Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Transformation of Substituted Glycals to Chiral Fused Aromatic Cores via Annulative π‑Extension Reactions with Arynes Nazar Hussain,†,‡ Kalyanashis Jana,∥,⊥ Bishwajit Ganguly,∥,⊥ and Debaraj Mukherjee*,†,‡ †
Natural Product Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu 180001, India Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India ∥ CSIR−Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, India ⊥ Academy of Scientific and Innovative Research (AcSIR-CSMCRI), Bhavnagar 364002, India ‡
S Supporting Information *
ABSTRACT: The Diels−Alder addition of arynes to appropriately substituted vinyl/aryl glycals followed by π-extension via pyran ring opening smoothly furnished meta-disubstituted fused aromatic cores containing a stereodefined orthogonally protected chiral side chain. The method is broad in terms of aryl homologation, affording benzene, naphthalene, and phenanthrene derivatives. Base-induced deprotonation followed by cleavage of the allylic C−O bond appear to be the crucial steps leading to the development of aromaticity, which is the driving force behind the annulative π-extension process. The present protocol can be used for the synthesis of meta-disubstituted naphthalene aldehydes and substrates for aldolases.
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Scheme 1. Synthetic Strategies for Chiral Tagged Naphthalene Cores
inearly fused aromatic ring systems can be found in various bioactive natural products and π-conjugated functional materials.1 Densely substituted fused aromatic cores with chiral side chains are of particular interest because of their ability to bind with receptor biomolecules via π-stacking and chiral recognition.2a−f Further, chiral naphthalenes such as BINAP, BINOL, or BINAM have attracted great attention as ligands in transition-metal-catalyzed cross-coupling reactions2d or as building blocks for the construction of chiral supramolecular and polymeric materials. The naturally occurring gilvocarcin, belonging to a family of naphthalene C-glucosides, has been shown to exhibit high cytotoxicity with low overall toxicity.2f However, gaining access to fused aromatic nuclei attached to chiral side chains having defined stereochemistry remains a challenge for synthetic chemists. Methods to achieve this include an organocatalytic approach via an aldol reaction (Scheme 1, reaction 1a)3a or stereospecific opening of tetrahydropyrans attached to aryl moieties by a Ni catalyst using diastereoselective cross coupling (Scheme 1, reaction 1b).3b Nevertheless, to date there is no method for synthesizing fused aromatic cores containing defined chiral polyols side chains via homologation of the aromatic core. The annulative π-extension reaction (APEX) using arynes is recognized to have tremendous potential as it facilitates a onepot π-extension without the requirement for prefunctionalization.3c Our long-standing interest in glycal chemistry4 allowed © XXXX American Chemical Society
us to surmise that a properly functionalized dihydro aromatic oxadecalin framework, easily constructed through Diels−Alder reaction between an aryne and a glycal-based diene, might undergo π-extension reaction via a translocation of the double bond with concomitant pyran ring-opening while retaining the other stereochemical centers (Scheme 1, reaction 1c) as development of aromaticity would provide the driving force Received: January 29, 2018
A
DOI: 10.1021/acs.orglett.8b00319 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters for such a transformation. The findings are described in this communication. We commenced the study by treating a benzyl-protected glucal-based diene5 with an aryne precursor in the presence of a suitable base and solvent at different temperatures. Thus, when compounds 1a and 2a were allowed to react with CsF in acetonitrile at room temperature, TLC after 4 h detected the formation of a new compound with partial consumption of 1a. The new product was characterized as the meta-disubstituted naphthalene derivative 3a (Table 1, entry 1). The presence of a
Scheme 2. Substrate Scope for Polyol-Attached Naphthalenesa
Table 1. Optimization of the Reactiona
entry
base (mmol)
solvent
1 2 3 4 5 6 7
CsF (2) CsF (2) CsF (2) CsF (3) KF (3) TBAF(3) KF (4)
MeCN MeCN THF MeCN MeCN MeCN MeCN
additiveb (equiv)
temp (°C)
time (h)
yield (%)c of 3a
(2.0) (2.0) (2.0) (2.5)
rt 60 60 rt rt rt rt
6 6 6 8 8 8 10
15 18 10 35 67 43 89
a Reaction conditions: 1a (1 equiv), 2a (1.2 equiv), KF (4 equiv), 18crown-6 (2.5 equiv) in 2 mL of solvent at 30 °C. bAdditive: 18-crown6. cYield after column chromatography.
