Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereoselective Tandem Synthesis of syn-1,3-Diol Derivatives by Integrating Olefin Cross-Metathesis, Hemiacetalization, and Intramolecular Oxa-Michael Addition Keisuke Murata, Keita Sakamoto, and Haruhiko Fuwa* Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
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S Supporting Information *
ABSTRACT: Stereoselective tandem synthesis of syn-1,3-diol motifs, abundantly present in polyketide natural products and relevant pharmaceuticals, was achieved from homoallylic alcohols, α,β-unsaturated ketones, and aldehydes. Olefin crossmetathesis of homoallylic alcohols with α,β-unsaturated ketones, hemiacetalization of the resultant alcohols with aldehydes, and subsequent intramolecular oxa-Michael addition of the derived hemiacetals furnished syn-1,3-dioxane derivatives in good to excellent yields without isolation of any intermediates. The acetal moiety of the resultant syn-1,3-dioxanes could be cleaved chemoselectively/regioselectively under mild conditions in subsequent transformations.
T
Scheme 1. Tandem Synthesis of Tetrahydropyrans and 1,3Dioxanes
here has been a longstanding interest in developing efficient methods for stereocontrolled synthesis of 1,3diol motifs because they are embedded in a plethora of biologically relevant polyketide natural products and pharmaceuticals.1,2 Allylation and aldol reactions of carbonyl compounds are established synthetic methods for accessing 1,3-diol motifs within complex polyketides.3 Meanwhile, David A. Evans and Gauchet-Prunet have described that hemiacetalization/intramolecular oxa-Michael addition of δ-hydroxy α,β-unsaturated esters/amides with benzaldehyde in the presence of a catalytic amount of a strong base provides syn1,3-dioxanes, which correspond to benzylidene acetal protected 1,3-diols.4 This reaction has been widely used in complex polyketide synthesis because of the synthetic versatility of the product syn-1,3-dioxanes.3 P. Andrew Evans et al.5 and more recently Hayashi et al.6 have reported bismuth-catalyzed hemiacetalization/intramolecular oxa-Michael addition7 of δ-hydroxy α,β-unsaturated aldehydes/ ketones with aldehydes to deliver syn-1,3-dioxane derivatives. These precedents usually require separate preparation of δhydroxy α,β-unsaturated carbonyl compounds using olefin cross-metathesis or Wittig-type olefination. Integration of catalytic reactions in a single reaction vessel realizes tandem synthesis of complex molecules from simple starting materials in a highly step-economical manner.8,9 We have previously reported tandem olefin cross-metathesis/ intramolecular oxa-Michael addition of δ-hydroxy olefins I for stereoselective synthesis of 2,6-cis-substituted tetrahydropyran derivatives III (Scheme 1A).10 This reaction can be carried out either by ruthenium catalysis10a−c or by ruthenium/ Brønsted acid catalyses,10d,f and its versatility has been demonstrated by us and others in total syntheses of complex polyketide natural products.10f,11 © XXXX American Chemical Society
As a logical extension of our previous work, we now disclose a tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition for stereoselective access to synReceived: April 4, 2019
A
