Synthesis of Chiral γ,γ-Disubstituted γ-Butenolides via Direct

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

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Synthesis of Chiral γ,γ-Disubstituted γ‑Butenolides via Direct Vinylogous Aldol Reaction of Substituted Furanone Derivatives with Aldehydes Takaaki Sakai, Shin-ichi Hirashima,* Yasuyuki Matsushima, Tatsuki Nakano, Daiki Ishii, Yoshifumi Yamashita, Kosuke Nakashima, Yuji Koseki, and Tsuyoshi Miura* Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

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S Supporting Information *

ABSTRACT: An organocatalyzed method for synthesizing chiral γ,γ-disubstituted γ-butenolides via direct vinylogous aldol reactions of γ-substituted β,γ-butenolides with aldehydes is reported. This reaction is catalyzed by a squaramide−sulfonamide organocatalyst to afford a range of anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities (reaching 95% ee). This is the first report of a successful stereoselective direct vinylogous aldol reaction of aldehydes with γ-substituted β,γ-butenolides. hiral γ,γ-disubstituted γ-butenolides are remarkably attractive moieties as they are ubiquitous in the skeletons of biologically active molecules and natural products;1 however, construction of such moieties bearing quaternary stereocenters is generally difficult due to steric hindrance. To construct chiral γ,γ-disubstituted γ-butenolide motifs, direct vinylogous reactions of γ-substituted β,γ-butenolides with electrophiles are among the most practical synthetic routes. Since Chen and co-workers developed direct asymmetric allylic alkylation of such butenolides with Morita−Baylis−Hillman carbonates using a (DHQD)2PYR (hydroquinidine 2,5diphenyl-4,6-pyrimidinediyl diether) organocatalyst,2 several research groups have reported asymmetric conjugate additions of γ-substituted β,γ-butenolides to electron-deficient alkenes using metal3 and organocatalysts4 (Scheme 1a). However, few studies describe direct vinylogous aldol or Mannich reactions of carbonyl derivatives with γ-substituted β,γ-butenolides. Feng and co-workers reported the reaction with isatin derivatives.5 Additionally, Mannich reactions with imine derivatives were also reported by Feng’s and Trost’s groups.6,7 To the best of our knowledge, there are still no reports on direct vinylogous aldol reactions of simple aldehydes with γ-substituted β,γbutenolides despite their usefulness. Mukaiyama et al. reported vinylogous aldol reactions of silyl enol ether (5-methyl-2siloxyfuran derived from α-angelica lactone) with benzaldehyde using an organocatalyst.8 Unfortunately, their method afforded only moderate yield and enantioselectivity (Scheme 1b). Additionally, Deng et al. reported that the organocatalyst

C

© XXXX American Chemical Society

promoted an asymmetric vinylogous aldol reaction of 5-ethyl2-siloxyfuran with benzaldehyde, forming the corresponding adduct in moderate yield with good enantioselectivity.9 Thus, direct asymmetric vinylogous aldol reactions between γsubstituted β,γ-butenolides and aldehydes remain largely undeveloped and continue to represent a challenging research area. As double hydrogen-bond donors, thiourea10 and squaramide11 groups are useful motifs in organocatalysis and are applied to several important asymmetric reactions. The sulfonamide−thiourea group functions as a triple hydrogenbond donor, exhibiting excellent asymmetric catalytic activity.12 We recently reported that an organocatalyst bearing a squaramide−sulfonamide motif as a triple hydrogen-bond donor promoted direct vinylogous aldol reactions of aldehydes with furan-2(5H)-one.13 Here, we report the first direct asymmetric vinylogous aldol reactions of aldehydes with γsubstituted β,γ-butenolides using a squaramide−sulfonamide organocatalyst (Scheme 1c). We began our investigation by evaluating the direct vinylogous aldol reaction of α-angelica lactone (2a) with 4chlorobenzaldehyde (1a) in the presence of organocatalysts A−G (Figure 1, Table 1). Hydroquinine (A) and thiourea organocatalyst B were poor catalysts for the direct vinylogous aldol reaction (entries 1 and 2). Moderate enantioselectivity Received: February 14, 2019

A

DOI: 10.1021/acs.orglett.9b00574 Org. Lett. XXXX, XXX, XXX−XXX

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Table 1. Catalyst Screening

entry

catalyst

yielda (%)

anti/synb

eec (%)

1 2 3 4 5 6 7

A B C D E F G

31 22 31 41 41 47 45

1.9:1 4.9:1 1.4:1 >20:1 >20:1 >20:1 >20:1

1 0 40 76 80 40 70

a c

Isolated yield. bDetermined by 1H NMR analysis of crude product. Determined by chiral HPLC analysis.

