Letter pubs.acs.org/OrgLett
Enantio- and Stereoselective Construction of Atisane Scaffold via Organocatalytic Intramolecular Michael Reaction and Diels−Alder Reaction Hiroko Sekita, Kyohei Adachi, Ippei Kobayashi, Yusuke Sato, and Masahisa Nakada* Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan S Supporting Information *
ABSTRACT: An enantio- and stereoselective construction of the atisane scaffold via organocatalytic intramolecular Michael reaction and Diels−Alder reaction is described. The organocatalytic intramolecular Michael reaction has been found to stereoselectively generate a trans-stereodiad comprising an all-carbon quaternary and a tertiary stereogenic centers. Use of the chiral secondary amine bearing thiourea with benzoic acid as additive is the key to obtaining the desired product with excellent ee in synthetically acceptable yield. The prepared chiral building block has been successfully converted to the compound including the atisane scaffold via the highly stereoselective intramolecular Diels−Alder reaction.
S
tructure A (Figure 1), which is found in terpenoids like atisane,1 ent-kaurane,2 and labdane,3 comprises a trans-
The Michael reaction is widely applicable, and a number of studies utilizing the Michael reaction have been reported. Furthermore, asymmetric catalysis of Michael reactions has been extensively studied, and the recent development of organocatalytic reactions has led to the development of the catalytic asymmetric intramolecular Michael reaction.6 However, to the best of our knowledge, the organocatalytic asymmetric intramolecular Michael reaction of an achiral substrate to form an allcarbon quaternary stereogenic center via enamine has not yet been reported thus far.7 In this study, we investigated organocatalytic asymmetric intramolecular Michael reactions that formed products incorporating structure A. Herein, we report our results and their application to the enantio- and stereoselective construction of the atisane scaffold. Compound 38 (Scheme 2) was selected as the substrate for the organocatalytic asymmetric intramolecular Michael reaction because product 4 incorporates structure A. The reaction of 5, which was derived from 4, with Grignard reagent 6 affords 7, which can then be converted to 8. Subsequently, the intramolecular Diels−Alder reaction of 8 affords 9, which includes the scaffold of atisane terpenoids. However, the organocatalytic asymmetric intramolecular Michael reaction of 3 proceeds via a six-membered chair-form transition state, in which the 1,3-diaxial interaction between two methyl groups hampers cyclization. Nevertheless, studying the organocatalytic reaction of 3 would contribute to understanding the scope and limitations of the organocatalytic asymmetric
Figure 1. Structures of A and terpenoids involving A.
stereodiad, which is composed of an all-carbon quaternary stereogenic center and a tertiary stereogenic center. In the synthesis of structure A, the stereoselective synthesis of the transstereodiad is especially challenging, more so than the synthesis of an isolated all-carbon quaternary stereogenic center. The intramolecular Michael reaction4 is a powerful tool that allows the generation of a carbocyclic ring and an all-carbon quaternary stereogenic center in one step. For example, the stereoselective syntheses of 2, which incorporates structure A, by the Michael reduction/intramolecular Michael reaction cascade was previously reported by us (Scheme 1).5 Scheme 1. Highly Stereoselective Michael Reduction/ Intramolecular Michael Reaction Cascade
Received: March 28, 2017 Published: April 24, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b00918 Org. Lett. 2017, 19, 2390−2393
Letter
Organic Letters
[methanol (Table 1, entry 7) and tert-butyl alcohol (Table 1, entry 8)] significantly increased the ee (to 70 and 69%, respectively). However, methanol decreased the yield to 11% because a byproduct was formed by the Michael reaction of 3 with methanol. The bulky nature of tert-butyl alcohol suppressed this side reaction and gave a yield of 26% (Table 1, entry 8). All the reactions in Table 1 proceeded with high diastereoselectivity. This can be explained by considering the transition state of 3. The reaction proceeds via the (E)- or (Z)enamine, which is generated in situ by the reaction of 3 with the catalyst. The four chair-form transition states which minimize steric strain, 10a−d, are shown in Figure 3. Transition states 10a
Scheme 2. Synthetic Plan of 9 via the Organocatalytic Asymmetric Intramolecular Michael Reaction
intramolecular Michael reaction. Thus, we decided to examine the reaction of 3. The organocatalytic asymmetric intramolecular Michael reaction of 3 was first examined using catalyst I (Figure 2), L-
Figure 3. Proposed transition states 10a−d in the reaction of 3 with the organocatalyst.