DOI: 10.1021/acs.orglett.9b01182 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 1,3-dioxane derivatives VII from homoallylic alcohols IV without isolation of intermediates V and VI (Scheme 1B). We envisioned that, by using catalytic amounts of a Grubbs-type ruthenium complex and a Brønsted acid, olefin crossmetathesis12 of homoallylic alcohols with α,β-unsaturated ketones and subsequent hemiacetalization/intramolecular oxa-Michael addition of the resultant δ-hydroxy α,β-unsaturated ketones with aldehydes could be integrated in a single reaction vessel. Initially, we investigated Brønsted acid catalyzed hemiacetalization/intramolecular oxa-Michael addition of δ-hydroxy α,β-unsaturated ketone 1a13 with a variety of commercially available, inexpensive aldehydes (Scheme 2A). Using aliphatic aldehydes such as paraformaldehyde and isobutyraldehyde, we quickly found that the reaction could be catalyzed efficiently under the influence of CSA (10 mol %) in toluene at room temperature for 2 h, giving the corresponding syn-1,3-dioxanes 2a and 3a, respectively, in excellent yields. However, treatment of 1a with benzaldehyde under the same conditions gave the desired product in only low yield even after a prolonged reaction time (Scheme 2B). Accordingly, we turned our attention to the use of aromatic aldehydes having an electronwithdrawing substituent(s). Actually, hemiacetalization/intramolecular oxa-Michael addition of 1a proceeded with p(trifluoromethyl)benzaldehyde to give syn-1,3-dioxane 4a in 63% yield with 19% recovery of 1a after 24 h (Scheme 2A). It was finally found that the reaction was complete within 24 h when o-nitrobenzaldehyde, p-nitrobenzaldehyde, and 3,5bis(trifluoromethyl)benzaldehyde were used, delivering the respective products 5a−7a in satisfactory yields (71−86%) with greater than 20:1 diastereoselectivity.14 Next, we examined whether the optimized reaction conditions were applicable to other δ-hydroxy α,β-unsaturated ketones 1b−d.15 As summarized in Scheme 2A, 1b,c underwent hemiacetalization/intramolecular oxa-Michael addition with aliphatic and aromatic aldehydes, providing syn-1,3dioxane derivatives 2b−7b and 2c−7c in excellent yields with greater than 20:1 diastereoselectivity. The reaction of 1d with paraformaldehyde and isobutyraldehyde proceeded cleanly and delivered the corresponding 1,3-dioxanes 2d and 3d in high yields (94 and 88%, respectively), whereas that with less reactive aromatic aldehydes gave the desired products 4d−7d in somewhat moderate yields (48−72%). In the latter case, several side products were observed.16 Our interest then turned to tandem olefin cross-metathesis/ hemiacetalization/intramolecular oxa-Michael addition of homoallylic alcohols 9a−d under sequential catalyses (Scheme 3, method A). Thus, 9a−d were initially reacted with methyl vinyl ketone (5 equiv) by the action of Nolan’s ruthenium alkylidene complex Ru-I17 (2 mol %) in toluene at room temperature to give δ-hydroxy α,β-unsaturated ketones 1a−d. Without isolation, 1a−d were then treated with aldehyde (5 equiv) and CSA (10 mol %) at room temperature. This reaction, under sequential catalyses, allowed us to obtain the desired syn-1,3-dioxane derivatives in good yields, demonstrating that the hemiacetalization/intramolecular oxa-Michael addition process was not disturbed by the presence of the ruthenium alkylidene catalyst and excess methyl vinyl ketone. However, the major shortcoming of this reaction was that it required long reaction time to reach completion, especially when less reactive aromatic aldehydes were used (26−90 h). Accordingly, we investigated whether all the requisite components/catalysts could be added together at the
Scheme 2. Brønsted Acid Catalyzed Hemiacetalization/ Intramolecular Oxa-Michael Addition of δ-Hydroxy α,βUnsaturated Ketonesa
a Reactions were performed using δ-hydroxy α,β-unsaturated ketones 1a−d, aldehyde (5 equiv), and CSA (10 mol %) in toluene at room temperature. Products were isolated by flash column chromatography using silica gel and identified as single stereoisomers (dr >20:1) by 1H NMR analysis. Yield in parentheses are recovered 1a.
