Wendian
Li‡
ad,
Tilong
Yang‡
c,
Nan
Song
a,
Ruihao
Li
a,
Jiao
Long
a,
Lin
He
b,
Xumu
Zhang
c and
Hui
Lv
*a
aSauvage Center for Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, Hubei Key Lab on Organic and Polymeric Optoelectronic Materials, Wuhan University, Wuhan, Hubei 430072, China. E-mail: huilv@whu.edu.cn
bKey Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, 832000, China
cDepartment of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P. R. China
dChina Tobacco Sichuan Industrial Company, Ltd., Chengdu, Sichuan 610065, China
First published on 18th January 2022
A general and highly efficient method for asymmetric sequential hydrogenation of α,β-unsaturated ketones has been developed by using an iridium/f-Ampha complex as the catalyst, furnishing corresponding chiral alcohols with two contiguous stereocenters in high yields with excellent diastereo- and enantioselectivities (up to 99% yield, >20:
1 dr and >99% ee). Control experiments indicated that the C
C and C
O bonds of the enones were hydrogenated sequentially, and the final stereoselectivities were determined by the dynamic kinetic resolution of ketones. Moreover, DFT calculations revealed that an outer sphere pathway was involved in both reduction of C
C and C
O bonds of enones. The synthetic utility of this method was demonstrated by a gram-scale reaction with very low catalyst loading (S/C = 20
000) and a concise synthetic route to key chiral intermediates of the antiasthmatic drug CP-199,330.
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Scheme 1 Asymmetric hydrogenation of exocyclic enones using H2 and typical bioactive molecules containing a chiral β-benzyl cyclic alcohol unit. |
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Scheme 2 Gram-scale experiment with high TON and asymmetric synthesis of the antiasthmatic drug CP-199,330. |
Chiral 4-chromanols and their derivatives are privileged structural motifs widely occurring in natural products and drug lead compounds (Scheme 1-1).5 Particularly, chiral 3-alkyl-chroman-4-ols are known to be medicinally important motifs with a wide range of biological activities. For instance, CP-199,330 and CP-199,331 are potent cysteinyl leukotriene-1 (LT1) receptor antagonists, targeted for the treatment of asthma.5a,i CP-85,958 is useful in the treatment of arthritis and asthma.5f,g Compound A, which was isolated from dehulled adlay seeds, displays an anti-inflammatory effect.6 Considerable efforts have been directed toward the synthesis of chiral chromanols.5a,f,g However, protocols for their enantioselective preparation are still very limited. To our surprise, asymmetric sequential reduction of exocyclic α,β-unsaturated ketones using molecular hydrogen, one of the most straightforward methods to synthesize chiral 3-alkylchroman-4-ols, has not been established.7 Devising new methods for the asymmetric synthesis of 3-alkylchroman-4-ols is urgently needed.
Recently, our group developed a series of ferrocene-based tridentate amino-phosphine ligands, such as f-Amphox,8 f-Ampha9 and f-Amphol,10 which showed excellent performance in the Ir-catalyzed asymmetric hydrogenation of prochiral ketones. We envision that the active Ir–H species may react with multiply substituted enones through 1,4-addition to form α-substituted ketones, followed by dynamic kinetic resolution (DKR) of ketones to achieve the asymmetric sequential hydrogenation of enones with high diastereo- and enantioselectivity. Herein, we report a general and efficient approach for the synthesis of chiral alcohols with two contiguous chiral centers by the Ir/f-Ampha complex enabled asymmetric sequential hydrogenation of α,β-unsaturated ketones.
Entry | Ligand | Solvent | Conv.b (%) | 2a/2a′/2a′′b | drb (2a) | eec (%) |
---|---|---|---|---|---|---|
a [Ir(COD)Cl]2/ligand/1a (0.1 mmol) ratio of 0.5![]() ![]() ![]() ![]() |
||||||
1 | L1 | i PrOH | >99 | 13/0/87 | >20![]() ![]() |
>99 |
2 | L2 | i PrOH | >99 | 100/0/0 | >20![]() ![]() |
87 |
3 | L3 | i PrOH | >99 | 100/0/0 | >20![]() ![]() |
90 |
4 | L3 | Dioxane | >99 | 14/86/0 | >20![]() ![]() |
90 |
5 | L3 | Toluene | >99 | 65/35/0 | >20![]() ![]() |
97 |
6 | L3 | Hexane | >99 | 100/0/0 | >20![]() ![]() |
98 |
7 | L3 | THF | >99 | 36/64/0 | >20![]() ![]() |
92 |
8 | L3 | DCM | >99 | 21/79/0 | >20![]() ![]() |
83 |
9 | L3 | DCE | >99 | 5/95/0 | >20![]() ![]() |
11 |
10 | L3 | EtOH | >99 | 31/69/0 | >20![]() ![]() |
19 |
11 | L3 | TFE | >99 | 3/97/0 | >20![]() ![]() |
— |
Subsequently, the effect of bases was investigated and the results are summarized in Table 2. The reaction did not occur in the absence of a base (Table 2, entry 1). Strong bases and moderately strong bases, such as NaOH, NaOMe, NaOtBu, KOtBu, and Cs2CO3, were good choices for this transformation, giving 2a with high yields and excellent stereoselectivities (Table 2, entries 2–6). When Na2CO3 was used, only 65% conversion was obtained and more than half of the converted starting material was only transformed to the product hydrogenated at the CC double bond, which indicated that weak bases had a detrimental impact on the sequential hydrogenation of 1a (Table 2, entry 7). To screen out the best base, a series of bases were re-evaluated under 0.05 mol% catalyst loading (S/C = 2000), and the results show that NaOH was superior to others (Table 2, entries 8–11). In addition, the effect of catalyst loading was also investigated. To our delight, on decreasing the catalyst loading to 0.01 mol% (S/C = 10
000), there was no loss of yield or diastereo- and enantioselectivity (Table 2, entry 12).
