Letter Cite This: Org. Lett. 2018, 20, 979−982
pubs.acs.org/OrgLett
Ru-Catalyzed Chemoselective Olefin Migration Reaction of Cyclic Allylic Acetals to Enol Acetals Kyeongdeok Seo, Ye ji Kim, and Young Ho Rhee* Department of Chemistry, POSTECH, 77 Cheongam-Ro, Nam-Gu, Pohang, Kyungbuk 37673, Republic of Korea S Supporting Information *
ABSTRACT: A Ru-catalyzed olefin migration reaction of chiral cyclic allylic acetal is reported. The reaction generates cyclic enol acetal in a highly chemoselective manner. A variety of O,O- and N,O-acetals participated in the reaction with conservation of the stereochemical integrity of the acetal moiety. The utility of the reaction was demonstrated by the short and protective group-free syntheses of (L)-deoxyribonucleoside and β-amicetose glycoside.
M
The proposed migration reaction raises numerous concerns. First, the chiral information on the acetal moiety at the 2position should not be destroyed by the potentially Lewis acidic metal catalysts. In addition, competing migration to ketene acetals C needs to be suppressed (path 2, Scheme 1), which is particularly challenging with the disubstituted acetal substrates. This type of selectivity derived from cyclic acetals is unprecedented to the best of our knowledge.3 However, we reasoned that it could be induced by the distinct electronic environments between two competing migration pathways. From a synthetic viewpoint, the chiral enol acetal products should be highly useful for further transformations. As an example, we envisioned that the acetal-directed hydroboration/ oxidation sequence would give a rapid access to various β-deoxy glycosides, which constitute the core structure of various bioactive, natural product and non-natural analogs depicted in Scheme 1.4,5 Due to the lack of directing groups, stereoselective synthesis of these compounds represents a significant synthetic challenge in synthetic organic chemistry.6−11 We commenced our study with the optimization of the isomerization reaction of structurally simple 2,5-dihydrofuran acetal (±)-1 to enol acetal (±)-2 using various Ru complexes. Initial attempts to employ catalyst 3 (5 mol %) at rt provided the product in low 37% NMR yield. Increasing the reaction temperature to 80 °C improved the yield to 62% (Table 1, entry 1). We then varied the catalysts for the isomerization reaction. As depicted in entry 2, switching to complex 4 generated the product in 81% (75% isolated yield). Using firstgeneration Grubbs catalyst 5 led to the decomposition of the starting material (entry 3), while employing second-generation catalyst 6 provided the product in 43% yield (entry 4). Notably, the addition of 7 (2 equiv), which is known to facilitate formation of Ru−H species,13 considerably improved the yield
etal-catalyzed olefin migration reactions have received significant attention from synthetic chemists due to their potential utility to create functional groups with optimal atomefficiency.1 Because positional olefin isomers can be formed by the migration, controlling the selectivity becomes a critical issue in designing new viable olefin migration reactions. Herein, we report unprecedented chemoselective olefin migration of chiral allylic dihydrofuran/dihydropyran acetals A to enol acetals B (path 1, Scheme 1).2
Scheme 1. Basic Concept
Received: December 14, 2017 Published: January 24, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03900 Org. Lett. 2018, 20, 979−982
Letter
Organic Letters
enantioenriched acetal substrate (R)-1 provided the product (R)-2 in 73% yield with no loss of ee (entry 1). (For a detailed procedure for the determination of ee, see the SI.) This result verifies that the chiral acetal moiety remains unharmed by the metal catalysis. In addition, the use of 2,5-disubstituteddihydrofuan 8 produced the enol ether 9 in 59% yield (entry 2). Remarkably, the competing regioisomer (ketene acetal C in Scheme 1) was not observed. We then tested various pyrimidine allylic acetals (entries 3−8).14 Racemic substrates possessing N-benzyluracil 10 and N-benzylthymine 12 reacted successfully under the optimized conditions to give the migrated products 11 and 13 in high yields, respectively (entries 3 and 4). Enantioenriched substrates 14 bearing unprotected uracil also worked well to provide 15 in 72% yield again with the conservation of ee, even though the reaction required higher catalyst loading (10 mol %) and longer reaction time (entry 5). Enol acetal 17, whose enantiomeric form has been used for d4TP synthesis, was prepared in 73% yield from 16.15 Remarkably, the scope of the migration reaction was successfully expanded to unknown enol acetals possessing ethyluracil 19 (entry 7) and Boc-protected cytosine 21 (entry 8). These examples demonstrate the potential utility of the current method in the synthesis of new modified nucleoside derivatives. In addition to the monosubstituted acetal substrates discussed above, 2,5-disubstituted acetal substrate 22 was efficiently isomerized to the enol acetal product 23 in 85% yield without formation of the regioisomeric olefin (entry 9). As with previous examples, unprotected thymine acetal 24 produced the product 25 in somewhat lower 67% yield (entry 10). Having established the migration reaction of chiral 2,5dihydrofuran acetals, we then expanded the reaction to the dihydropyran acetals (Scheme 2). A preliminary reaction of
Table 1. Optimization of the Reaction Conditions
entry
catalyst
1 2 3 4 5
3 4 5 6 6
additive
time (h)
yielda (%)
7 (2 equiv)
0.5 0.5 12 12 12
62 81 (75b) dec 43 69
a
Determined by the integration of the crude NMR using 1,3,5trimethylbenzene as an internal standard. bIsolated yield.