Representative reaction solvents for the direct vinylogous aldol reaction of 1a with 2a using organocatalyst E were then studied (Table 2). Among the reaction solvents examined, Table 2. Study of Reaction Conditions

entry

solvent (M)

1 2 3 4 5 6 7 8d 9d 10d

CH2Cl2 (0.2) toluene (0.2) MeOH (0.2) THF (0.2) 1,4-dioxane (0.2) Et2O (0.2) Et2O (0.4) Et2O (0.4) Et2O (0.4) Et2O (0.4)

cat. (mol %) yielda (%) 10 10 10 10 10 10 10 10 5 1

41 48 42 66 67 69 81 84 82 74

anti/ synb

eec (%)

>20:1 >20:1 16:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

80 81 71 85 87 89 87 91 91 92

a c

Isolated yield. bDetermined by 1H NMR analysis of crude product. Determined by chiral HPLC analysis. dAt 25 °C.

satisfactory yields and stereoselectivities were obtained with Et2O (entries 1−6). Thus, Et2O was the most suitable reaction solvent. Further optimization of the reaction conditions was performed. Increasing the concentration (0.4 M) increased the yield (entry 7). Conducting the reaction at a lower temperature (15 °C) improved both the yield and enantioselectivity (entry 8). The enantioselectivity was retained without lowering the yield when the catalyst loading was reduced to 5 mol % (entry 9). However, the yield decreased when the catalyst loading was reduced to 1 mol % (entry 10). Thus, entry 9 represents the optimal conditions. Under the optimized reaction conditions, the scope and limitations of direct asymmetric vinylogous aldol reactions of γ-substituted β,γ-butenolides 2 with various aldehydes 1 were assessed (Scheme 2A). Aromatic aldehydes 1a−c bearing chloro groups as electron-withdrawing groups at the para, meta, and ortho positions reacted with α-angelica lactone (2a, R2 = R3 = H, R4 = Me) in the presence of organocatalyst E to give the corresponding anti-products 3a−c, respectively, in high yields with excellent enantioselectivities. The reactions of

Figure 1. Structure of organocatalysts.

was observed with squaramide organocatalyst C (entry 3). Squaramide−sulfonamide organocatalysts D and E, which we previously reported,13 gave good stereoselectivities (entries 4 and 5). Organocatalyst F, which introduced a chiral cyclohexanediamine unit rather than a cinchona motif, afforded lower enantioselectivity (entry 6). The reaction with organocatalyst G introduced a trifluoromethanesulfonamide rather than a perfluorobutanesulfonamide group, giving a slightly decreased enantioselectivity (entry 7). Thus, squaramide− sulfonamide organocatalyst E was the most favorable catalyst for the model vinylogous aldol reaction. B

DOI: 10.1021/acs.orglett.9b00574 Org. Lett. XXXX, XXX, XXX−XXX

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Compounds 1-naphthaldehyde (1i) and 2-naphthaldehyde (1j) reacted smoothly with 2a to provide adducts 3i and 3j with excellent enantioselectivities. The reaction of furfural (1k) also gave excellent stereoselectivity. Cyclohexanecarbaldehyde (1l) and hexanal (1m) as an aliphatic aldehyde were also applicable to this reaction and gave the corresponding adducts with excellent stereoselectivities but low yields. Other γsubstituted β,γ-unsaturated butenolides were then examined. The reactions of 5-ethylfuran-2(3H)-one (2n, R2 = R3 = H, R4 = Et) and 5-benzylfuran-2(3H)-one (2o, R2 = R3 = H, R4 = Bn) with aldehyde 1a afforded addition products 3n and 3o with excellent enantioselectivities. Other substituted substrates 3,5-dimethylfuran-2(3H)-one (2p, R2 = R4 = Me, R3 = H) and 4,5-dimethylfuran-2(3H)-one (2q, R2 = H, R3 = R4 = Me) reacted with 1a, affording adducts 3p and 3q, respectively, with high stereoselectivities. The absolute configurations of products 3d and 3p14 were determined by X-ray crystallographic analysis. The stereochemistries of the other products were tentatively assigned by analogy. To demonstrate the applicability of this method, we performed 1.0 mmol scale reactions of p-chlorobenzaldehyde (1a) with 2a, 2o, and 2p to obtain the corresponding adducts 3a, 3o, and 3p in good yields and with excellent stereoselectivities, respectively (Scheme 2B). Based on the stereochemistry of the aldol products 3, this observed stereocontrol can be rationalized by the plausible transition-state models (Scheme 3). We infer that aldehyde is

