Letter pubs.acs.org/OrgLett
Lewis Acid Mediated “endo-dig” Hydroalkoxylation−Reduction on Internal Alkynols for the Stereoselective Synthesis of Cyclic Ethers and 1,4-Oxazepanes Santosh J. Gharpure,* Dharmendra S. Vishwakarma, and Santosh K. Nanda Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India S Supporting Information *
ABSTRACT: Lewis acid mediated 5/6/7-endo-dig hydroalkoxylation−reduction cascade on internal alkynols gave an expedient, stereoselective synthesis of cyclic ethers and 1,4oxazepanes. The strategy has been extended to the first examples of hydroalkoxylation−alkyne Prins-type cyclization cascade of alkyne-tethered alkynols, giving access to oxabicyclic scaffolds. This method was used as the key step in the stereoselective total synthesis of calyxolane A-B, as well as (±)-centrolobine and its homologue.
T
oxazepanes remain largely unexplored. This is particularly intriguing given that hydroalkoxylation of alkenols has been studied extensively for the synthesis of small ring cyclic ethers.7 In the continuation of our interest in the synthesis of cyclic ethers and 1,4-heterocycles,8 herein we disclose the first examples of the 5/6/7-endo-dig hydroalkoxylation−reduction cascade mediated by TMSOTf for the stereoselective synthesis of THFs, THPs, and 1,4-oxazepanes. This general method is further used in the synthesis of bicyclic ethers and natural products, such as centrolobine (1) and calyxolane A (2) and B (3). Recently, we have reported the stereoselective synthesis of tetrahydrofurano/pyrano chromenes employing the metal-free hydroalkoxylation-formal [4 + 2] cycloaddition cascade of alkynol with salicylaldehyde.9 Based on this study, we envisioned that alkynol 7 in the presence of Lewis/Brønsted acid would form transiently more reactive cyclic enol ether Int-A via 5/6/7endo-dig hydroalkoxylation, which would lead to oxonium ion, whose trapping with nucleophile would furnish cyclic ether derivative 8 (Scheme 1). In order to test the proposed hypothesis, alkynol 7a was subjected to treatment with Lewis/Brønsted acid and Et3SiH under various conditions. It was found that when the reaction of alkynol 7a was carried out using TMSOTf (2 equiv) and Et3SiH (1 equiv) in CH2Cl2 at 0 °C−rt, the THF derivative 8a was obtained in good yield albeit with poor diastereoselectivity (Table 1). The latter result was not entirely surprising as, in general, it is known that diastereoselectivity for the formation of 2,5-disubstituted tetrahydrofuran derivatives through oxonium ion reduction is poor.10 The stereochemistry of the major diastereomer was assigned as cis based on NOE experiments and comparison with the reported data. Very recently, Shibuya et al. reported a closely related method for the stereoselective synthesis of cyclic ether and amines from terminal alkynes
etrahydrofurans (THFs), tetrahydropyrans (THPs), and oxazepanes are often encountered in bioactive natural products. (−)-Centrolobine (1, Figure 1), isolated from the
Figure 1. Natural products and bioactive molecules having THF/THP/ 1,4-oxazepane core.