of 2 to 69% yield (entry 5). (For more detailed information on the optimization, see the Supporting Information (SI).) With the optimized conditions in hand using 4, we then explored the scope of the reaction (Table 2). First, Table 2. Migration of 2,5-Dihydrofurans
Scheme 2. Migration of Dihydropyran Acetals
easily available 2612c furnished the product 27 only in moderate yield (∼40%) under the optimization conditions, despite the complete conversion. After further optimization, we discovered that separately prepared Ru−H complex 2816 (promoted by ethyl vinyl ether) significantly improved the yield of the desired migration.17 Thus, heating 26 in the presence of catalyst 28 (5 mol %) at 95 °C in toluene for 36 h gave 27 in 82% yield. As with the previous examples, potentially competing ketene acetal was not obtained in this case. More densely substituted dihydropyran acetals 29 also produced enol acetal 30 in 88% yield under the same conditions. The migration reaction of substrate 31 possessing bulkier ketal moiety was considerably slower than the previous examples. Exposure of this compound to 28 (5 mol %) at 95 °C proceeded in 5 days to give 32 in 75% yield. To investigate the chemoselectivity more rigorously, we explored competing migration of acyclic allylic ether 33 vs allylic acetal 34. As depicted in Scheme 3, 33 led to the complete conversion to 35, while 34 showed no formation of
Method A: catalyst 4 (5 mol %) in toluene at 80 °C. Method B: catalyst 4 (5 mol %) in dichloroethane at 85 °C. Method C: catalyst 4 (10 mol %) in dichloroethane at 85 °C. bIsolated yield. cn-BuOH (2 equiv) was used. a
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DOI: 10.1021/acs.orglett.7b03900 Org. Lett. 2018, 20, 979−982
Letter
Organic Letters
In summary, we developed a Ru-catalyzed olefin migration reaction of cyclic allylic acetals that evolved into a general de novo synthesis toward various deoxyglycosides. Considering the facile synthesis of the chiral acetal developed by us, we believe that this chemoselective migration reaction should find further use in the synthesis of various new nucleoside-based bioactive compounds as well as complex oligosaccharides. In addition to this fascinating future aspect, we are also working on expanding the scope of the isomerization reaction to other heterocyclic compounds.
Scheme 3. Mechanism for the Chemoselectivity
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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.7b03900. Experimental data and 1H and 13C spectra for all new compounds (PDF)
36 with substantial recovery (70%) of the starting material upon heating with 28.18 This observation verifies the critical substituent effect on the chemoselectivity. Based upon these results, the selectivity in dihydrofuran acetal migration may be rationalized by the effect of alkyl group at the 5-position that stabilizes Ru−H intermediate (compared with heteroatom substituent at the 2-position).19,20 The final stage of the work focused on the conversion of the enol acetal products to various deoxyglycosides (Scheme 4).
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Young Ho Rhee: 0000-0002-2094-4426
Scheme 4. Application
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support for this work was provided by the National Research Foundation of Korea, which is funded by the Korean Government (NRF-2015R1A2A1A15056116 and NRF2017R1A2B1010757).