beginning of the reaction (Scheme 3, method B). Thus, the reaction under cocatalysis should be more efficient and faster than that under sequential catalyses examined earlier, provided all the components/catalysts do not interfere negatively with each other. Possibly, intermolecular oxa-Michael additions of homoallylic alcohols and intermediary δ-hydroxy α,β-unsaturated ketones to excess methyl vinyl ketone might take place as side reactions under Brønsted acid catalysis. However, we envisioned that intermolecular oxa-Michael addition of secondary alcohols to methyl vinyl ketone should be slow B
DOI: 10.1021/acs.orglett.9b01182 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
CSA (10 mol %) in toluene at room temperature. As expected, the reaction under cocatalysis was generally faster to complete (13−50 h) than that under sequential catalyses. We have also investigated the use of an α,β-unsaturated ketone other than methyl vinyl ketone (Scheme 4A, sequential
Scheme 3. Olefin Cross-Metathesis/Hemiacetalization/ Intramolecular Oxa-Michael Addition by Sequential Catalysesa or by Cocatalysisb
Scheme 4. Application to Convergent Synthesis of Complex System
catalyses). Exposure of a mixture of homoallylic alcohol 9a and α,β-unsaturated ketone 10 (2 equiv) to Ru-II (2 mol %) in toluene at room temperature generated α,β-unsaturated ketone 11, which was treated in situ with 3,5-bis(trifluoromethyl)benzaldehyde (5 equiv) and a catalytic amount of AuCl(PPh3)/AgOTf (10 mol %) at room temperature to afford syn1,3-dioxane 12 in 70% yield with greater than 20:1 diastereoselectivity, along with α,β-unsaturated ketone 13 in 9% yield. In this case, a cationic Au(I) complex19 was found to be effective for catalyzing the hemiacetalization/intramolecular oxa-Michael addition; the use of CSA instead resulted in a significant amount of side product 13, which should be generated through elimination of methanol. Meanwhile, exposure of a mixture of the requisite three components 9a, 10 (2 equiv), and 3,5-bis(trifluoromethyl)benzaldehyde (5 equiv) to Ru-II (2 mol %) and AuCl(PPh3)/AgOTf (10 mol %) in toluene at room temperature for 24 h provided 12 in 57% yield (dr >20:1), along with 13 in 6% yield and unreacted 9a in 16% yield20 (Scheme 4B, cocatalysis). Further investigations into the use of cationic Au(I) complexes in our tandem reaction are currently underway. Importantly, these results demonstrated that, in contrast to previous
a Reactions were performed using homoallylic alcohols 9a−d, methyl vinyl ketone (5 equiv), and Ru-I (2 mol %) in toluene at room temperature. After consumption of 9a−d (TLC control), aldehyde (5 equiv) and CSA (10 mol %) were added and stirring was continued at room temperature. Products were isolated by flash column chromatography using silica gel and identified as single stereoisomers (dr >20:1) by 1H NMR analysis. bReactions were performed using homoallylic alcohols 9a−d, methyl vinyl ketone (5 equiv), aldehyde (5 equiv), Ru-II (2 mol %), and CSA (10 mol %) in toluene at room temperature. Products were isolated by flash column chromatography using silica gel and identified as single stereoisomers (dr >20:1) by 1H NMR analysis.
and hence less problematic under the reaction conditions. Here we used the second-generation Hoveyda−Grubbs complex Ru-II18 because it was superior to Ru-I in this reaction. We were able to obtain syn-1,3-dioxane derivatives 3a−d, 6a−d, and 7a−d in good to excellent yields from homoallylic alcohols 9a−d, methyl vinyl ketone (5 equiv), and aldehyde (5 equiv) under the influence of Ru-II (2 mol %) and C
DOI: 10.1021/acs.orglett.9b01182 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters relevant reactions,4−6 our tandem reaction should be applicable to fragment assembly processes in complex polyol synthesis. Finally, we examined the derivatization of syn-1,3-dioxanes 6c and 7c as model cases (Scheme 5). Treatment of 6c and 7c
developed reaction to complex molecule synthesis is currently ongoing in our laboratory and will be reported shortly.
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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.9b01182. Experimental procedure and 1H and 13C NMR spectra of new compounds (PDF)
Scheme 5. Derivatization of 1,3-Dioxanes
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AUTHOR INFORMATION
Corresponding Author
*E-mail for H.F.:
[email protected]. ORCID
Haruhiko Fuwa: 0000-0001-5343-9023 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research (C) (Grant No. JP17K01941) from JSPS and by The Naito Foundation.