heartwood of Centrolobium robustum and from the stem of Brosimum potabile in the Amazon rain forest, exhibits antiinflammatory, antibacterial and antileishmania1 activity.1 THF derivatives calyxolane A (2) and B (3) were isolated from the Caribbean marine sponge Calyx podatypa.2 Isolaurepan (4) is a fully saturated analogue of the core of (+)-isolaurepinnacin and other chiral oxepane derivatives.3 Orientalol F (5), bearing a bicyclic ether moiety, was isolated from the plant Alisma orientalis, whose dried rhizomes have been used as folk medicines for diabetes and diuretics.4 1,4-Heterocyclic ethers, such as morpholines and 1,4-oxazepanes too are important pharmacophores. For example, 1,4-oxazepanes (6) are used as dopamine D4 receptor ligands.5 Recent years have seen the emergence of transition metal catalyzed intramolecular hydroalkoxylation of alkynols as a method of choice for the synthesis of cyclic ketals and complex scaffolds.6 Surprisingly, corresponding metal and metal-free hydroalkoxylation for the synthesis of THF, THP, and © 2017 American Chemical Society
Received: October 17, 2017 Published: November 22, 2017 6534
DOI: 10.1021/acs.orglett.7b03241 Org. Lett. 2017, 19, 6534−6537
Letter
Organic Letters Scheme 1. Envisioned Hydroalkoxylation−Reduction Cascade for Cyclic Ether Synthesis
Scheme 2. Stereoselective Synthesis of THF Derivative 8: Substrate Scope
Table 1. Optimization for the Stereoselective Synthesis of 8a
entry
acid
equiv
temp (°C)
time (h)
yield (%)a
1 2 3 4 5 6 7 8 9 10
Cu(OTf)2 BF3·OEt2 BF3·OEt2 TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf TfOH
1 1 2 1 2 2 2 0.1 2 2
0−rt 0−rt 0−rt 0−rt 0−rt −78 0−rt 0−rt 0−rt 0−rt
24 72 30 24 6 48 20 24 4 5
c 34 57 45 78 c 72d 29 e 51
drb
the major diastereomer was found to have THF moiety with trans-stereochemistry. On the contrary, the cis-alkynyl cyclopentanol 7l furnished THF derivative 8l with excellent diastereoselectivity (dr ≥ 19:1). Spiro-fused tetrahydrofuran derivative 8m could also be accessed, albeit in lower yield, perhaps due to the unstable nature of the tertiary alcohol 7m under the reaction conditions employed. The 2,4-disubstitued THF 8n was obtained with slightly improved diastereoselectivity. This transformation was finally used in the total synthesis of calyxolane A (2) and B (3) in good yield as a mixture of diastereomers (dr = 3:2).12 Stereoselective synthesis of tetrahydropyran derivatives 11 was studied next, using TMSOTf as Lewis acid and Et3SiH as reducing agent. Alkynol 10a, as well as the ones having electrondonating groups 10b−c, gave THP derivatives 11a−c in good yield and excellent diastereoselectivity (dr ≥ 19:1) (Scheme 3). However, alkynol 10d with electron-withdrawing NO2 substituent on the aryl ring did not furnish the desired THP derivative 11d, and starting material was recovered completely. Not only alkyl substituted alkynols 10e−g but also alkynyl cyclohexanol 10h−j provided the corresponding THP derivatives 11e−j in excellent diastereoselectivity and no competing
1:1 1:1 1.3:1 1.3:1 1.3:1 1.3:1 1:1
a
Isolated yield. bdr was determined on the basis of crude 1H NMR. c Starting materials were as such. dReaction was carried out using molecular sieves. eCH3CN was used as solvent and corresponding hydrolyzed product was obtained.
using bis-(trifluoromethanesulfonyl)-imide and silane catalytic system.11 It is pertinent to mention that the alkynols underwent 5/6-exo-dig hydroalkoxylation under the reaction conditions that were employed by them. Further scope and limitation of the method was then investigated using optimized reaction conditions. Alkynol 7b− c with an electron releasing group on the aryl ring (Me) gave corresponding THF derivatives 8b−c in good yield (Scheme 2). Alkynol 7d bearing a strong electron releasing OMe group furnished the desired THF derivative 8d as a minor product (20%) along with 5-(4-methoxyphenyl)pentan-2-ol 9 as the major product (38%). The latter is an outcome of over-reduction of the formed THF derivative 8d. In contrast, alkynol 7e with electron-withdrawing NO2 substituent did not participate in the hydroalkoxylation−reduction cascade, and starting material was recovered back even after a prolonged reaction time. These observations are consistent with the formation of a vinyl cation intermediate in the presence of acid. As anticipated, the presence of a strong electron-withdrawing group destabilizes the vinyl cation and slows down the reaction. Interestingly, diastereoselectivity of the reaction was found to improve with the bulkier substituents on carbon bearing hydroxy group. Thus, alkynols 7f−g with isopropyl and cyclohexyl substituent furnished THF derivatives with better diastereoselectivity as compared to alkynols 7a,b,h,i with methyl, benzyl, or benzyloxymethyl substituents. Both the cis- and trans-fused cyclohexyl THF derivatives 8j and 8k were obtained in good yield from corresponding alkynol 7j−k. Interestingly, in the former case,
Scheme 3. Stereoselective Synthesis of THP Derivatives 11: Substrate Scope
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DOI: 10.1021/acs.orglett.7b03241 Org. Lett. 2017, 19, 6534−6537
Letter
Organic Letters
turn was trapped by triflate to furnish the oxa-bicyclic vinyl triflate 16 in good yield (Scheme 6). To our knowledge, these are the first examples of transition-metal-free hydroalkoxylation− Prins type cyclizations.