Scheme 2. Asymmetric Direct Vinylogous Aldol Reactionsa,b

Scheme 3. Plausible Transition-State Models

a Isolated yield. bDetermined by chiral HPLC analysis. cCatalyst (10 mol %) was used. dAt 25 °C.

activated by the sulfonamide and squaramide, whereas the 5substituted 2-furanolate interacts with squaramide and protonated amine to afford product 3. We propose that the addition of furanolate to aldehyde using organocatalyst E proceeds via the Si → Re transition state leading to the major (R,S) product 3. On the other hand, the Si → Si and Re → Si transition states generate steric hindrance between the aldehydes and the furanolates. The lone pair−lone pair repulsion between the oxygens in the aldehyde and the furanolate would destabilize the Re → Si and Re → Re transition states.4o

4-bromobenzaldehyde (1d) and 4-(trifluoromethyl)benzaldehyde (1e) with 2a afforded anti-adducts 3d and 3e in high yields with excellent stereoselectivities. Benzaldehyde (1f) as a simple aldehyde was also a good substrate, affording corresponding adduct 3f in high yield with excellent stereoselectivity. The reactions of aldehydes 1g and 1h, with methyl and methoxy electron-donating groups, and 2a gave moderate yields; however, excellent stereoselectivities were observed. C

DOI: 10.1021/acs.orglett.9b00574 Org. Lett. XXXX, XXX, XXX−XXX

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Mukherjee, S. Chem. Commun. 2012, 48, 5193. (c) Zhang, W.; Tan, D.; Lee, R.; Tong, G.; Chen, W.; Qi, B.; Huang, K.-W.; Tan, C.-H.; Jiang, Z. Angew. Chem., Int. Ed. 2012, 51, 10069. (d) Manna, M. S.; Mukherjee, S. Chem. - Eur. J. 2012, 18, 15277. (e) Kumar, V.; Ray, B.; Rathi, P.; Mukherjee, S. Synthesis 2013, 45, 1641. (f) Das, U.; Chen, Y.-R.; Tsai, Y.-L.; Lin, W. Chem. - Eur. J. 2013, 19, 7713. (g) Guo, Y.L.; Jia, L.-N.; Peng, L.; Qi, L.-W.; Zhou, J.; Tian, F.; Xu, X.-Y.; Wang, L.-X. RSC Adv. 2013, 3, 16973. (h) Manna, M. S.; Mukherjee, S. Chem. Sci. 2014, 5, 1627. (i) Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D. J. Nat. Commun. 2014, 5, 4479. (j) Sekikawa, T.; Kitaguchi, T.; Kitaura, H.; Minami, T.; Hatanaka, Y. Org. Lett. 2015, 17, 3026. (k) Wang, Z.-H.; Wu, Z.-J.; Huang, X.-Q.; Yue, D.-F.; You, Y.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Chem. Commun. 2015, 51, 15835. (l) Simlandy, A. K.; Mukherjee, S. Org. Biomol. Chem. 2016, 14, 5659. (m) Lagoutte, R.; Besnard, C.; Alexakis, A. Eur. J. Org. Chem. 2016, 2016, 4372. (n) Rout, S.; Joshi, H.; Singh, V. K. Org. Lett. 2018, 20, 2199. (o) Trost, B. M.; Gnanamani, E.; Kalnmals, C. A.; Hung, C.-I.; Tracy, J. S. J. Am. Chem. Soc. 2019, 141, 1489. (5) Tang, Q.; Lin, L.; Ji, J.; Hu, H.; Liu, X.; Feng, X. Chem. - Eur. J. 2017, 23, 16447. (6) Zhou, L.; Lin, L.; Ji, J.; Xie, M.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3056. (7) (a) Trost, B. M.; Gnanamani, E.; Tracy, J. S.; Kalnmals, C. A. J. Am. Chem. Soc. 2017, 139, 18198. (b) Trost, B. M.; Hung, C.-I.; Scharf, M. J. Angew. Chem., Int. Ed. 2018, 57, 11408. (8) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 8. (9) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2010, 132, 9558. (10) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. For reviews, see: (b) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785. (c) Held, F. E.; Tsogoeva, S. B. Catal. Sci. Technol. 