asymmetric twostep sequence was studied with respect to both 1 and 2 under the optimized conditions, and the results are given in Scheme 3. Generally, the reactions furnished the expected spirobridged products 5a−l and 5′a−l in moderate to good yields and with good to excellent enantioselectivities (most >99%), regardless of the electronic and steric properties of the substituents on the aromatic rings of chromane, indole, and oxindole moieties that are contained in the two reaction partners 1 and 2. Note that the corresponding N-benzylprotected or N-unprotected substrates 2 could also be applied to this transformation (5m−n and 5′m−n). Inspired by the success of the preparation of spiro-bridged heterocyclic compounds consisting of chromane, indole, and oxindole moieties, we further attempted to install three such potential pharmacophores in spiro-fused heterocyclic systems based on the inversion strategy. However, to our surprise, the initial Michael addition between chroman-2-ol 6a and 3methoxy-3-indolyl-disubstituted oxindoles 7a did not take place under the optimized conditions for the synthesis of spirobridged products 5 and 5′. This may be presumably attributed B

DOI: 10.1021/acs.orglett.8b02731 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Substrate Scope of Spiro-Bridged Heterocyclic Products

Scheme 5. Substrate Scope of Spiro-Fused Heterocyclic Products

step sequence tolerates both electron-donating and -withdrawing substituents at different positions on the aromatic ring of both 6 and 7, thus furnishing the spiro-fused heterocyclic products in moderate to good yields and with excellent enantioselectivities (9a−i and 9′a−i). The starting lactol containing a naphthalene ring can also be applied in this sequential reaction (9j and 9′j). To our surprise, Nunprotected substrate 7k delivered only one spiro-fused isomer 9′k with excellent enantioselectivity, while 9k was extensively decomposed under the current conditions. The absolute configurations of product 5′i (CCDC 1863213) and 9′c (CCDC 1863212) were unequivocally determined by X-ray crystallographic analysis (see Scheme 3 for 5′i and Scheme 5 for 9′c; the H atoms are omitted for clarity), and all other products were assigned by analogy. To further expand the concept and also to investigate the synthetic utility of both spiro-bridged and spiro-fused products, several transformations were carried out (Scheme 6). With the exception of 3-indolyl-substituted oxindoles, the reaction of 3pyrrolyl-oxindole 10 and 1a could also be achieved under the optimal conditions, leading to the generation of two separable epimers 11 and 11′ in a spiro-bridged heterocyclic system and each with excellent enantioselectivity. Spiro-bridged 5′a was treated with LiAlH4 to afford the hemiaminal intermediate 12, which subsequently underwent a p-TsOH promoted ringexpansion reaction, yielding the bridged seven-membered heterocyclic scaffold 13 containing two adjacent indole moieties. Additionally, the hemiaminal intermediate 14 was obtained by treatment of spiro-fused 9′a with LiAlH4, followed by an unexpected ring cleavage reaction to afford indolo[3,2a]carbazole derivative 15 in high isolated yield (90% over two steps), which might exhibit potential biological activity.19 Finally, the lactol intermediate 8′a could also be reduced by LiAlH4 to provide an unstable hemiaminal intermediate 16, which was stabilized by methylation protection to give 17 in 54% yield (two steps) with excellent diastereoselectivity (dr >20:1). In conclusion, based on the reactivity inversion strategy, we developed two different two-step sequences to synthesize

to the fact that 7a did not produce the required carbocation intermediate in the absence of acid.18 Therefore, we proposed that the MacMillan imidazolidinone catalysts in conjunction with different protonic acids might be the proper choice for the initial Michael addition, since the acids might serve as the promoter resulting in the departure of the methoxy group to give the required carbocation intermediate. Pleasingly, as shown in Scheme 4, after screening several MacMillan Scheme 4. Synthesis of Spiro-Bridged Heterocyclic Products 9a and 9′a

imidazolidinone catalysts in aqueous media (MeCN/H2O, v/ v = 5/1) at 25 °C (see Table S2 in the SI for full optimization studies),18a we found that the Michael adducts 8a and 8′a could be obtained as two separable diastereomers, when using 3′ as the aminocatalyst, and the subsequent p-Toluenesulfonic acid (p-TsOH) catalyzed intramolecular Friedel−Crafts alkylation between the indole and lactol moieties afforded the desired spiro-fused heterocyclic product 9a and 9′a in good yield (9a, 30%; 9′a, 42%; over two steps based on 7a) and with excellent enantioselectivities (98% and 99% for two diastereomers, respectively). Next, the substrate scope with respect to 6 and 7 was initially explored. As shown in Scheme 5, the designed twoC

DOI: 10.1021/acs.orglett.8b02731 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters Scheme 6. Useful Transformations

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ACKNOWLEDGMENTS

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REFERENCES

This work was supported by the NSFC-Shandong Joint Fund for Marine Science Research Centers (No. U1606403), the Scientific and Technological Innovation Project Financially Supported by Qingdao National Laboratory for Marine Science and Technology (No. 2015ASKJ02-06), and the National Natural Science of China (No. 81561148012).

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spiro-bridged and spiro-fused heterocyclic products containing chromane, indole, and oxindole moieties, and these three potential pharmacophores may be potentially applied as pharmaceutical agents. Further transformations of both spirobridged and spiro-fused heterocyclic products were achieved under mild reaction conditions, providing biologically interesting heterocyclic structures. It is noteworthy that almost all the synthesized spiro-bridged and spiro-fused chiral heterocyclic products were obtained with excellent enantioand diastereoselectivities. Studies toward the biological activity of the obtained products are currently underway in our laboratory.

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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.8b02731. Detailed optimization, experimental procedures, spectroscopic data for all new compounds, X-ray data, and proposed reaction mechanism of the two different twostep sequences (PDF) Accession Codes

CCDC 1863212−1863213 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

Yu Tang: 0000-0001-8224-4639 Yan-Kai Liu: 0000-0002-6559-2348 Notes

The authors declare no competing financial interest. D

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