side reactions were observed. In the case of THP 11j, the diastereoselectivity was poor; however, the cis- and trans-isomers could be readily separated by silica gel column chromatography. Alkynyl-1,3-propane diol 10l under reaction conditions also led to the formation of THP derivative 11l in good yield, albeit in poor diastereoselectivity. To further expand the scope of the hydroalkoxylation− reduction cascade, the strategy was applied to the synthesis of 1,4-oxazepane derivatives 13. Thus, 2,7-disubstituted 1,4oxazepane derivatives 13a−b could be obtained in good yield and excellent diastereoselectivity starting from alkynols 12a−b. Even cyclohexane-fused 1,4-oxazepanes 13c−d formed with excellent diastereoselectivity (Scheme 4). Furthermore, natural
Scheme 6. Hydroalkoxylation−Prins Cyclization Cascade
Scheme 4. Synthesis of 1,4-Oxazepanes 13 To further expedite the synthesis of THP derivatives, a “onepot” process involving the generation of requisite alkynol and hydroalkoxylation−reduction cascade was designed. Alkynal 17 was treated with allyl tributyltin (18) in the presence of BF3·OEt2 followed by addition of 1 equiv of water. Et3SiH and TMSOTf were then added sequentially to furnish allyllated THP derivative 11n in good yield and excellent diastereoselectivity (Scheme 7). It is interesting to note that the reaction sequence was successful only when 1 equiv of water was added in order to hydrolyze the tin alkoxide intermediate. Scheme 7. “One-Pot” Allylation−Hydroalkoxylation− Reduction for the Synthesis of THP Derivative 11n
α-amino acid derived alkynols 12e−h also lead to the requisite 3,7-disubstituted 1,4-oxazepane derivatives 13e−h in good yield and poor to good diastereoselectivity. The stereochemistry of the major diastereomer was confirmed by NOE and X-ray diffraction studies (13b, 13e, and 13g). In order to study the versatility of established protocol, we tried to trap the in situ formed oxonium ion with other nucleophiles. Thus, when we used TMSCN as the nucleophile along with TMSOTf, the desired THP/THF derivatives 11m and 8o were obtained in good yield from the corresponding alkynols 10c and 7a, respectively (Scheme 5).
To examine the relative rates of Lewis acid mediated 5-endo-dig vs 6-endo-dig hydroalkoxylation reduction cascade, the alkyne diol 7o was reacted under optimized conditions. The THF derivative 8p was obtained as the sole product, and none of the THP derivative 11n was detected in the crude reaction mixture (Scheme 8). This was further unambiguously confirmed by the benzylation of the THF derivative 8p, which furnished the product 8i (cf. Scheme 2).
