Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
α‑Alkylation of Chiral Sulfinimines for Constructing Quaternary Chiral Carbons by Introducing Removable Directing Groups Shuanglin Qin,†,‡,§ Shuangwei Liu,†,§ Yuting Cao,† Jiangnan Li,†,‡ Chuanke Chong,† Tongtong Liu,† Yunhao Luo,† Jiyun Hu,‡ Shende Jiang,‡ Honggang Zhou,† Guang Yang,*,† and Cheng Yang*,† †
The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300350, People’s Republic of China ‡ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *
ABSTRACT: This study developed a facile and efficient synthetic strategy to construct quaternary chiral centers at the α-position of imines and ketones. High regioselectivity and diastereoselectivity were achieved through the synergetic effect of electron-withdrawing directing groups and N-tert-butyl sulfinamide as chiral auxiliaries. Either of them could be removed under the optimized conditions without any epimerization.
α-Functionalization of carbonyl group provides the structural motifs found in numerous natural products and potent medicines.1−18 In our previous study, highly efficient palladium(0)catalyzed asymmetric allylic alkylation (AAA) reactions perfectly controlled the stereochemistry at the α-position of sulfinimines, which were derived from simple ketones by using tert-butyl sulfinamide as chiral auxiliaries.19,20 However, the direct alkylation of these chiral sulfinimines in the presence of strong bases (e.g., LDA, LiHMDS, and NaHMDS) failed. It led to a complex mixture of multiply substituted products and some eliminated ones. Moreover, the formation of chiral quaternary
carbons was also found to be more problematic.21−45This paper reports an alternative and facile synthetic strategy to construct a quaternary chiral center at the α-position of cyclic sulfinimines (see Scheme 1).44,45 An electron-withdrawing moiety was employed as a directing group (DG) at the α-position of cyclic sulfinimines. The NaHMDS-promoted asymmetric alkylation constructed a quaternary carbon with excellent regioselectivity and diastereoselectivity due to the synergetic effect of both directing groups and chiral auxiliaries. More importantly, Table 1. Optimization of Asymmetric Alkylation Reaction
Scheme 1. Overview
a
The values of dr were determined by 1H NMR.
Received: January 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00105 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Table 2. Typical Examples for Formation of Chiral β-Ketone Esters
Scheme 2. Alkylation of Cyclic Sulfinimines
a
The er values were determined by chiral HPLC.
Table 3. Comparison of the Specific Rotation of 13 with Its R Isomer in Previous Literature
the Supporting Information). It was selected as the model substrate to optimize the alkylation step to form the quaternary chiral center (Table 1). First, by employing the previously reported conditions,46−50 inorganic bases and DBU were used for investigation (entries 1−3). Encouragingly, mixing the model starting material 3 with K2CO3 and benzyl bromide (BnBr) in acetone could produce 4a effectively at yield rate of 81%. However, the dr value was 5:1 (entry 1). To our surprise, both Cs2CO3 and DBU led to alternative regioselectivity. Dibenzylated compound 5 was produced at the yield of 60% and 40%, respectively (entries 2 and 3). The use of NaH as the base could help gain a yield rate of 42% and a diastereoselectivity of 7:1 (entry 4). The reaction using LiHMDS as the base resulted in a good isolated yield (72%) but poor dr (2:1, entry 5). Fortunately, the reaction using NaHMDS as the base produced the desired product 4a with a high diastereoselectivity (entries 6−8). It was found that alkylation did not occur before the reaction mixture was
a The values of dr were determined by 1H NMR. bThe reactions were carried out at 50 °C.