singlet at δ 8.01 (s, 1H) besides peaks for six additional protons between δ 7.83 and 8.80 in the 1H NMR (400 MHz, CDCl3) clearly indicated the formation of a meta-disubstituted naphthalene core. Opening of the pyran moiety was further confirmed by acetylation of the newly generated hydroxyl group (see the Supporting Information). We noted that increasing the reaction temperature did not have any remarkable effect on the yield of 3a (Table 1, entry 2), while changing the solvent from acetonitrile to THF decreased it (Table 1, entry 3). The use of 2 equiv of 18-crown-6 along with 3 equiv of CsF noticeably enhanced the yield of the desired product (Table 1, entry 4). These findings prompted us to keep 18-crown-6 as the additive for further optimization studies. When we replaced CsF with KF, a further improvement in the yield of the desired product was recorded (Table 1, entry 5), but TBAF did not appear to give satisfactory results (Table 1, entry 6). Finally, increasing the amount of KF and 18-crown-6 while carrying out the reaction in acetonitrile at rt for 10 h resulted in complete conversion of the starting diene 1a to 3a (Table 1, entry 7), and these proved to be the optimized reaction conditions. We next explored application of the methodology to react benzyne sources with a series of glycal-based dienes having a broad array of substituent patterns and stereochemical relationships. Screening of different dienes showed that electron-withdrawing groups such as esters in conjugation with the diene moiety accelerated the ring opening. Thus, alkoxycarbonyl or cyano attached at the terminal carbon of glucal-based dienes yielded meta-disubstituted naphthalenes in good-to-excellent yields (Scheme 2, 3a−c). A phenyl sulfonyl substituent also yielded the desired product, albeit in somewhat lower yield (Scheme 2, 3d). Examination of other arynes
a
Reaction conditions: 1 (1 equiv), 2 (1.2 equiv), KF (4 equiv), 18crown-6 (2.5 equiv) in 2 mL of MeCN at 30 °C for 8 h.
revealed the formation of single regioisomers in good yield employing a 3-methoxy-substituted aryne (Scheme 2, 3e), but a 4-methyl-substituted aryne yielded the product as an inseparable mixture of regioisomers (Scheme 2, 3f). As anticipated, a 4,5-dimethoxyaryne gave the desired product as a single regioisomer (Scheme 2, 3g). In order to broaden the substrate scope, dienes from other glycals such as L-rhamnal, D-galactal, and D-xylal were next tested under the optimized conditions. Dienes derived from Lrhamnal gave the desired product in good-to-excellent yields (Scheme 2, 3h−j). Xylal- and galactal-derived dienes were also viable substrates for the π-annulation reaction (Scheme 2, 3k,l). These experiments established the generality of substrate scope. Next, dienes having different protecting groups on the sugar moiety were tested. Ethers such as tri-O-methyl-protected glucal derived diene afforded the desired product in comparable yields with benzyl-protected derivatives (Scheme 2, 3m). An ester protecting group as in tri-O-benzoyl-D-glucal-derived diene 1n survived under the optimized reaction conditions, affording the product 3n in excellent yield. However, in the case of acetyl protection, two products (3o, 3oo) were obtained in almost 1:1 ratio due to migration of the acetyl group from the C-4 to the C-5 position. The diene derived from 3,4-dihydro2H-pyran also reacted under the optimized reaction conditions, B
DOI: 10.1021/acs.orglett.8b00319 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters generating the naphthalene-based long chain alcohol 3p (Scheme 2) in good yield. Fused aromatic rings flanked by two sugar units are reported to serve in the defense mechanism of plants against herbivores.6 We therefore thought of synthesizing their C-analogues using our methodology. Toward this, we prepared a chiral difunctionalized naphthalene glucoside derivative in a single step by subjecting substrate 4 (Scheme 3) to this reaction with a 3-methoxyaryne derived from 5. The reaction indeed furnished the desired product 6 in good yield (73%).