Entry | Base | Conv.b (%) |
2a![]() ![]() |
drb (2a) | eec (%) |
---|---|---|---|---|---|
a Unless otherwise mentioned, all reactions were carried out with a [Ir(COD)Cl]2/f-Ampha/1a (0.1 mmol) ratio of 0.5![]() ![]() ![]() ![]() ![]() |
|||||
1 | — | NR | NA | NA | NA |
2 | NaOH | 99 | >20![]() ![]() |
>20![]() ![]() |
98 |
3 | NaOMe | 99 | 15![]() ![]() |
>20![]() ![]() |
97 |
4 | NaOtBu | 99 | >20![]() ![]() |
15![]() ![]() |
98 |
5 | KOtBu | 99 | >20![]() ![]() |
>20![]() ![]() |
98 |
6 | Cs2CO3 | 99 | >20![]() ![]() |
>20![]() ![]() |
98 |
7 | Na2CO3 | 65 | 0.9![]() ![]() |
15![]() ![]() |
94 |
8d | NaOH | 99 | >20![]() ![]() |
>20![]() ![]() |
99 |
9d | Cs2CO3 | 99 | 2.3![]() ![]() |
17![]() ![]() |
97 |
10d | KOtBu | 99 | 0.1![]() ![]() |
>20![]() ![]() |
87 |
11d | NaOtBu | 99 | >20![]() ![]() |
15![]() ![]() |
99 |
12e | NaOH | 99 | >20![]() ![]() |
>20![]() ![]() |
99 |
With the optimal conditions in hand, the substrate scope of this reaction was explored with 0.1 mol% catalyst and the results are summarized in Table 3. Delightfully, the reaction exhibited good tolerance to a variety of exocyclic α,β-unsaturated ketones, furnishing the corresponding products in quantitative yields with excellent diastereo- and enantioselectivities. Generally, the reaction was not affected by the substitution pattern and the electronic properties of the aryl group, giving target products with 99% yield and 99% ee (2a–2l). Heteroaryl substituted substrates (2m–2o) were also well tolerated. Changing the position and the electronic properties of the R group didn't cause any changes in reactivity and in stereocontrol, affording target products with high yields and excellent diastereo- and enantioselectivities (2p–2s). When the O atom on the ring was replaced by a methylene group, the reactivity dropped, it required 0.5–1 mol% catalyst loading to achieve this transformation, delivering 2t–2v with good yields and high stereoselectivities. Interestingly, when the ring size was changed from a 6-membered to a 5-membered ring, the reaction proceeded smoothly, offering chiral 3-hydroxyl-2,3-dihydrobenzofurans, the core structure of several natural products,11 in 99% yield with 93% ee (2w).
a Unless otherwise mentioned, all reactions were carried out with a [Ir(COD)Cl]2/f-Ampha/1 (0.5 mmol) ratio of 0.5![]() ![]() ![]() ![]() |
---|
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To further explore the substrate scope of this methodology, other types of enones, such as endocyclic enones and acyclic enones, were also examined under standard conditions. As shown in Table 4, various 3-aryl substituted endocyclic enones, regardless of the electronic properties and the position of the substituents on the benzene ring, were well tolerated in this transformation, furnishing 3-arylchroman-4-ones 4a–4o with high yields and excellent enantioselectivities. Alkyl substituted endocyclic enones were also compatible in this reaction, delivering target products 4p–4q in high yields with good diastereo- and enantioselectivities. Moreover, acyclic enones also proved to be good substrates for this transformation, affording corresponding alcohols 4r–4t in 99% yield with 98–99% ee.
a Unless otherwise mentioned, all reactions were carried out with an [Ir(COD)Cl]2/f-Ampha/3 (0.2 mmol) ratio of 0.5![]() ![]() ![]() ![]() |
---|
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To demonstrate the potential utility of this catalytic system, the gram-scale reaction with 0.005 mol% catalyst loading (S/C = 20000) was conducted, and it proceeded very smoothly, affording 2a in high yield and excellent diastereo- and enantioselectivity (Scheme 2-1, 91% yield, >99% ee, >20
:
1 dr), which indicated that the Ir/f-Ampha complex is very efficient for the sequential asymmetric hydrogenation of enones, and has a practical application prospect. In addition, a highly efficient and concise synthetic route to the antiasthmatic drug CP-199,330 was developed. As shown in Scheme 2-2, 1x can be sequentially hydrogenated efficiently to afford 2x in 88% yield and 99% ee, which can be transformed into the antiasthmatic drug CP-199,330 according to the reported procedure.5a Compared with the previous method through racemic resolution,12 the sequential asymmetric hydrogenation strategy is more cost-effective and more environmentally friendly.