either the DG or auxiliaries could be removed under mild conditions without any epimerization. Initially, the chiral compound 3 with electron-withdrawing directing group (DG) could be prepared from the stable chiral cyclic sulfinimines 1 and commercially available allyl chloroformate 2 with high chemical yield (more details are available in B
DOI: 10.1021/acs.orglett.8b00105 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters warmed to 0 °C (entries 6 and 7). A larger amount of BnBr could increase reaction rate and help obtain a higher chemical yield (entry 8). The studies of suitable alkylation conditions indicated that the reaction could be further investigated in terms of substrate scope, covering different cyclic sulfinimines with various alkyl halides (Scheme 2). Under the optimized conditions, most substrates, such as those with 6-, 7-, and 8-membered rings, could construct quaternary chiral carbons with a moderate to good yield rate (68%−95%) and a high dr value (15:1−25:1). When the ring changed to a 5-membered ring, the reaction led to a slightly lower dr of products (e.g., 6c, 6k and 6l). It should be noted that the corresponding alkyl halides had to be alkyl iodides instead of bromides when the substitutions were saturated alkanes (e.g., 4k−m, 6l−o, 7c, and 8c). The N-tert-butanesulfinaimde, the chiral auxiliary, could be removed efficiently (Table 2).19 As a result, the β-ketone esters 9−13 were obtained without any epimerization and all contained chiral quaternary carbons. To the best of our knowledge, only few literature reported on the preparation of these chiral β-ketone esters in highly enantiomeric manners.51−53 These structures (such as compounds 9, 10, 11, and 12) shown in Table 2 were first synthesized with high er values by this facile alkylation strategy. It is quite difficult to distinctly identify the absolute configuration of alkylation products. Based on the proposed mechanism (Scheme 3), it would be tentatively assigned as S at the
Table 4. Typical Examples of Decarboxylation
Scheme 3. Diastereoselective Alkylation of Cyclic Sulfinimines with Alkyl Halides
a
The dr values were determined by 1H NMR.
might be formed on the basis of the previous literature.54−56 The stereoselectivity can be explained by the fact that the steric repulsion between the tert-butyl group and the approaching alkyl halides (R−X) in transition state C is a determining factor to drive the reaction via transition state B. The diastereoisomer D was finally produced with a high yield and high diastereoselectivity. In summary, we have demonstrated a facile and diastereoselective alkylation strategy to construct quaternary chiral centers at the α-position of chiral sulfinimines. Specifically, a removable directing group was introduced at the α-position of cyclic sulfinimines in a highly efficient way. A NaHMDS-promoted alkylation reaction was then realized under mild conditions to construct quaternary chiral center diastereoselectively. The products bearing various alkyl substitutions were obtained with a high yield as well as high regioselectivity and diastereoselectivity. Furthermore, either the directing group or chiral auxiliary could
α-position of these sulfinimines. As its proof, the comparison was drawn between the specific rotation of compound (S)13([α]D27 = 29.2, 1.0 in CH2Cl2, er = 99.4:0.6) and what was reported previously in the literature ([α]D27 = −27.3 (R)-13, 0.92 in CH2Cl2, 83% ee), as shown in Table 3.51 Based on these encouraging results, we also demonstrated that the directing group could be removed through a Pd(0)catalyzed decarboxylation process (Table 4). The reaction proceeded smoothly in mild Pd(0)-catalytic conditions with diastereocenters retained with good to excellent yield (73%−94%) and excellent diastereoselectivity (dr > 25:1). The absolute configuration of those newly formed chiral centers was determined as “R” by comparing the NMR spectra of 15, 18, and 20 with those shown in our previous work.20 The proposed mechanism is explained in Scheme 3. When substance A was treated with NaHMDS, transition state B C
DOI: 10.1021/acs.orglett.8b00105 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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be cleaved under optimized conditions with the chirality retained. This synthetic strategy could be useful for producing imines and a ketone scaffold with quaternary chiral carbons in diastereomeric or enantiomeric pure form. Further investigations of this method and its application in the total synthesis of natural products are currently ongoing, 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.8b00105. Optimization and experimental procedures, spectral data, and chiral HPLC data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*
[email protected] *
[email protected] ORCID
Guang Yang: 0000-0002-1773-9392 Author Contributions §
S.Q. and S.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (NSFC) (No. 81703343 to G.Y.), a General Financial Grant from the Natural Science Foundation of Tianjin − China (No. 16JCQNJC13300) to G.Y., Fundamental Research Funds for the Central Universities to G.Y., Tianjin science and technology innovation system and the condition of platform construction plan (Grant No. 14TXSYJC00572), National Biomedical Special Project of International Innovation Park (Grant No. 13ZCZDSY03300), National Natural Science Funds of China (Grant Nos. 81402973 and 81703581), Tianjin Science and Technology Project (Grant No. 15PTGCCX00140), Tianjin Science and Technology Project (10ZCKFSY07200, 10ZCKFSY08800, 13ZCZDSY03800, 13ZXCXSY13500, and 13ZCZDSY03300), and Innovation fund for technology based firms (Grant No. 12ZXCXSY06500).
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DOI: 10.1021/acs.orglett.8b00105 Org. Lett. XXXX, XXX, XXX−XXX