Scheme 5. Hydroalkoxylation Nucleophile Trapping
Scheme 8. 5-endo-dig vs 6-endo-dig Hydroalkoxylation As expected, the diastereoselectivity was better in the case of THP than the THF derivative. In continuation of this idea, we envisaged that the in situ generated oxonium ion can be trapped in an intramolecular fashion, which would lead to oxa-bicyclic scaffolds in one step. To test the hypothesis, alkene tethered alkynol 10k was treated with TMSOTf in CH2Cl2 to furnish an inseparable regioisomeric mixture (7:2) of oxa-bicyclo alkene 14 via hydroalkoxylation−intramolecular Prins cyclization.13 The mixture of ethers 14 was then reduced with H2/Pd−C to give oxa-bicyclo nonane derivative 15 in quantitative yield. Interestingly, when alkynol 10h with a tethered alkyne was treated with TMSOTf, the reaction proceeded through hydroalkoxylation−alkyne Prins-type cyclization to generate a vinyl cation,14 which in
Finally, this hydroalkoxylation−reduction cascade was employed as a key step in the total synthesis of (±)-centrolobine as well as its homologue. Thus, alkyne 11j (cf. Scheme 3) upon Sonogashira coupling with p-iodo phenol furnished the protected centrolobine 11o, which upon catalytic reduction using H2/Pd−C afforded centrolobine (1) in excellent yield. A similar sequence on the alkyne 11i gave the homocentrolobine 6536
DOI: 10.1021/acs.orglett.7b03241 Org. Lett. 2017, 19, 6534−6537
Letter
Organic Letters
We are grateful to UGC and CSIR, New Delhi for the award of research fellowship to D.S.V. and S.K.N.
(1a) with excellent diastereoselectivity. To improve overall diastereoselectivity of the sequence, alkynol 10m was reacted under the optimized reaction condition, 15 followed by debenzylation using H2/Pd−C, which afforded (±)-centrolobine (1) in excellent yield with excellent diastereoselectivity (Scheme 9).16
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(1) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; MariniBettolo, G. B. Gazz. Chim. Ital. 1964, 287. (b) Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz. Chim. Ital. 1965, 95. (c) Arango Craveiro, A.; da Costa Prado, A.; Gottlieb, O. R.; Welerson de Albuquerque, P. C. Phytochemistry 1970, 9, 1869. (d) Jurd, L.; Wong, R. Y. Aust. J. Chem. 1984, 37, 1127. (e) de C. Alcantara, A. F.; Souza, M. R.; Piló-Veloso, D. Fitoterapia 2000, 71, 613. (2) Rodriguez, A. D.; Cóbar, O. M.; Padilla, O. L. J. Nat. Prod. 1997, 60, 915. (3) (a) Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett. 1973, 14, 4135. (b) Suzuki, M.; Kurata, K.; Kurosawa, E. Bull. Chem. Soc. Jpn. 1986, 59, 2953. (c) Fukuzawa, A.; Masamune, T. Tetrahedron Lett. 1981, 22, 4081. (4) Penga, G.-P.; Tiana, G.; Huanga, X.-F.; Lou, F.-C. Phytochemistry 2003, 63, 877. (5) Audouze, K.; Nielsen, E. O.; Peters, D. J. Med. Chem. 2004, 47, 3089. (6) For reviews on hydroalkoxylation of alkynol: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079. (b) Wu, X. F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (7) (a) Murayama, H.; Nagao, K.; Ohmiya, H.; Sawamura, M. Org. Lett. 2015, 17, 2039. (b) Fujita, S.; Abe, M.; Shibuya, M.; Yamamoto, Y. Org. Lett. 2015, 17, 3822. (c) Shigehisa, H.; Hayashi, M.; Ohkawa, H.; Suzuki, T.; Okayasu, H.; Mukai, M.; Yamazaki, A.; Kawai, R.; Kikuchi, H.; Satoh, Y.; Fukuyama, A.; Hiroya, K. J. Am. Chem. Soc. 2016, 138, 10597. (d) Ferrand, L.; Tang, Y.; Aubert, C.; Fensterbank, L.; Mouries- Mansuy, V.; Petit, M.; Amatore, M. Org. Lett. 