The change of product distribution with reaction time was investigated to shed light on the reaction mechanism. As shown in Fig. 1, most of 1a was quickly transformed into 2a′ within 0.17 hours by selective reduction of CC bonds, without any 2a′′ and 2a being detected. Prolonging the reaction time to one hour, the starting material 1a was completely consumed, affording target product 2a in 82% yield along with 2a′ in 18% yield. On further increasing the reaction time, the amount of 2a′ decreased gradually until it was totally transformed into 2a. It was noteworthy that no 2a′′ was detected in these experiments. In order to further identify the reaction pathway, the possible intermediates 2a′ and 2a′′ were synthesized and then hydrogenated under the standard reaction conditions. The results show that the intermediate 2a′ was hydrogenated smoothly, affording chiral 3-benzylchroman-4-ol 2a in a quantitative yield with excellent enantioselectivity and diastereoselectivity (Scheme 3-1), which demonstrated that a dynamic kinetic resolution (DKR) was involved in the reaction process. 2a′′ can't be hydrogenated under standard conditions, which indicated that the reaction pathway involving the asymmetric hydrogenation of a ketone followed by the reduction of C
C double bonds was excluded (Scheme 3-2). Taking together, these results clearly demonstrated that the hydrogenation of 1a proceeded through the hydrogenation of the C
C double bonds of 2a to form 2a′, then asymmetric hydrogenation of 2a′via DKR to afford the desired product 2a.
DFT calculations were also conducted to understand the reaction pathway and the enantioselectivity in the DKR process. The hydrogenation of 1a to 2a was considered in our DFT calculations. Referring to the above mechanistic discussion and our related work,13 an outer sphere pathway for 1,4-addition to produce 2a′, followed by hydrogenation of CO is proposed (Scheme 4). The role of alkali cation in hydrogenation reactions has been demonstrated in recent publications14 and our previous study.9 The trihydride IrH3(f-Ampha) complex I involving an alkali cation Na+ was proposed as the starting point in our DFT study. Complex I attracts 1a and gives complex II, and the reaction is exothermic by 10.7 kcal mol−1. The Ir(III)-hydride can make a nucleophilic attack on the carbonyl carbon or the β-carbon on the Re/Si face of 1a. DFT calculations indicate that hydride transfer to the β-carbon of the 1a Re face gives the most favorable transition state (TSII–III) with a barrier of 9.4 kcal mol−1 (with respect to complex II) (see the ESI, Fig. S1 and S2†). It is understandable that the carbonyl as a π withdrawing group increases the contribution of the β-carbon to the LUMO, thus promoting the hydride transfer to the β-carbon. A similar mechanism of nucleophilic attack of the Cu–B σ bond on α,β-unsaturated carbonyl compounds was well studied.15 After hydride transfer, molecular H2 coordinates to the Ir(III) and forms a dihydrogen Ir(III)(η2-H2) complex III+H2. The H2 activation between the Ir(III) and the enolate anion (formed by hydride transfer to 1a) is barrierless and gives an enol compound 2a′–1. The compound 2a′–1 undergoes a keto-to-enol isomerization to the more stable keto 2a′. Compound 2a′ enters the cycle B. The hydrogenation of 2a′ to the β-benzyl cyclic alcohol 2a is also achieved through hydride transfer and H2 activation processes (see the ESI, Fig. S3†). The hydride transfer to the carbonyl carbon is the enantio-determining step. The energy barrier leading to the major product 2a(R,R) is 10.9 kcal mol−1 from complex V, which is lower than the barriers to 2a(S,R), 2a(S,S) and 2a(R,S) by 2.2, 4.3 and 7 kcal mol−1, respectively (see the ESI, Fig. S4†). The DFT-calculated ee and dr values are 99.9% and 40
:
1, which are well consistent with the experimental results (ee 99%, dr > 20
:
1). The unique chair pocket of the Ir(III)/f-Ampha catalyst can account for the excellent enantioselectivities and diastereoselectivities in the DKR process.
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Scheme 4 Proposed catalytic cycles. Cycle A: 1,4-addition of 1a; cycle B: DKR to form 2a. Relative free energies are given in kcal mol−1. |
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc05963g |
‡ W. L. and T. Y. contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2022 |