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REFERENCES
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with L-Selectride delivered syn-alcohols 14c and 15c in 89% and 85% yields with good diastereoselectivity. Regioselective reductive cleavage of the benzylidene acetal of 15c could be achieved with LiAlH4/AlCl3,21 providing 1,3-diol 16c in 90% yield as a single regioisomer.13 Methylation of 14c and 15c with MeI/NaH gave methyl ethers 17c (82%) and 18c (99%). Reduction of 18c with DIBALH22 afforded alcohol 19c in 85% yield as a single regioisomer.13 Meanwhile, reduction of the nitro group of 17c with Zn in AcOH/H2O accompanied in situ cleavage of the resultant p-aminobenzylidene acetal to give 1,3diol 20c in good yield. Conversion of 17c to 20c could also be achieved via hydrogenolysis in a near-quantitative yield. In the same manner, hydrogenolysis of 18c occurred smoothly to afford 1,3-diol 20c in high yield. Thus, a series of differentially protected polyol derivatives could be easily prepared from syn1,3-dioxane derivatives. In conclusion, we have developed a tandem olefin crossmetathesis/hemiacetalization/intramolecular oxa-Michael addition for stereoselective synthesis of syn-1,3-dioxanes as acetal-protected syn-1,3-diol derivatives. The reaction does not require any special techniques and can be easily performed just by mixing requisite components and catalysts under mild conditions. Furthermore, we have demonstrated that the product syn-1,3-dioxanes can be derivatized into a series of synthetically useful polyol derivatives; their acetal moiety could be cleaved chemoselectively/regioselectively under mild conditions in subsequent transformations. Application of our D
DOI: 10.1021/acs.orglett.9b01182 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 1001. (j) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365. (9) (a) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40. (b) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62, 7505. (10) (a) Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2010, 12, 1636. (b) Fuwa, H.; Noto, K.; Sasaki, M. Heterocycles 2010, 82, 641. (c) Fuwa, H.; Suzuki, T.; Kubo, H.; Yamori, T.; Sasaki, M. Chem. Eur. J. 2011, 17, 2678. (d) Fuwa, H.; Noguchi, T.; Noto, K.; Sasaki, M. Org. Biomol. Chem. 2012, 10, 8108. (e) Fuwa, H.; Sasaki, M. Bull. Chem. Soc. Jpn. 2016, 89, 1403. (f) Sakurai, K.; Sasaki, M.; Fuwa, H. Angew. Chem., Int. Ed. 2018, 57, 5143. (11) (a) Wang, G.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 8088. (b) Kammari, B. R.; Bejjanki, N. K.; Kommu, N. Tetrahedron: Asymmetry 2015, 26, 296. (c) Trost, B. M.; Stivala, C. E.; Hull, K. L.; Huang, A.; Fandrick, D. R. J. Am. Chem. Soc. 2014, 136, 88. (d) Waldeck, A. R.; Krische, M. J. Angew. Chem., Int. Ed. 2013, 52, 4470. (e) ElMarrouni, A.; Lebeuf, R.; Gebauer, J.; Heras, M.; Arseniyadis, S.; Cossy, J. Org. Lett. 2012, 14, 314. (f) Park, H.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 3742. (12) For a review, see: Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (13) See the Supporting Information for details. (14) Ketones such as acetone and cyclohexanone are not effective for this reaction because of their low reactivity. (15) Racemic mixtures are indicated as rac. (16) δ-Hydroxy α,β-unsaturated esters did not participate in hemiacetalization/intramolecular oxa-Michael addition with aliphatic and aromatic aldehydes under Brønsted acid catalysis, as expected from our earlier work. See: (a) Fuwa, H.; Ichinokawa, N.; Noto, K.; Sasaki, M. J. Org. Chem. 2012, 77, 2588. (b) Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2011, 13, 1820. (17) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5416. (18) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973. (19) Jung, H. H.; Floreancig, P. E. J. Org. Chem. 2007, 72, 7359. (20) The reason part of the starting material remained unreacted even after 24 h under these conditions remains unknown. Increasing the loading amount of Ru-II or raising the reaction temperature was ineffective. (21) Kim, W. H.; Jung, J. H.; Sung, L. T.; Lim, S. M.; Lee, E. Org. Lett. 2005, 7, 1085. (22) (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 12, 1593. (b) Johansson, R.; Samuelsson, B. J. Chem. Soc. Chem. Commun. 1984, 201.
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DOI: 10.1021/acs.orglett.9b01182 Org. Lett. XXXX, XXX, XXX−XXX