2017, 19, 2062. For acid mediated hydroalkoxylation of alkenol: (e) Deka, M. J.; Indukuri, K.; Sultana, S.; Borah, M.; Saikia, A. K. J. Org. Chem. 2015, 80, 4349. (f) Sultana, S.; Devi, N. R.; Saikia, A. K. Asian J. Org. Chem. 2015, 4, 1281. For reviews on hydroalkoxylation of alkene: (g) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68, 8079. (8) (a) Gharpure, S. J.; Shukla, M. K.; Vijayasree, U. Org. Lett. 2009, 11, 5466. (b) Gharpure, S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519. (c) Gharpure, S. J.; Reddy, S. R. B. Tetrahedron Lett. 2010, 51, 6093. (d) Gharpure, S. J.; Prasad, J. V. K. Eur. J. Org. Chem. 2013, 2013, 2076. (9) Gharpure, S. J.; Nanda, S. K.; Padmaja; Shelke, Y. G. Chem. - Eur. J. 2017, 23, 10007. (10) Carreño, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladie, G. J. Org. Chem. 2003, 68, 7779. (11) Shibuya, M.; Fujita, S.; Abe, M.; Yamamoto, Y. ACS Catal. 2017, 7, 2848. (12) (a) Hilt, G.; Bolze, P.; Harms, K. Chem. - Eur. J. 2007, 13, 4312. (b) Liang, X.; Wei, K.; Yang, Y.-R. Chem. Commun. 2015, 51, 17471. (c) Shuler, W. G.; Combee, L. A.; Falk, I. D.; Hilinski, M. K. Eur. J. Org. Chem. 2016, 2016, 3335. (d) Zhao, F.; Li, N.; Zhang, T.; Han, Z.-Y.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed. 2017, 56, 3247. (13) (a) Barluenga, J.; Fernandez, A.; Diéguez, A.; Rodríguez, F.; Fañanás, F. J. Chem. - Eur. J. 2009, 15, 11660. (b) Vandavasi, J. K.; Hu, W. P.; Boominathan, S. S. K.; Guo, B. C.; Hsiao, C. T.; Wang, J. J. Chem. Commun. 2015, 51, 12435. (14) (a) Miranda, P. O.; Ramirez, M. A.; Martin, V. S.; Padron, J. I. Chem. - Eur. J. 2008, 14, 6260. (b) Gharpure, S. J.; Shelke, Y. G.; Kumar, D. P. Org. Lett. 2015, 17, 1926 and the references cited therein. (15) For the detailed procedure of the synthesis of alkynol 10m, see Supporting Information. (16) For total synthesis of centrolobine, see: (a) Nagarjuna, B.; Thirupathi, B.; Rao, C. V.; Mohapatra, D. K. Tetrahedron Lett. 2015, 56, 4916. (b) Latif, M.; Yun, J. I.; Seshadri, K.; Kim, H. R.; Park, C. H.; Park, H.; Kim, H.; Lee, J. J. Org. Chem. 2015, 80, 3315 and the references cited therein.
Scheme 9. Total Synthesis of (±)-Centrolobine (1) and Its Homologue 1a
In conclusion, we have developed a metal-free, Lewis acid mediated hydroalkoxylation−reduction cascade of alkynols for the stereoselective synthesis of cyclic ethers as well as 1,4oxazepanes. The strategy was also extended for the synthesis of oxa-bicyclic scaffolds using alkynols tethered to carbon nucleophiles. The developed method was applied in the total synthesis of natural products such as (±)-calyxolane A and B and (±)-centrolobine, as well as its homologue.
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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.7b03241. Synthetic procedures and characterization data of products (PDF) Accession Codes
CCDC 1580402−1580405 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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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Santosh J. Gharpure: 0000-0002-6653-7236 Santosh K. Nanda: 0000-0002-6304-492X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank SERB, New Delhi for financial support. We thank Mr. Darshan Mhatre of the X-ray facility of the Department of Chemistry, IIT Bombay for collecting the crystallographic data. 6537
DOI: 10.1021/acs.orglett.7b03241 Org. Lett. 2017, 19, 6534−6537