2016, 6, 645. See also references cited therein. (11) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. For a review, see: (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. - Eur. J. 2011, 17, 6890. (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. (d) Rouf, A.; Tanyeli, C. Curr. Org. Chem. 2016, 20, 2996. (12) (a) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 1431. For a review see: (b) Fang, X.; Wang, C. - J. Chem. Commun. 2015, 51, 1185. See also references cited therein. For selected examples, see: (c) Ogura, Y.; Akakura, M.; Sakakura, A.; Ishihara, K. Angew. Chem., Int. Ed. 2013, 52, 8299. (d) Li, T.-Z.; Wang, X.-B.; Sha, F.; Wu, X.-Y. J. Org. Chem. 2014, 79, 4332. (13) Sakai, T.; Hirashima, S.; Yamashita, Y.; Arai, R.; Nakashima, K.; Yoshida, A.; Koseki, Y.; Miura, T. J. Org. Chem. 2017, 82, 4661. (14) The absolute configuration of 3p was determined by the X-ray crystallographic analysis of the p-bromobenzoyl derivative. See the Supporting Information. (15) (a) Nagamitsu, T.; Takano, D.; Shiomi, K.; Ui, H.; Yamaguchi, Y.; Masuma, R.; Harigaya, Y.; Kuwajima, I.; O̅ mura, S. Tetrahedron Lett. 2003, 44, 6441. (b) Shiomi, K.; Ui, H.; Suzuki, H.; Hatano, H.; Nagamitsu, T.; Takano, D.; Miyadera, H.; Yamashita, T.; Kita, K.; Miyoshi, H.; Harder, A.; Tomoda, H.; O̅ mura, S. J. Antibiot. 2005, 58, 50. (c) Nagamitsu, T.; Takano, D.; Seki, M.; Arima, S.; Ohtawa, M.; Shiomi, K.; Harigaya, Y.; O̅ mura, S. Tetrahedron 2008, 64, 8117. (d) Onodera, Y.; Suzuki, T.; Kobayashi, S. Org. Lett. 2011, 13, 50. (e) Ohtawa, M.; Matsunaga, M.; Fukunaga, K.; Shimizu, R.; Shimizu, E.; Arima, S.; Ohmori, J.; Kita, K.; Shiomi, K.; Omura, S.; Nagamitsu, T. Bioorg. Med. Chem. 2015, 23, 932.

In conclusion, cinchona organocatalyst E bearing a squaramide−sulfonamide motif as a multiple hydrogenbonding donor efficiently catalyzes the direct vinylogous aldol reactions of various aldehydes with γ-substituted β,γbutenolides to give the corresponding anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities. This is the first report of a successful direct asymmetric vinylogous aldol reaction of aldehydes with γ-substituted β,γ-butenolides. This methodology will lead to the development of more efficient syntheses for bioactive compounds such as nafuredin-γ.15 Application of the squaramide−sulfonamide organocatalysts to syntheses of bioactive compounds is currently in progress in our laboratory and will be reported in due course.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00574. Experimental procedures, characterization data, and 1 H/13C NMR spectra (PDF) Accession Codes

CCDC 1897312−1897313 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 Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Shin-ichi Hirashima: 0000-0001-8125-5010 Tsuyoshi Miura: 0000-0003-1216-4507 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Enago (www.enago.jp) for the English language review. REFERENCES

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DOI: 10.1021/acs.orglett.9b00574 Org. Lett. XXXX, XXX, XXX−XXX