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REFERENCES
(1) For selected recent reviews on the metal-catalyzed olefin migration, see: (a) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8, 209−219. (b) Hassam, M.; Taher, A.; Arnott, G. E.; Green, I. R.; van Otterlo, W. A. L. Chem. Rev. 2015, 115, 5462−5569. (c) Larionov, E.; Li, H.; Mazet, C. Chem. Commun. 2014, 50, 9816− 9826. (d) Kuznik, N.; Krompiec, S. Coord. Chem. Rev. 2007, 251, 222− 233. (e) Hilt, G. ChemCatChem 2014, 6, 2484−2485. (f) Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord. Chem. Rev. 2008, 252, 1819−1841. (g) Schmidt, B. Eur. J. Org. Chem. 2004, 2004, 1865−1880. (2) For selected examples on the migration to enol ethers and related enamides, see: (a) Trost, B. M.; Cregg, J. J.; Quach, N. J. Am. Chem. Soc. 2017, 139, 5133−5139. (b) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 4565−4572. (c) Kerrigan, N. J.; Bungard, C. J.; Nelson, S. G. Tetrahedron 2008, 64, 6863−6869. (d) Crivello, J. V.; Kong, S. J. Org. Chem. 1998, 63, 6745−6748. (e) Menicagli, R.; Malanga, C.; Dell’Innocenti, M.; Lardicci, L. J. Org. Chem. 1987, 52, 5700−5704. (f) Geherty, M. E.; Dura, R. D.; Nelson, S. G. J. Am. Chem. Soc. 2010, 132, 11875−11877. (3) For selected examples of migration reaction of 2-(mono)alkyl2,5-dihydrofuran, see: (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390−13391. (b) Schmidt, B. Eur. J. Org. Chem. 2003, 2003, 816−819. (c) Trost, B. M.; Brown, B. S.; McEachern, E. J.; Kuhn, O. Chem. - Eur. J. 2003, 9, 4442−4451. (4) (a) For a review on the deoxy-N-glycoside, see: Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Nat. Rev. Drug Discovery 2013, 12, 447−464. (b) For a review on the β-deoxypyrano glycoside, see: Bennett, C. S. Selective Glycosylations with Deoxy Sugars, in Selective
First, reaction of 9 with 9-BBN followed by the treatment with H2O2 generated the β-deoxyribose derivative 37 in 62% isolated yield.21 In an analogous manner, 2-deoxythymidine 38 was prepared from 23 as single diastereomer in 62% yield. This de novo strategy highlights a rare directing group-free synthesis of the 2-deoxyribonucleoside. Another interesting feature of the method is demonstrated by the synthesis of (L)-2-deoxythymidine (ent-38), a bis-benzyl derivative of antiviral telbivudine.22 This non-natural nucleoside was prepared in comparable efficiency to the enantiomeric (D)-isomer.23,24 The proposed method also proved useful for the synthesis of βamicetose glycoside 39 from 27.25 Remarkably, this challenging β-2,3,6-trideoxy glycoside could be synthesized from the allylic acetal 26 in only two steps without the need of activating/ protecting groups.26 981
DOI: 10.1021/acs.orglett.7b03900 Org. Lett. 2018, 20, 979−982
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Organic Letters Glycosylations: Synthetic Methods and Catalysts; Bennett, C. S., Ed.; Wiley-VCH, Weinheim, 2017; DOI: 10.1002/9783527696239.ch13. (c) For a study on d4TP and other related compounds, see: Kim, C. U.; Luh, B. Y.; Martin, J. C. J. Org. Chem. 1991, 56, 2642−2647. (5) For a reference to muraminomicin F, see: Chi, X.; Baba, S.; Tibrewal, N.; Funabashi, M.; Nonaka, K.; Van Lanen, S. G. MedChemComm 2013, 4, 239−243. (6) For reviews on the synthesis of β-deoxyglycosides, see: (a) Zeng, J.; Xu, Y.; Wang, H.; Meng, L.; Wan, Q. Sci. China: Chem. 2017, 60, 