Figure 2. Structures of organocatalysts I−III.
and 10b, which are derived from the (E)-enamine, lead to the formation of 4 and ent-4, respectively. However, transition states 10c and 10d, derived from the (Z)-enamine, lead to the formation of diastereomers of 4. The most energetically favorable transition state is 10a because the steric strain between the enamine and the nitroalkene is minimized. However, the strong 1,3-diaxial interaction increases the energy of all the transition states, which may explain the low conversion rates of all the reactions. We suggest that the reaction using catalyst III did not proceed because the enamine either could not be formed or could not undergo the reaction, owing to the bulkiness of catalyst III. Because thiourea has been known to activate nitroalkene by forming a hydrogen bond,11 the enamine formed by 3 and catalyst IV12 (Figure 4) could accelerate the reaction by causing
proline, in acetonitrile. However, almost no reaction occurred at room temperature (Table 1, entry 1). Therefore, the reaction was Table 1. Catalytic Asymmetric Intramolecular Michael Reactions of 3 with Catalysts I−III
entry
cat.
solvent
temp/time (°C/h)
yield (%)a
ee (%)b
1 2 3 4 5 6 7 8
I II III II II II II II
MeCN MeCN MeCN DMSO THF CH2Cl2 MeOH t BuOH
rt/24 then 50/96 rt/120 rt/24 then 50/96 rt/120 rt/120 rt/96 rt/120 rt/144
34 (50)c 44 (49)c 0d 10 (70)c 9 (79)c 17 (69)c 11 (57)c 26 (52)c
13 61 57 63 51 70 69
a
Isolated yields of an inseparable mixture of 3 and 4. The corresponding yields were calculated based on the 1H NMR spectrum. b The ee was determined by HPLC analysis using a chiral stationary phase. For HPLC conditions, see Supporting Information. cRemaining amount of 3 (%). d3 remained but was not isolated.
Figure 4. X-ray crystal structure of 4 (left) and transition model for the organocatalytic reaction of 3 with IV (right).
the reacting enamine and nitroalkene to move closer, as shown in Figure 4, and at the same time, the favorable transition state could be limited, resulting in the improvement of the enantioselectivity. The reaction of 3 using catalyst IV was first carried out in acetonitrile at room temperature, but the reaction was slow, and was then conducted at 50 °C. The product was obtained in 27% yield and 76% ee. The ee was improved when compared with that in the reaction using catalyst II (Table 2, entry 1). The reaction was faster in the presence of benzoic acid13 although heating was needed, affording the product in 44% yield and 93% ee after 7.5 h
carried out at 50 °C. The product was obtained in 34% yield, the ee was 13%, and 50% of 3 was recovered. The reaction with catalyst II9 proceeded slowly at room temperature. After 120 h, the yield was 44%, the ee was 61%, and 49% of 3 was recovered (Table 1, entry 2). Interestingly, the reaction using catalyst III10 afforded no products even at 50 °C, and 3 remained (Table 1, entry 3). The use of other solvents [DMSO, THF, and CH2Cl2 (Table 1, entries 4−6)] decreased the yield, although the ee increased slightly in the reaction using THF. Protic solvents 2391
DOI: 10.1021/acs.orglett.7b00918 Org. Lett. 2017, 19, 2390−2393
Letter
Organic Letters Table 2. Catalytic Asymmetric Intramolecular Michael Reactions of 3 with Catalyst IV
entry
solvent
1 2 3 4 5 6 7 8e 9
MeCN MeCN (CH2Cl)2 THF benzene benzene toluene benzene benzene
additivea PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H HCO2H
Scheme 3. Preparation and Diels−Alder Reaction of 8
time (h)
yield (%)b
ee (%)c
384 7.5 48 10 96 10 6.5 27 34
27 44 44 31 (27)d 26 60 59 54 60
76 93 90 85 95 96 97 98 95
a
1.0 equiv was used. bIsolated yields. cThe ee was determined by HPLC analysis. For HPLC conditions, see Supporting Information. d Remaining amount of 3 (%) is indicated in parentheses. e30 mol % of IV was used. In the gram scale reaction of 3, 4 (96% ee) was obtained after 10 h in 56% yield. See Supporting Information.
epimers, which indicated that the reaction proceeded with excellent stereoselectivity. The structure of 14 was elucidated by X-ray crystallographic analysis.14 The Diels−Alder reaction of 817 could proceed via the transition state 15-exo, which would be energetically favorable over 15-endo, which has the steric strain between the methoxy group and the angular methyl group (Figure 5). The results of the Diels−Alder reaction indicated that the C5 stereogenic center had no effect on the stereoselectivity.