Scheme 6. Synthetic Applications of Downstream Products
Scheme 3. Utilization of Pseudo-disaccharides as Coupling Partners
Zemplén deacetylation and thereafter oxidative cleavage of the vicinal diol to form a meta-disubstituted naphthaldehyde moiety in quantitative yield, which would otherwise be difficult to obtain. Another application of our methodology utilizes the availability of a free hydroxyl group at C-5 position, which can easily be oxidized to obtain putative substrates for aldolases (reaction 2). To gain insights into the tandem annulative π-extension and ring-opening reaction, we performed a few control experiments. Though benzyne produced the meta-disubstituted naphthalene derivative having a chiral side chain 6 (Scheme 7, eq 2), maleic
After achieving success in the synthesis of chiral naphthalene derivatives, we tested whether the same strategy would work for the homologation of other chiral-fused aromatic cores. Thus, a glucal-derived diene was reacted with 1,2-naphthyne precursor 8 to generate the chiral phenanthrene regioisomers 9a and 9b (Scheme 4) in equal amounts and in excellent yield.
Scheme 7. Control Experiments
Scheme 4. Synthesis of Polyol-Attached Phenanthrene Derivatives from Sugar Dienes
anhydride 13a underwent only [4 + 2] cycloaddition and no subsequent ring opening (eq 1). On the basis of control experiments, we arrived at a possible mechanism for this tandem reaction as depicted in Scheme 8. Initially, the normal cycloaddition takes place between diene 1a and benzyne source 2a. The Diels−Alder adduct A thereafter undergoes a basecatalyzed proton abstraction from the benzylic carbon to form an allylic carbanion B, which eliminates alkoxide with
Gratifyingly, when we used tri-O-benzyl-2-aryl-D-glucals7 10a (derived from 2-iodo-D-glucal under Suzuki coupling conditions) instead of a conjugated diene and reacted with the benzyne precursor 2a (Scheme 5), the chiral phenanthrene derivatives (11a, 11b) were obtained in moderate yields. Aromatic aldehydes are very important substrates in multicomponent reactions of value for drug discovery and natural product total synthesis. As an application of the current protocol, we subjected product 3o (Scheme 6, reaction 1) to
Scheme 8. Plausible Mechanism of the Annulative πExtension Reaction
Scheme 5. Synthesis of Polyol-Attached Phenanthrene Derivatives Using a 2-Aryl-D-glucal
C
DOI: 10.1021/acs.orglett.8b00319 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) Bringmann, G.; Irmer, A.; Büttner, T.; Schaumlöffel, A.; Zhang, G.; Seupel, R.; Feineis, D.; Fester, K. J. Nat. Prod. 2016, 79, 2094. (7) Jana, S.; Rainier, J. Org. Lett. 2013, 15, 4426.
subsequent protonation from the solvent leading to the annulative π-extension. Development of aromaticity is the driving force for this transformation as maleic anhydride failed to give the desired ring-opened product (Scheme 8). In summary, we have demonstrated the formation of the benzannulated dihydro aromatic framework via a cycloaddition of glycal-derived dienes and benzynes, which undergo annulative π-extension reaction to generate meta-substituted fused aromatic moieties carrying chiral side chain(s) with tunable defined stereochemistry. The method is broad in terms of substrate scope and can be applied in the homologation of benzene to naphthalene and phenanthrene. It can be applied to the synthesis of meta-disubstituted naphthaldehydes and putative substrates for aldolases.
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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.8b00319. Experimental procedures, 1H and 13C NMR spectra, and characterization of all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kalyanashis Jana: 0000-0001-9792-8195 Bishwajit Ganguly: 0000-0002-9858-3165 Debaraj Mukherjee: 0000-0002-2162-7465 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are thankful to DST-India (EMR-2016-004710) for funding. N.H. and K.J. thank UGC New Delhi for SRF. IIIM Publication No. IIIM-2191-2018.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00319 Org. Lett. XXXX, XXX, XXX−XXX