1162−1179. (b) Song, W.; Wang, S.; Tang, W. Chem. - Asian J. 2017, 12, 1027−1042. (c) Borovika, A.; Nagorny, P. J. Carbohydr. Chem. 2012, 31, 255−283. (7) For a report on deoxy-N-glycoside synthesis by way of glycosyl halide, see: Chaudhuri, N. C.; Moussa, A.; Stewart, A.; Wang, J.; Storer, R. Org. Process Res. Dev. 2005, 9, 457−465. (8) For selected recent examples of β-deoxypyranoglycoside synthesis based on the use of stoichiometric activators, see: (a) Zhu, D.; Baryal, K. N.; Adhikari, S.; Zhu, J. J. Am. Chem. Soc. 2014, 136, 3172−3175. (b) Issa, J. P.; Bennett, C. S. J. Am. Chem. Soc. 2014, 136, 5740−5744. (c) Beale, T. M.; Moon, P. J.; Taylor, M. S. Org. Lett. 2014, 16, 3604−3607. (d) Kaneko, M.; Herzon, S. B. Org. Lett. 2014, 16, 2776−2779. (e) Ruei, J.-H.; Venukumar, P.; Ingle, A. B.; Mong, K.K. T. Chem. Commun. 2015, 51, 5394−5397. (f) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Angew. Chem., Int. Ed. 2007, 46, 2505− 2507. (9) For a recent example on metal-catalyzed α-selective deoxyglycoside synthesis, see: Palo-Nieto, C.; Sau, A.; Galan, M. C. J. Am. Chem. Soc. 2017, 139, 14041−14044. (10) Selected examples on the β-deoxy-pyranoglycoside synthesis using gold catalysis, see: (a) Ma, Y.; Li, Z.; Shi, H.; Zhang, J.; Yu, B. J. Org. Chem. 2011, 76, 9748−9756. (b) Zhang, X.; Zhou, Y.; Zuo, J.; Yu, B. Nat. Commun. 2015, 6, 5879−5888. (11) For selected examples on de novo deoxypyranoglycoside synthesis via Pd-catalyzed glycosylation and the subsequent modification, see: (a) Yu, X.; O’Doherty, G. A. Org. Lett. 2008, 10, 4529−4532. (b) Zhou, M.; O’Doherty, G. A. Org. Lett. 2008, 10, 2283−2286. (12) (a) Kang, S.; Jang, S. H.; Lee, J.; Kim, D.-g.; Kim, M.; Jeong, W.; Rhee, Y. H. Org. Lett. 2017, 19, 4684−4687. (b) Kim, H.; Rhee, Y. H. Synlett 2012, 23, 2875−2879. (c) Lim, W.; Kim, J.; Rhee, Y. H. J. Am. Chem. Soc. 2014, 136, 13618−13621. (d) Kim, M.; Kang, S.; Rhee, Y. H. Angew. Chem., Int. Ed. 2016, 55, 9733−9737. (13) For selected examples on related studies, see: (a) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. J. Org. Chem. 2006, 71, 4255−4261. (b) Ohno, S.; Takamoto, K.; Fujioka, H.; Arisawa, M. Org. Lett. 2017, 19, 2422−2425. This condition references: (c) Donohoe, T.; O’Riordan, T. J. C.; Rosa, C. P. Angew. Chem., Int. Ed. 2009, 48, 1014−1017. (d) Liniger, M.; Liu, Y.; Stoltz, B. M. J. Am. Chem. Soc. 2017, 139, 13944−13949. (14) For the synthesis of allylic acetal substrates, see the SI. (15) This synthesis requires multistep transformations from (D)deoxythymidine featuring successive C−O and C−C bond cleavage. See ref 4c. (16) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153−2164. Also see ref 13a. (17) This catalyst system showed significantly poorer reactivity for the migration reaction of dihydrofuran acetals. (18) For a related example of migration of allylic O,O-acetal, see: Cheng, J.; Ji, R.; Gao, S.-J.; Du, F.-S.; Li, Z.-C. Biomacromolecules 2012, 13, 173−179. (19) According to our computational study, enol acetal 9 is more stable than the corresponding ketene acetal. Thus, it is reasonable to assume that the transition state leading to 9 has lower barrier than that leading to the corresponding ketene acetal. For detailed information on the computational study, see the SI. (20) The trans-stereoisomer of allylic acetal substrates 8 and 22 generated the migrated products in much poorer yield (