(Table 2, entry 2). The ee was decreased in the reactions using dichloroethane (44%, 90% ee) or THF (31%, 85% ee) (Table 2, entries 3 and 4) as the solvent. The ee was increased when benzene (26%, 95% ee) was used (Table 2, entry 5), but use of benzoic acid as additive was needed to increase the yield (60%, 96% ee, Table 2, entry 6), and almost the same result was obtained by using toluene (59%, 97% ee, Table 2, entry 7). Use of a reduced amount of the catalyst slightly lowered the yield, but the ee was almost unchanged (Table 2, entry 8). The same effect of benzoic acid on the rate enhancement was observed when formic acid was used, although the ee slightly decreased (Table 2, entry 9). The product (96% ee), which was obtained in entry 6 of Table 2, was successfully purified by recrystallization to be the enantiomerically pure crystal, which was suitable for X-ray crystallographic analysis.14 The crystal structure suggested that the absolute configuration of 4 would be well explained by the transition state model in Figure 4. The structure features the two axial methyl groups that lean outward from the cyclohexane ring, indicating how the reaction with organocatalyst IV was powerful even when it suffered from the significant 1,3-diaxial interaction. Next, preparation of 8 was examined starting from the prepared chiral 4. The Wittig reaction of 4 afforded 12 (Scheme 3), but interestingly, subsequent Henry reaction did not occur, and alkylations of 12 afforded only unidentified products. These results could be explained by the steric hindrance of the nitro group, which was attributed to the two adjacent all-carbon quaternary centers. After several transformation studies, although Nef reaction of 12 did not proceed, too, 12 was successfully converted to the corresponding oxime 13 using Carreira’s reaction conditions.15 The reaction of 13 with Grignard reagent 6 did not afford the desired product, and conversion of 13 to the corresponding aldehyde 5 also failed. Hence, 13 was converted to 5 by dehydration and DIBAL-H reduction. The Diels−Alder reaction of 8 did not proceed at room temperature but proceeded in refluxing toluene to afford 9 as a mixture of two inseparable isomers.16 Treatment of the mixture with potassium carbonate in methanol and subsequent oxidation afforded 14 as a single isomer. Hence, the two isomers were C5
Figure 5. Proposed transition state models for the Diels−Alder reaction of 8.
In summary, a highly enantio- and stereoselective construction of the atisane scaffold via organocatalytic intramolecular Michael reaction and Diels−Alder reaction has been developed. The organocatalytic intramolecular Michael reaction has been found to stereoselectively generate a trans-stereodiad, which comprises an all-carbon quaternary stereogenic center and a tertiary stereogenic center. Use of the chiral secondary amine bearing thiourea with benzoic acid as additive is the key to obtaining the desired product with excellent ee in synthetically acceptable yield. The prepared chiral building block has been successfully converted to the compound, including the atisane scaffold, via the highly stereoselective intramolecular Diels−Alder reaction. Further synthetic studies using the prepared chiral building block are now underway, and the results will be reported in due course.
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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.7b00918. Procedure and characterizations of the substrates and products (PDF) X-ray data for 4 (CIF) X-ray data for 14 (CIF) 2392
DOI: 10.1021/acs.orglett.7b00918 Org. Lett. 2017, 19, 2390−2393
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(11) For reviews, see: Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (12) (a) Touchard, F.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1997, 8, 3319. (b) He, T.; Qian, J.-Y.; Song, H. − L.; Wu, X.-Y. Synlett 2009, 2009, 3195. For a review, see: (c) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051. (13) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887. (14) (a) CCDC 1536844 (4) and 1535684 (14) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.1536844 and www. ccdc.cam.ac.uk/data_request/cif.1535684, respectively. (15) Carreira, E. M.; Czekelius, C. Angew. Chem., Int. Ed. 2005, 44, 612. (16) The Diels−Alder reaction of 8 would indicate the high reactivity of masked o-benzoquinone (MOB). For a review of MOB, see: Liao, C.C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856. (17) For related studies, see: Liu, X.-Y.; Cheng, H.; Li, X.-H.; Chen, O.H.; Xu, L.; Wang, F.-P. Org. Biomol. Chem. 2012, 10, 1411.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Masahisa Nakada: 0000-0001-6081-5269 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge support by the Materials Characterization Central Laboratory, Waseda University, for characterization of new compounds. This work was financially supported in part by the Grant-in-Aid for Scientific Research on Innovative Areas 2707 Middle molecular strategy from MEXT and a Waseda University Grant for Special Research Projects.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00918 Org. Lett. 2017, 19, 2390−2393
